Lysosomal Storage Disorders

The Pediatrician’s Role in Identifying and Understanding Fabry Disease

Robert J. Hopkin, MD, Associate Professor of Clinical Pediatrics at Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine - Discussing the unique challenges in identifying Fabry disease and what key signs and symptoms of which pediatricians should be aware - The importance of family history and genotyping - Understanding the differences of Fabry disease in males and females - Enzyme replacement therapy - Organ specific treatment and symptom management - Treatment for Fabry disease is a complex subject

When common complaints are the signs of Lysosomal Storage Diseases

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At the end of the Session participants will: (1) Understand the signs and symptoms of lysosomal storage diseases. (2) Have the ability to identify the key diagnostic features and differentiate them from more common diseases. (3) Evaluate the ‘next steps’ to take after a diagnosis and how to maximize treatment for the patient.

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8th Excellence in Pediatrics, London 8-10 December 2016
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Practical advice on spotting the signs of Rare Diseases and Chronic Conditions in the everyday practice

Lysosomal Storage Diseases Clinical Recognition, Diagnosis and Management

Lysosomal Storage Diseases
This is an accredited eLearning course. User engagement 1 Hour. The course covers the assessment of lysosomal storage diseases, their prevalence and lifetime consequences. Learn how lysosomal storage diseases matter, and what their underlying causes are.


Hakim Rahmoune, Nada Boutrid, Belgacem Bioud

Excellence in Pediatrics Conference 2015


Introduction: Some surgical aspects may reveal authentic metabolic disorders that have “soft” presentation. We report the case of a 30 months boy with an increasing umbilical hernia.

Materials & Methods: A 2.5 years old boy of non-consanguineous parents without specific history consults in pediatric surgery and then in pediatric out-clinic for a progressive, giant umbilical hernia that develops from few months.

Results: Ophthalmology examination reveals a bilateral corneal opacity, while systemic visceral evaluation is free from other organic dysfunction / abnormality, except small dysmorphic features (coarse face) A high suspicion of lysosomal storage disease (e.i. Mucopolysaccharidosis type 1) allows enzymatic assay and confirms the mild Scheie syndrome.

Discussion: Scheie syndrome is the mildest form of mucopolysaccharidosis type 1, caused by mutations in the IDUA gene (4p16.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate. Symptoms commonly occur after the age of 5 years. Corneal opacification occurs progressively and diffusely. Patients present with mild coarsening of the facial features, including a large mouth with thick lips. Genetic counseling is highly recommended in such condition. Enzyme replacement therapy should be started at diagnosis as early treatment slows the progression of the disease.

Conclusion: Surgeon should consider a careful pediatric/metabolic consultation for some peculiar hernias, specially for their giant or recurrent aspect.

University of Setif-1, University Hospital of Setif, Algeria

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Emerging therapies and therapeutic concepts for lysosomal storage diseases

1. Background

Since the discovery and initial characterization of lysosomes by Francois Applemans, Robert Wattiaux and Christian de Duve in 1955 [1-3], the interest for this still enigmatic organelle and its close relatives has seen a resurgence in the past two decades spurred by the rediscovered and increasing realization of their crucial roles in physiological homeostasis. The interest in lysosomes from not only academia but also biotech and pharma has been further kindled by a number of clinical, regulatory and commercially transforming events that have provided a new paradigm for developing therapies for not only lysosome-related diseases but also other rare and orphan diseases.

With the introduction of the Orphan Drugs Act in the USA in 1983, which was followed by similar legislation in Singapore (1991), Australia (1993), Japan (1997) and the EU (1999), a regulatory framework has been laid down for guiding the development of drugs for rare diseases with highly unmet need. However, the commercial potential of developing drugs for lysosomal storage diseases (LSDs) was not realized until the development of Cerezyme (recombinant glucosylceramidase (glucocerebrosidase) for the treatment of type I Gaucher disease) by the Boston-based biotech company Genzyme.

The scientific rationale for the development of lysosometargeted therapies however predates the advent of Cerezyme by several decades and driven by the re-kindled interest in lysosomal diseases several novel therapeutic concepts and therapies are now emerging for these devastating disorders.

1.1 Lysosomes

As the main compartment for intracellular degradation and subsequent recycling of cellular constituents, the lysosomes receive both hetero- and autophagic cargo, which in the lumen of this multifaceted organelle find their final destination. The degradation is carried out by a number of acid hydrolases (glycosidases, proteases, sulfatases, lipases, etc.) capable of digesting all major cellular macromolecules [4]. These acid hydrolases function optimally at the acidic pH of the lysosomes (pH 4 -- 5) although several can still function and have distinct roles at the neutral pH outside the lysosomes, albeit having decreased stability and/or altered specificity [5].

Until recently, the function of many of these enzymes was thought to be limited to intralysosomal macromolecule turnover. However, from the complex and diverse clinical presentation of the diseases originating from lysosomal malfunction and involvement in neoplastic events it is clear that the lysosomes have an absolutely critical role in physiological homeostasis [6,7]. As such, the potential impact of therapeutically addressing the lysosomes and their constituents should not be underestimated.

Interestingly, recent data suggest that the biogenesis and functioning of endosomal and autophagosomal pathways is partially controlled by the transcription factor EB (TFEB), which regulates a coordinated lysosomal expression and regulation (CLEAR) gene network [8], a finding which argues for an evolutionary need to intimately control and efficiently adapt the lysosomal system to rapid changes in the cells metabolic state.

1.2 Dynamics of the lysosomal system

The intracellular trafficking of vesicles involved in, or related to, the lysosomal system, serve an essential role in the mammalian cell through its delivery of membrane components, various solute molecules and receptor-associated ligands to a range of intra- and extracellular compartments. The main pathways involved in this system are depicted in Figure 1, along with highlights of the various facets of these pathways being targeted for therapeutic intervention in the LSDs (Figure 1).

As a testament to the importance of this system and its constituents, defects in any part of it leads to a number of severe diseases or syndromes. Be it defects in lysosomal exocytosis (e.g., Chediak--Higashi syndrome), reduced lysosomal catabolic efficacy (e.g., Niemann--Pick disease types A and B and Gaucher disease), lysosomal transport machinery defects (e.g., Griscella syndrome and Charcot--Marie--Tooth disease), lysosomal metabolite efflux impairment (e.g., Niemann--Pick type C and cystinosis/Fanconi syndrome) or dysfunction of lysosomal integral membrane proteins (e.g., Danon disease), the disease most often affect multiple organs and tissues, involves the central nervous system (CNS) and is often fatal at a young age in its aggressive forms [7,9-13].

In order to understand the complexity of the LSDs and why defects in this refined machinery can lead to such detrimental clinical manifestations as well as grant the reader an initial overview of the possibilities that might exist for therapeutic intervention, a brief description of the inter-relations in the lysosomal system is provided below.

1.2.1 Endocytic route to lysosomes The best understood endocytic pathway, which is also extensively exploited in enzyme replacement therapies (ERTs) for the LSDs, is the receptor-mediated endocytosis of molecules via the formation of clathrin-coated pits [14]. In the conventional receptor-mediated endocytic pathway, receptors such as the transferrin receptor, the low-density lipoprotein receptor and the mannose 6-phosphate receptor (M6PR) concentrate into clathrin-coated pits on the surface of the plasma membrane and form early endosomes [15,16]. Although the majority of lysosomal enzymes are targeted to the lysosomes from the trans-Golgi network (TGN) through mannose-6-phosphate (M6P)-mediated binding to M6PRs in the medial Golgi and then released once the Golgi-derived transport vesicles fuse with late endosomes (detailed in Section 1.2.2), some amounts of lysosomal enzymes are destined for secretion and subsequent reuptake from the extracellular space via plasma membrane receptors that are either the same or similar to those involved in intracellular sorting and the biosynthetic route to the lysosomes [15]. This concept developed from a number of metabolic complementation studies in cells from patients with different LSDs and is the fundamental principle for enzyme therapies of LSDs [17].

As the endosome mature, its luminal pH steadily drops, mainly through the action of the vacuolar-type proton ATPase (V-ATPase) [18], facilitating the dissociation of receptor and ligand while shifts in membrane lipid and protein composition also occur as the vesicles mature to form late endosomes and subsequently lysosomes. The late endosomes and lysosomes differ from endosomes primarily in their degree of acidification, higher buoyant density, higher abundance of integral lysosome-associated membrane proteins (LAMPs) and enrichment of acidic hydrolases [19].

1.2.2 Biosynthetic route to lysosomes Apart from endocytosis, late endosomes and lysosomes also receive cargo via the M6PR pathway from the TGN (the biosynthetic route). The cation-dependent M6PR and the cation-independent (CI) M6PR/insulin-like growth factor II (IGF-II) receptor share the task of delivery of newly synthesized acid hydrolases from the TGN to the lysosomes. The recognition of acid hydrolases by M6PRs requires the addition of carbohydrates in the endoplasmic reticulum (ER) and the subsequent modification and phosphorylation of the carbohydrate residues to M6P moieties in the cis-Golgi [15,20]. The M6PR-bound hydrolases are first delivered to endosomes, where they dissociate from the receptors due to the drop in the lumenal pH, hereby allowing the receptors to recycle back to the TGN.

1.2.3 Autophagic routes to lysosomes Autophagy is the third relatively well-characterized route by which macromolecules reach the lysosome. Autophagy is an evolutionary conserved pathway involved in the turnover of long-lived proteins and organelles and is essential for maintaining cellular energy and metabolic homeostasis [21-23]. There are three main modes of autophagy: macro-, microand chaperone-mediated autophagy; macroautophagy is characterized by a flat membrane cistern wrapping around cytoplasmic organelles and/or a portion of cytosol thereby forming a closed double-membrane bound vacuole, the autophagosome. The autophagosome finally fuses with lysosomes forming autophagolysosomes/autolysosomes, where the degradation and recycling of the engulfed macromolecules occur. Microautophagy is characterized by engulfment of cytosol by the lysosomes through invaginations of the lysosomal membrane. Besides the macromolecules, which are present in the engulfed cytosol, this process may also involve the uptake of organelles such as peroxisomes and mitochondria, with these particular autophagic processes being coined the terms pexoand mitophagy, respectively [24,25]. Finally, chaperonemediated transport of cytosolic proteins into the lysosomal lumen presents a more direct and selective form of autophagy. This pathway is dependent on the presence of the constitutively expressed member of the heat shock protein 70 (Hsp70) family, Hsc70 (HspA8), on both sides of the lysosomal membrane and its interaction with an isoform of the lysosomal membrane protein, LAMP-2, the protein that is defective in the LSD Danon disease [10,26].

1.2.4 Reformation of lysosomes and lysosomal secretion/exocytosis After fusion of lysosomes with late endosomes or autophagosomes, the lysosomes are reformed from the resultant hybrid organelles through sequestration of membrane proteins and condensation of the lumenal content [21]. The lysosomes, however, cannot be seen as the terminal point of the endocytic pathways as they are also able to form secretory lysosomes through fusion with secretory granules, a process that is Ca2+- dependent and was first recognized in secretory cells of hematopoietic origin [27,28]. However, evidence also exists for a Ca2+-regulated membrane-proximal lysosomal compartment responsible for exocytosis in non-secretory cells [29,30], a process which is dependent on the protein Rab27a, a member of the Rab protein family of small GTPases that have key regulatory roles in most membrane-transport steps including vesicle formation, motility, docking and fusion. At least 13 Rab proteins are utilized in the endocytic pathways in order to determine the fate of the various endocytosed molecules and their vesicles and alterations in the Rab GTPases or associated regulatory molecules give rise to a number of diseases ranging from bleeding and pigmentation disorders (Griscelli syndrome) through mental retardation and neuropathy (Charcot--Marie--Tooth disease) to kidney disease (tuberous sclerosis) and blindness (choroideremia) [11,31].

Ultimately, the reformation of lysosomes from autolysosomes (autophagosomes fused with lysosomes), endolysosomes (late endosome--lysosome fusion) and other lysosome-hybrid organelles completes each cycle of lysosomal degradation yielding functional lysosomes that are available for another round of macromolecular breakdown.

Importantly, the efficient processing of macromolecular substrates in the hybrid organelles are essential for lysosomal reformation, a process which does not occur de novo, but is the result of a reformation/budding from the hybrid organelles [32-34].

Defects in lysosome reformation which is thought to be required for the exocytosis of lysosomal cargo-containing membrane vesicles have also been shown to have pathological consequences as evidenced by studies in Niemann--Pick type C1 and C2 deficient cells (NPC1 and NPC2). These studies have revealed a significant difference in the lysosomal consequences of defects in the NPC1 and NPC2 proteins which otherwise share virtually indistinguishable clinical pathology in patients. For NPC1, one of the primary lysosomal consequences is a compromised ability to form the initial hybrid organelle, whereas in NPC2 deficient cells the impairment of lysosome reformation appears to be the primary cellular defect [7,35-38].

Interestingly, the impaired reformation of lysosomes could also constitute a more general molecular pathological feature of LSDs as secondary storage material in other LSDs, arising as a consequence of the primary genetic deficiency, could cause abnormalities in the necessary lipid dynamics involved in not only lysosomal reformation but also vesicle docking and fusion [39].

1.3 Lysosomal storage diseases

Individually, the LSDs are ultra-orphan diseases with prevalences ranging from 1/60,000 live births for Gaucher disease to 1/4.2 million live births for sialidosis. As a group however, the combined prevalence has been estimated to be ca. 1/7700 live births [40].

As delineated in the previous section, the interdynamics of the lysosomal system is a complex maze of a number of crucial events that all needs to function properly for the lysosomes to be the effective multifunctional organelles they are. The LSDs are excellent examples of the importance of these events as > 50 LSDs to this day have been characterized, ranging from primary defects in membrane proteins, transporters, fusion machinery and of course hydrolytic enzymes with the manifest cellular pathology associated with the diseases (lysosomal accumulation and storage) coining the name to these devastating diseases.

More than 50 LSDs are classified according to the major storage material accumulating, although their monogenetic origin does not always directly predict the affected substrates causing some discrepancies in understanding the molecular etiology of the diseases. In sphingolipidoses for example, the major storage materials are glycosphingolipids and immediate derivatives thereof, whereas for the neuronal ceroid lipofuscinosis, lipofuscins are the major storage materials accumulating, but on the background of a genetically and functionally mixture of deficient proteases, peptidases, membrane proteins and other proteins with as yet unknown function.

The mechanisms by which the accumulated substrates impact cellular function and cause the pathological manifestations of the primary genetic defects are still not well understood, although several recent advances in the understanding of these processes are now shedding light into this dark(er) corner of human biology. These discoveries include mechanisms related to alterations of intracellular calcium homeostasis, impairment of autophagy, activation of signal transduction pathways by substrates and their derivatives, inflammation, altered intra- and limiting membrane properties and others [7,8,39,41-44].

Earlier, clinical management of LSDs was mainly confined to treatment of complications, although in some of the sphingolipidoses such as Gaucher and Fabry diseases attempts were made to improve the patients’ condition by transplantation of the major organs affected (liver and kidney, respectively), but these interventions did not alter the course of the diseases [45]. In mucopolysaccharidosis type I (Hurler syndrome, MPSIH), bone marrow transplantations has shown some benefit, however, provided the intervention is performed early enough [46]. The benefit of early intervention is a principle that holds not only for bone marrow transplantations but for all therapies applied to the LSDs, due to the irreversible nature of some of the pathological changes during the course of the diseases.

The breakthrough in the treatment of LSDs began modestly > 40 years ago when Neufeld and collaborators demonstrated the principle of metabolic complementation in cell cultures from patients with different LSDs [17,47]. Subsequent studies provided insight into the nature of the corrective factors (secreted lysosomal enzymes) and that these were endocytosed by binding to the M6PR [48]. These early studies showed that LSDs should be generally amenable to therapy relying on reconstitution of the deficient enzymes by exogeneous administration of a functional version, a concept which is known as ERT. In some cell types, exogenous lysosomal enzymes are not recognized by the M6PR but rather by other receptor systems which bind, for example, terminal galactose (hepatocytes) or mannose residues (macrophages) [49]. That several receptor systems exist, needs careful consideration during the development of effective ERTs, but also holds opportunities for changing or modifying the targeting signals of a given enzyme in order to manipulate its pharmacodynamic properties. A classic example is the modification of glucosylceramidase that in order to be targeted to macrophages in Gaucher disease, has to be modified in order to expose mannose residues [49].

The success of ERT in Gaucher disease has made this approach the standard for treating lysosomal storage disorders (Table 1), although the first clinical trial of an ERT in 1973 (GM2-gangliosidosis) was not a clinical success although it did confirm the biochemical principle. In this trial, an infant was injected with hexosaminidase A that had been purified from human urine, resulting in a remarkable reduction of the storage substance in the circulation. However, the patient’s clinical condition remained unchanged [50]. The success of treating Gaucher and the apparent failure in treating GM2-gangliosidosis stresses the crucial point, that therapies should be developed that affect the primary sites of pathology. Unfortunately for the LSDs, the major organ involved in most of these diseases is the CNS which by no means is an easy organ to reach and even less so to rescue. This realization has prompted the development of a number of therapies aimed not only at addressing the peripheral symptoms of the LSDs but importantly these novel concepts often aim at providing a clinical benefit in terms of manifestation of CNS-related symptoms, the holy grail of LSD therapy.

2. Medical need

The LSDs number over 50 diseases with a combined incidence of approx. 1/7700 and with only a very limited number having approved therapies available.

The clinical manifestations of these diseases are extremely variable ranging from severe debilitating, lethal diseases in early infancy, to attenuated presentations in late adulthood, often with no clear genotype/phenotype correlation as exemplified by Niemann--Pick disease type C in which the disease can vary from severe, lethal infantile disease to a more psychiatric symptom-driven disease that gradually manifest itself during the later decades [51].

The current standard of treatment has evolved from mainly supportive care and symptomatic treatment to the standard of today, ERT, that became available to patients with Gaucher disease two decades ago and now has also been developed and approved for other LSDs such as Fabry disease, MPS types I, II and VI and Pompe disease (Table 1). The efficacy of many of these therapies is limited however, due to the fact that the exogenously provided enzymes do not have effect on all aspects of the diseases. This is caused in part by the irreversibility of some aspects of these diseases but is also due to the enzyme formulations’ inherent inability to reach all major target organs in therapeutically efficacious amounts. Particularly the CNS, but also bone, cartilage, cardiovascular and renal systems are not necessarily efficiently targeted by enzyme replacement strategies due to the extremely selective permeability of the blood--brain barrier (BBB) and restricted receptor expression and lack of sufficient blood flow to support the needed doses for efficacy in other peripheral tissues and organs.

Furthermore, the formation of antibodies against the exogenously delivered enzyme may have a negative impact on efficacy as well as elicit unwanted infusion-related adverse events [52,53].

It comes as little surprise therefore, that there exists a substantial unmet need for the development of therapies addressing the limitations described above as well as providing alternative treatment regimens that eventually might even supplement each other based on a rational understanding of their distinguishing mechanisms of action.

3. Existing and emerging therapies

The currently approved pharmacological therapies for LSDs are summarized in Table 1, while emerging therapies and therapeutic concepts are extensively covered in Tables 2 and 3. As can be readily seen, both established and emerging therapies are dominated by ERT or second-generation variants thereof. The following sections provide a comprehensive overview of current and emerging therapies for the LSDs and will focus on the scientific and medical rationale for these therapeutic concepts.

3.1 Bone marrow transplantation/hematopoietic stem cell transplantation

Bone marrow and hematopoietic stem cell transplantations (BMT/HSCT) can trace the origin of their scientific rationale back to the same fundamental principle of metabolic crosscorrection as the ERTs, that is, the ability of lysosomal enzymes to enter into a secretion-reuptake cycle. The first uses of transplantation approaches emerged in the 1980s and have seen its use in many of the LSDs including MPS types I, VI and VII, metachromatic leukodystrophy (MLD), alpha-mannosidosis, fucosidosis, Krabbe disease and type III Gaucher disease [54]. Despite a rather extensive use of BMT/HSCT in MPS type I and 1H (Hurler variant) and with some promising results, particularly in terms of reducing visceromegaly, cardiac function and airway obstruction [55], it is unfortunately still hard to conclude decisively on the status of this potentially effective therapy as most reports on BMT and HSCT are both anecdotal and/or only encompass a small number of patients. However, with the advancement of methods for HSCT and with a more systematic approach in evaluating the therapy there is no scientific reason as to why BMT/HSCT should not be a both viable and a promising therapy for many of the LSDs, although several challenges such as the occurrence of variable musculoskeletal disease progression even after successful stem cell transplantation (SCT) in MPSIH patients have to be overcome [56,57].

3.2 Enzyme replacement therapies

As for bone marrow and hematopoietic SCTs the fundamental principle of ERT is the same: the substitution of the deficient enzyme by a functional version hereof. Provided the enzyme can be manufactured and safely administered, the administration of the enzyme usually takes place through either weekly or biweekly infusions although more frequent administrations are also seen for some ERTs such as asfotase alfa in development for hypophosphatasia (Clinicaltrials identifier: NCT01176266). The promise of most ERTs lies in their potential capacity to correct the pathology of non-neural tissue as the enzymes are incapable of traversing the BBB, although many peripheral tissues such as bone, cartilage, cardiovascular and renal systems are not easily reached due to the biology of the receptor systems needed for the endocytosis of the exogenously delivered enzymes. Tables 1 and 2 summarize the ERTs that have been approved for marketing authorization and those that are in current development, respectively.

The first marketed ERT was developed for type I Gaucher disease, a sphingolipid storage disorder, characterized by splenomegaly, thrombocytopenia and anemia. The first clinical trial was performed by Brady and collaborators with an enzyme preparation purified from human placenta, treated with specific glycosidases to facilitate uptake by mannose receptors on the macrophages which is the main cell type involved in the disease [49]. Based on the positive data from this trial, the enzyme preparation (Ceredase, Genzyme) was approved for patients with Gaucher disease and was some years later replaced by a recombinant form, imiglucerase (Cerezyme, Genzyme). A number of reports and publications have confirmed the long-lasting positive effect as well as the safety and tolerability of imiglucerase in patients suffering from type I Gaucher disease which has led to ERT becoming the standard of care for these patients [58,59] but does not have any influence on the CNS symptoms of the disease as seen in the neuropathic forms of the disease, not even at high doses [60].

The initial success of imiglucerase, has led to the development of ERT for other LSDs such as Fabry disease, Pompe disease and several of the MPS. In Fabry disease for example, two different a-galactosidase enzymes have been developed, but although Fabry disease is a glycosphingolipidosis just as Gaucher disease, its pathology is significantly different from that of Gaucher, giving rise to a number of challenges mainly associated with the proper engagement of the ERT with the target organs. In Fabry disease, kidney failure, cardiomyopathy and cerebrovascular events are the main complications which give rise to the morbidity and mortality associated with this disease while most clinical efficacy measurements have been based on plasma Gb3 levels (the main accumulating lipid) [61,62]. While plasma Gb3 levels are quite easily quantifiable and respond readily to intravenous injections of ERT, the main organs giving rise to disease symptomatology are neither as readily accessible to therapy nor as well investigated [61]. This inconsistency in addressing clinically relevant end points has made a clear conclusion on the benefits of ERT for Fabry disease difficult and the experience with ERT for Fabry disease has not been as satisfying as that in Gaucher disease, in which the pathological storage mainly involves a more easily targetable cell population. Also, recently the central role of Gb3 in Fabry disease and its relevance as a surrogate marker has been questioned as the lysoderivative of Gb3 (globotriaosylsphingosine) may be a more pathologically relevant metabolite [63,64]

The findings in Fabry disease highlights the importance for a given therapy to reach the clinically relevant target organs in therapeutically efficacious doses, and the need to monitor this rigorously to aid conclusions on the effectiveness of a given therapy. It also points to the challenge that not only for Fabry disease, but for many of the LSDs, the current understanding of their molecular pathology is still far from complete. If one turns to another group of LSDs, the MPS, the pattern observed for Fabry disease repeats itself. In MPS, there are 11 known genetic deficiencies all involving enzymes that are part of the catabolism of glycosaminoglycans (GAGs), giving rise to seven distinct MPS types. As with Fabry disease, the MPS are multisystemic diseases, affecting a multitude of cell types in a variety of tissues [65]. For MPSI, II and VI, ERT is now available [66-69], while first- or second-generation ERTs are also in development for several of the diseases (Table 2). For all of the approved ERTs, hepatosplenomegaly responds rapidly to the administration of intravenous enzyme with a concomitant reduction in urinary excretion of GAGs but as for Fabry disease, the main disease burden lies not within the easiest accessible organs, as the functional problems the MPS patients suffer are rather due to skeletal dystosis and involvement of the soft tissues, heart and lungs. The clinical efficacy of ERT when measured in terms of joint mobility, vital capacity and walk tests, has not been nearly as clear as the effects observed on surrogate markers, and while the ERTs have evidently not been able to influence the CNS manifestations of the diseases, they have to some extent been able to alter the natural history of the disease and can in some cases improve the patient’s quality of life. As for the other LSDs, the earlier the intervention, the better.

The latest ERT marketed for a new LSD indication is alglucosidase alfa for the treatment of Pompe disease (glycogen storage disease type II, acid maltase deficiency), which is primarily affecting the muscle tissue, enabling a better ERT targeting of the clinically relevant tissue. For this disease, as for many of the LSDs, there is a broad spectrum of disease presentation with the most severe, infantile onset cases presenting in the first weeks after birth with both cardiovascular and skeletal myopathy while later onset cases usually sees a sparing of the cardiovascular tissue but manifesting itself with a progressive proximal myopathy which can lead to respiratory failure, if involving the musculature of the diaphragm. The clinical efficacy of this ERT has been very encouraging with early intervention in the infantile cases being lifesaving, even in cases of advanced disease [70,71]. The efficacy of the ERT has furthermore been confirmed by several clinical trials in patients with different age of onset and disease severity and alglucosidase alfa has received approval for treatment of Pompe disease for all age groups [72].

It is evident that several factors define the clinical success of a given ERT: the primary challenge for any ERT lies in its clinical efficacy on the organ systems involved. As described, these systems vary from disease to disease but are often organs which are not readily accessible to ERT.

Although there are reports of enzymes successfully crossing the BBB in animal models of MLD and alpha-mannosidosis [73,74], clinical data for all commercially available ERTs have not shown any evidence of ERTs being able to penetrate the BBB and provide a therapeutic benefit to the patients. It is therefore of little surprise that all the second-generation ERTs (as well as many of the other emerging therapies) are aiming at either crossing the BBB and/or increasing the uptake of enzyme into the relevant peripheral tissue.

Of the latter there are currently several biologically similar approaches in development for the treatment of Pompe disease in which the primary tissue to target is the muscle tissue. Whether through carbohydrate remodeling of the enzyme itself, its conjugation to a IGF2-derived peptide tag or the engineering of a precursor form of the enzyme, all of these second-generation approaches aim at changing the biodistribution toward increased uptake in muscle tissue of the active enzyme by increasing its affinity to the CI-M6PR [75-77].

When it comes to targeting second-generation ERTs for transport across the BBB several approaches are in development. One approach is intrathecal delivery of standard ERT which is in clinical development for MPSII, MPSIIIA and MLD. Another and well-characterized alternative approach is the more physiological approach of utilizing endogeneous receptor systems for enzyme transcytosis across the BBB, an approach that is considered to have several advantages compared with the rather invasive surgical procedure of intrathecal infusion of enzymes [78]. Although several receptor systems have been characterized that facilitate transport across the BBB, for the LSDs two main receptor systems are currently being targeted by various companies in the hope that these will provide access for the engineered enzymes to the neurons of the CNS in therapeutically relevant doses. These emerging approaches are targeting enzymes for the treatment of MPSI, MPSII, MLD and other LSDs to the CNS via either the insulin receptor or the probably best characterized blood-- brain transcytosis receptor, LRP-1 (low-density lipoprotein receptor-related protein 1) (CD91) [79-84].

For the targeting of the insulin receptor, engineered versions of the enzyme are fused to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (mAb) to the human insulin receptor (HIR). These HIRmAb--enzyme fusion proteins then cross the BBB via the endogenous insulin receptor and acts as a so-called molecular Trojan horse to ferry the enzyme into brain with approximately 2 -- 3% of injected dose reaching the brain [80,85].

The LRP-1 and -2 have been exploited to target a large variety of drugs to the brain and LRP is the best characterized system for BBB penetration to date [78]. LRP-1 has a number of physiological ligands and this has formed the basis for two alternate fusion protein approaches, one relying on the conjugation of p97/melanotransferrin to the enzyme of interest, the other on an optimized peptide, a so-called angiopep, with increased affinity for the LRP-1 receptor [82,84]. Interestingly, the human molecular chaperone Hsp70 which is being developed for the treatment of a panel of LSDs and covered later in this review also utilize LRP-1 as one of its primary receptors [86].

Besides the above, a number of different targeting systems are being explored academically, such as intercellular adhesion molecule (ICAM) and apolipoprotein B (ApoB)-mediated carriers [87,88] but it is considered beyond this review to cover all early discovery pharmacology not in a company or company-related pipeline.

Based on the preclinical activity surrounding the second generation ERTs, one can only hope that any of these approaches will prove successful, but a number of challenges are facing the development of these more extensively engineered enzymes: Although promising data have been generated in murine models of the disease for many of these compounds, only a marginal ratio of the total injected enzyme becomes available to the CNS and it remains to be seen if this amount of enzyme can confer the same therapeutic benefit in human subjects. This challenge unfortunately only becomes harder when one considers that chronic administration of these modified enzymes will be necessary for sustained effect in patients as this will almost certainly give rise to significant antibody responses, as has been seen for all ERTs, albeit to various degrees.

Also, the use of any receptor system begs the question as to what effect will be caused by the extra-physiological use of such a system to deliver drugs, that is, could any adverse signaling cascades be activated or will the natural receptor halflife, distribution and activity be compromised by this extra utilization. Also, does the receptor actively transport the drug across the BBB or is the drug just binding to the receptor and sequestered in the BBB endothelium? For LRP-1 for example, these considerations are not necessarily a major problem as the receptor is rather promiscuous with many ligands already using the receptor and as it also has one of the fastest transcytosis rates (transfer coefficient/Kin) of any BBB receptor system [89], adverse receptor signaling, saturation and re-distribution as well as drug sequestration in the endothelium should not pose a significant risk for this system although this of course remains to be tested clinically.

Given all the challenges that remain to be faced by the second-generation ERTs, one should bear in mind however, that significant clinical benefit has been achieved for other diseases in which receptor systems have been exploited, for example, in the case for dopamine/L-Dopa for Parkinson’s disease patients, in which the large neutral amino acid carrier has been used to deliver L-Dopa, the metabolic precursor of dopamine, to the brain resulting in a clear clinical benefit as dopamine in itself is not able to cross the BBB.

3.3 Substrate reduction therapies

Whereas ERTs focus on increasing the catabolism of buildup substrate, the principle in substrate reduction therapy (SRT) is to limit the production of substrate to the catabolically compromised lysosomes. The first demonstration of this principle was done by Platt et al. in 1994 with the imino sugar N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) which has the ability to inhibit the enzymatic activity of ceramide glucosyltransferase (glucosylceramide synthase) which synthesizes glucosylceramide, the precursor of several glycosphingolids such as the globo- and gangliosides, and which is the main accumulating lipid in Gaucher disease [90]. Miglustat was subsequently tested in a clinical trial with 28 Gaucher disease patients, who for several reasons did not receive ERT and on basis of this trial miglustat gained marketing approval in Europe and the USA for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom ERT is not a therapeutic option [91].

An SRT based on the inhibition of ceramide glucosyltransferase holds the potential of being a therapy for all LSDs with glycosphingolipid storage and since miglustat crosses the BBB, this therapy has been evaluated for a number of sphingolipidoses with prominent neurodegeneration such as Tay--Sachs disease, type 3 Gaucher disease, MPSIII, juvenile GM2-gangliosidosis and Niemann--Pick type C disease [92-96]. Except for Niemann--Pick type C disease, none of these trials have shown improvement in the miglustat-treated patients although some of these data should be handled with care as the studies were done on very limited numbers of patients. For Niemann--Pick type C, miglustat received marketing approval in Europe in 2009 based on a clinical trial in patients aged 12 or older, which demonstrated that treatment with miglustat improved eye movement velocity and swallowing capacity [95].

Being a small molecule sugar analog, the side-effect profile of miglustat is significantly different from the side-effect profiles associated with ERTs with miglustat having a broader array of side effects including gastrointestinal symptoms, particularly diarrhea.

A conceptually similar, but chemically different, approach for SRT centered on ceramide-based inhibitors of ceramide glucosyltransferase provides a novel alternative to the imino sugar-based SRT. Based on this approach, a new inhibitor of ceramide glucosyltransferase, eliglustat tartrate (Genz- 112638) is currently in development for Gaucher disease type I, and has shown promising results in an open-label Phase II trial, combining a higher specificity for ceramide glucosyltransferase with a more beneficial side-effect profile compared with miglustat and having a clear effect on several disease parameters [97].

For the MPS, the accumulation of GAGs can be inhibited by genistein, an isoflavone extract from soybeans being explored academically. The effect of genistein on urinary GAG excretion, hair morphology and behavior has been tested in an open-label study of 10 patients suffering from either MPSIIIA or IIIB and a 2-year follow-up including eight patients assessing the cognitive function and general status was recently published. Albeit consisting of a small number of patients, after 1 year of oral administration of a genisteinrich soy isoflavone extract (5 mg/kg/day), a statistically significant improvement was observed with a larger variance in efficacy being apparent after 2 years [98].

3.4 Chaperone technologies

As most LSDs are characterized by significantly reduced enzyme activity due to missense mutations rather than a complete loss of function, the LSDs have long been thought amenable to chaperoning by chemical substrate mimics targeting the active site of the relevant enzyme for increased stability/folding.

A more recent approach relies on utilizing the already existing molecular chaperone machinery available in the cells in order to avoid the inherently counterproductive mechanism of enzyme inhibition associated with chemical chaperone therapies. The advantages to both approaches compared with ERT include better distribution profiles including CNS availability as well as easier drug administration as the small molecule approaches for both concepts offer the potential of oral administration rather than the more patient-demanding infusions of ERT.

3.4.1 Molecular chaperone technologies

There are currently two approaches in development for utilizing the naturally occurring molecular chaperone machinery, both exploiting the recently discovered mechanism for how the archetypical molecular chaperone Hsp70 aside from its well-characterized cytoprotective effects also enhances cell survival and functionality through a direct lysosomal action [43]. One approach relies on the receptor-mediated endocytic uptake of a recombinant version of Hsp70 whereas the second approach relies on utilizing small molecules capable of enhancing the endogenous production of heat shock proteins, here amongst Hsp70. Hsp70 is an evolutionarily highly conserved molecular chaperone which has been shown to promote the survival of stressed cells by inhibiting lysosomal membrane permeabilization [99-101], a hallmark of stressinduced cell death [6,102]. Recently, Kirkegaard et al. described how Hsp70 stabilizes lysosomes by binding to the endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential co-factor for lysosomal sphingolipid metabolism hereby facilitating the BMP binding and increased activity of acid sphingomyelinase (ASM), the enzyme compromised in Niemann--Pick diseases. Notably, the reduced ASM activity in cells from patients with Niemann--Pick disease A and B was shown to associate with a marked decrease in lysosomal stability, and this phenotype as well as the pathological accumulation of unstable lysosomes could be effectively corrected by treatment with recombinant Hsp70. The mechanism of action of Hsp70 entails the prospect of using the protein for the treatment of several LSDs, most notably the sphingolipidoses involving enzymes that are dependent on interaction with BMP [103] and it is currently in preclinical development for a number of these diseases.

The approach to utilize small molecules to increase the expression of heat shock proteins during pathological stress conditions and harness this response for therapeutic use, stems from the ability of these molecules to stabilize the transcription factor for the heat shock proteins, heat shock factor- 1 (HSF-1) [104]. Interestingly, this emerging approach for LSDs is also in development for a number of neurodegenerative conditions, including amyotrophic lateral sclerosis and has a well-described safety record with very limited side effects, which could possibly accelerate the development of this therapeutic concept for LSDs [105].

3.4.2 Chemical chaperone technologies

Contrary to the molecular chaperone approach which utilizes the potentiating effects of endogenous cellular chaperones, chemical chaperone technologies rely on using competitive inhibitors of lysosomal enzymes at subinhibitory concentrations in order to facilitate the transition of poorly folded lysosomal enzymes otherwise caught in the ER/proteasomal degradation machinery to the lysosomes as first described by Fan et al in 1999 [106]. On maturation and entry in the lysosomes, the concept demands that the kinetics of the enzyme/inhibitor interaction are shifted due to for example, the reduced pH of the lysosomes, facilitating the dissociation of the inhibitor and the enzyme, thus finally leaving a larger fraction of the functionally compromised enzyme available for increased substrate degradation in the lysosome [106,107].

A number of molecules are in development for LSDs based on this approach, including combination efforts with ERTs. The most advanced program for a LSD utilizing a chemical chaperone as stand-alone therapy is deoxygalactonojirimycin (DGJ; migalastat hydrochloride) which is currently in Phase III for Fabry disease. Despite a considerable power in this study as 67 patients diagnosed with Fabry disease with genetic mutations amenable to chaperone monotherapy were enrolled, the study recently reported an initial negative outcome, as it did not meet any of its primary end points during its first phase [108].

Although not in formal development programs for LSDs, the Food and Drug Administration (FDA)-approved drugs pyrimethamine and ambroxol have been identified as possible chemical chaperones for hexosaminidase A and ceramide glucosyltransferase and both have been tested in cells from patients suffering from late-onset forms of GM2-gangliosidosis (Tay--Sachs and Sandhoff disease) and Gaucher disease [109,110]. Recently, data from a small-scale open-label Phase I/II clinical study of the tolerability and efficacy of pyrimethamine in Sandhoff disease patients have been reported [111]. A significant side-effect profile was observed at doses of 75 mg pyrimethamine daily, while variable enzyme activity enhancement was seen at 50 mg/day. Although the design of the study does not allow for proper conclusions, the significant side-effect profile characterized by neurological side effects such as ataxia and incoordination experienced in all subjects of the study, and the very narrow window to the dose conferring a seemingly increased enzymatic activity presents significant challenges for the further development of this compound. Combination therapies of chemical chaperones and ERTs are being pursued for Gaucher, Fabry and Pompe diseases and are currently in preclinical (Gaucher) and Phase II (Fabry and Pompe) stages of development. Given the recent development challenges of the chemical chaperones (duvoglustat and migalastat) for Pompe and Fabry disease, respectively, the evaluation of these inhibitors in ERT combination studies for Pompe and Fabry diseases will be interesting.

3.5 Substrate optimization

The mechanism of action of current therapies targeting the substrates accumulating in LSDs such as miglustat and eliglustat tartrate is focused on the inhibition of enzymes necessary for substrate biosynthesis and as such this approach entails the risk of reducing the substrate to a level where its normal functions are compromised. As an alternative to this, a concept has been described in which small molecules are used, not to prevent synthesis of substrates, but rather to modify their biosynthesis in order to change the structure of the substrate, which then no longer is dependent on the deficient enzyme for degradation but can be degraded by alternative enzymes with normal function [112]. This strategy has been termed substrate optimization therapy and is currently in development for MPS types I, II and III in which the targets for the substrate optimization are glucosaminoglycans (GAGs). By compound library screening, 15 inhibitors of GAG synthesis were identified that can be categorized into N-, 2-O-, or 6-O sulfation inhibitors. A 2-O sulfation inhibitor, ZP2345, could reduce the levels of 2-O sulfation with a compensatory increase in 6-O sulfation of heparan sulfate with the modified heparan sulfate being more amenable to degradation in vitro in fibroblasts from MPS type II patients (iduronate sulfatase deficiency) [113]. Albeit still early stage, the technology has the potential of being able to target more than one MPS with the same compound as well as being able to cross the BBB and other organs that have proven hard to reach for ERTs.

3.6 Gene therapy

A number of gene therapeutic approaches using retro-, lenti- or adeno-associated viral vectors have been evaluated pharmacologically in a comprehensive array of animal models of LSDs and the general conclusion is that this therapeutic approach has shown clear disease-modifying capacity in vivo [114]. The main challenges that remain to be overcome are the transfer of these findings to larger brains (the human brain volume is ca. 2000 times that of the mice, making efficient pan-cerebral delivery a challenge even with intracranial injections), the possible immunogenic responses to the viral vectors carrying the gene of interest as well as the potential need for immune suppression for the patients who are complete null for the enzyme. Despite these challenges, a number of clinical trials have been initiated for the LSDs, but as is the case for many trials within the LSD field the trials are featuring small number of patients and solid conclusions are hard to make as only a small number of studies have been completed. Reports on completed studies of gene therapy in Gaucher disease and MPS type II using retroviral vectors showed only low expression of the gene product and no improvement in disease pathology [115,116]. However, these were the first two clinical trials of gene therapy in LSDs and since their initiation more than a decade ago there has been a marked development and improvement of vector design and delivery which will hopefully lead to improved results. Although a recently completed study in Batten disease involving direct injection of a recombinant adeno-associated viral (rAAV) serotype 2-based vector into the CNS of affected children indicated that progression of disease might have been slowed, a clear therapeutic benefit was not established and significant serious adverse events were also encountered, the causes of which could not be identified [117]. However, as for the retroviruses, rAAV-based gene therapy has also evolved substantially since the initiation of this study and several studies are underway utilizing other rAAV serotype vectors in for example, Pompe disease [118] and MPS types IIIA and IIIB, the latter two being researched and developed in commercial settings. The ongoing Pompe disease study uses a rAAV serotype 1 (rAAV1) vector encoding acid-a-glucosidase, and recently reported preliminary findings [118]. No adverse events or systemic toxicities related to vector administration were reported and significant elevation in respiratory parameters was noted for the first cohort of patients on the lower dose of treatment. These findings are encouraging for the development of gene therapies for LSDs, but the hope that all pathological components of a given LSD can be corrected by a systemic delivery of a single vector is probably too optimistic as the complex nature of these devastating diseases makes even this approach extremely difficult. A number of factors such as the timing of gene transfer in relation to diagnosis and symptom onset/aggravation, the variable levels of gene product needed to efficaciously treat various organ pathologies and the possible immune consequences related to administration procedures, choice of vector and naivety to gene therapy product will all have to be addressed in order to bring about the full potential of this therapeutic approach.

On top of these scientific and development challenges, challenges regarding regulatory considerations and commercial feasibility of developing gene therapies are also considerable. Very encouragingly however, for gene therapy as a future therapy for a number of genetic diseases, not only the LSDs, the first European regulatory approval of a gene therapy was recently announced, with this therapy also being based on an rAAV1 vector, AAV1-LPLS447X (alipogene tiparvovec, Glybera) targeting lipoprotein lipase deficiency, an ultra-rare genetic disease [119].

3.7 Other therapies and emerging approaches

The LSD cystinosis involves lysosomal storage of the amino acid cystine in all organs and tissues due to a defect in the lysosomal membrane transport protein, cystinosin, and was the first LSD recognized to be due to defective lysosomal membrane transport, and thus serves as a prototype for a small group of lysosomal transport disorders. In 1994, a novel therapy was approved based on depleting cysteine in the form of orally administered cysteamine bitartrate (Cystagon), which has revolutionized the management and prognosis of nephropathic cystinosis [120]. On administration, cysteamine enters the lysosomes and reacts with cystine, forming the mixed disulfide of half cystine (cysteine) and cysteamine. This complex can then exit the lysosomes via the transport system for cationic amino acids [121]. The efficacy of cysteamine has been validated in a number of studies and cysteamine therapy should be considered for all affected individuals, regardless of age and transplantation status [122].

The side-effect profile of cysteamine includes unpleasant taste, nausea and other digestive issues with the most common side effect being nausea that can be alleviated with antiemetics in the early stages of therapy initiation [122]. A different route of administration targets photophobia associated with the disease as topical cysteamine eye drops, administered every 1 -- 2 h, dissolve corneal crystals and ameliorate this part of the pathology within a few weeks [123].

As nonsense mutations have been identified in a number of LSDs, leading to premature translation termination and the synthesis of truncated protein as in the case of the Arg220X mutation in Fabry disease, and as there exist evidence that small molecule drugs such as gentamicin can induce the readthough of such premature stop codons, bringing about increases in otherwise null enzymatic activity, the concept of stop-codon readthrough has been explored in the severe form of MPS type I (Hurler disease). In cell cultures of patient fibroblasts carrying different nonsense mutations, gentamicin treatment increased the a-L-iduronidase activity in all cell lines tested except one providing an initial in vitro proof-ofconcept for this approach [124]. Further development of aminoglycoside analogs exhibiting reduced cell toxicity and superior readthrough efficiency compared with gentamicin might hold hopes for an even better therapeutic future for this emerging concept [125]. In addition to the aminoglycosides, a novel chemical compound was recently identified, which selectively induces ribosomal readthrough of premature, but not normal termination codons [126]. This compound, PCT124 (ataluren), has entered clinical trials and might hold great potential for genetic disorders such as cystic fibrosis, for which no other therapeutic options are available [127].

As exemplified with the use of cysteamine for cystinosis, the reduction of storage material might not only be achieved by enhancement of enzymatic activity or inhibition of substrate synthesis as covered in the previous sections. Accumulating substrates might also be eliminated by substances such as 2-hydroxy-propyl-b-cyclodextrin, which is capable of binding unesterified cholesterol and other hydrophobic molecules. As unesterified cholesterol is one of the major storage compounds in Niemann--Pick type C disease, the compound has been tested in both the murine and feline model of the disease. Encouraging data from the most commonly used mouse model of the disease (the NPCnih model) led to the FDA approval of a compassionate use trial of cyclodextrin in a small number of patients suffering from advanced Niemann--Pick type C disease [128-130]. As cyclodextrins have been widely used as formulation vehicles to increase the amount of drug, including hormones and vitamins, which can be solubilized in aqueous vehicles [131], its use and toxicological profile has been extensively studied in rodents, dogs and monkeys where it is well tolerated at low doses [131,132]. However, daily i.v. administration of greater than 200 mg/kg caused reduced body weight, foamy macrophage infiltration of the lungs, elevations in hepatic enzymes, increased Kuppfer cells in the liver and renal cortical tubular vacuolization in rodents [131,133,134].

Doses used to reach therapeutic effect in the murine model of Niemann--Pick type C are several-fold higher than the doses at which no adverse events are seen (4000 mg/kg used in the NPC mouse models) and apart from the available toxicological data in healthy animals increasing data from animal models of LSDs strongly suggest that the use of this compound for any LSD should be carefully evaluated as a number of side effects have been seen on treatment including hearing loss and increased cholesterol burden and macrophage infiltration of the lungs [128,135-137]. Furthermore, as cyclodextrin does not cross the BBB [138] and as its use in other murine models of cholesterol-storing LSDs such as GM1-gangliosidosis and MPSIIIA had no effect on storage [130], it is clear that the mechanism of action is not fully understood. Addressing these challenges will hopefully aid the development and future therapeutic approaches relying on this class of compounds.

Based on the complex pathology of the LSDs and the various cellular and biological organelles and processes involved, a number of experimental strategies, some including commercially available compounds, are being researched for their use as disease modifiers. These approaches include calcium modulation, enhancing exocytosis, regulation of proteostasis, modulation of autophagy and the use of non-steroidal antiinflammatory drugs [42,139-145]. While most of these approaches are at an early stage and still have a long way ahead to the clinic, it is clear that a multifaceted approach is most likely needed to address the complex pathology of LSDs. No doubt, as the understanding of disease pathology advance, additional creative approaches to treatment will emerge and undergo similar early development with the hope that any of these approaches ultimately lead to clinical benefit for the patients.

4. Competitive environment

Table 1 summarizes the current status of the competitive environment for LSD therapies with market approval, while Tables 2 and 3 summarize the various emerging therapies and concepts and provide a thorough overview of the status of the programs in primarily commercial development pipelines for the LSDs. The emerging concepts being explored for LSDs with high unmet clinical needs or unaddressed pathology such as CNS deterioration is an exciting field which holds a number of promises for complimentary mechanisms of action offering a potentially larger arsenal of drugs for future therapy but in addition hereto, a number of primarily ERT projects are also being developed for LSDs with established and effective therapy as for example, type 1 Gaucher disease. For type 1 Gaucher disease, three therapies are already commercially available (two ERTs (imiglucerase and velaglucerase alfa) and one SRT (miglustat)), with two ERT programs, a CCT/ERT combination program and an SRT also currently in development. The two ERT programs are based on alternative manufacturing systems and whether the products of these programs have significant differentiating factors with therapeutic relevance to the established therapies will be interesting to follow. Interestingly, one of these products, taliglucerase (Elelyso, Protalix/Pfizer), was recently approved by the FDA (1 May 2012), but was rejected marketing approval by the EU commission as velaglucerase alfa (VPRIV) has 10 years marketing exclusivity under the orphan drug framework.

5. Expert opinion

The current state of the LSD field is both complex and encouraging. Complex as the understanding of the underlying molecular pathology of the vast heterogeneity in clinical presentation is still limited and constantly evolves. Encouraging as novel therapeutic approaches evolve from these discoveries, carrying with them the hope that they may eventually impact the course of these devastating diseases.

Among this multitude of approaches, the ERTs still reign supreme in number of products commercially available, as well as number of programs in the development pipelines of pharmaceutical companies, although a number of alternative approaches are emerging.

Gaucher disease was the first LSD for which ERT became available and the impact made by this approach not only clinically but also commercially subsequently prompted the development of ERTs for a number of other LSDs. Recently, a 10-year follow-up study of Gaucher disease patients treated with ERT reported the lasting impact on patients health by treatment with imiglucerase but the same degree of success has unfortunately not been achieved with all ERTs although early intervention in for example, infantile Pompe disease has also been a marked success as this has proved life-saving [59,70]. Importantly, lessons learned from the use of ERTs in the clinic have clarified the challenges still facing ERTs and these are by no means trivial; adverse immunological reactions to infusion of enzyme are common and many sites of pathology are not effectively treated by intravenous administration of enzyme as these sites are not easily reached by the infused enzyme. In addition, some manifestations of disease has proven very hard to alleviate such as bone disease in Gaucher disease and the MPS, renal complications in Fabry disease and the degeneration of the CNS observed in many LSDs. All of these sites provide therapeutic targets which have yet to be efficiently reached by an ERT or therapeutic variant hereof.

A major therapeutic advancement will therefore be molecules which can reach these sites of pathology and a number of the emerging therapies are indeed aiming at exactly this, with therapies being able to cross the BBB being a particular focus for many of these development efforts. Until now only one drug approved for an LSD has shown indications that it might affect CNS complications. The orally administered SRT, miglustat, was first approved for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom ERT is not a therapeutic option [91] and has since been approved in the EU and other countries for the treatment of Niemann--Pick type C based on a clinical trial, which demonstrated that treatment with miglustat improved eye movement velocity and swallowing capacity indicating an effect on CNS pathology [95]. The challenges facing SRTs are based on their inherently unspecific mechanism of action as the inhibition of ceramide glucosyltransferase (an early core component in the glycosphingolipid synthesis pathway) by virtue of the sequential synthesis steps in this pathway unavoidably affects the synthesis and equilibrium of all downstream derivatives. Furthermore, miglustat is known to inhibit several glycosidases, including a-glucosidase I and II as well as sucrase and maltase, which might also explain parts of its sideeffect profile [146]. This inherent non-specificity raises concerns about long-term toxicities or adverse events for any SRT but to date the side effects such as diarrhea have been controllable, although there are still concerns regarding the tremors and paresthesias that develop in some treated patients [91]. A novel SRT in development, eliglustat tartrate, has shown promising data including a more benign sideeffect profile, probably owing to its higher selectivity, but unfortunately this agent is a target for P-glycoprotein meaning that it is efficiently pumped out of the brain and hence will most likely not have an impact on CNS disease in patients [97,147,148]. Nevertheless, the higher specificity and milder adverse events indicate that this compound hold great potential for being an efficacious SRT for the treatment of peripheral disease in Gaucher disease and other sphingolipidoses, and the promise of SRT still spurs design of new agents combining increased specificity and brain penetrating properties, providing a continued flow of potentially beneficial drugs for a large subset of the LSDs [148].

Gene therapy strategies are a possibly very important intervention which has seen a breakthrough with the EU approval of the first gene therapy (Glybera). This approach might offer an alternative to existing therapies as might oral approaches and approaches with mechanisms of action across diseases such as the SRT and molecular chaperone therapies.

In case of chaperone approaches to treating LSDs, two intriguing concepts with the potential of addressing several LSDs including diseases with CNS involvement are in development. These are approaches that employ either endogenous molecular or chemical chaperones, respectively. The approaches are inherently dissimilar as the molecular chaperone therapy approach utilizes the endogenous chaperone machinery to not only enhance the activity of compromised enzymes but also provide the dysfunctional lysosomes and cells with the survival promoting benefits of the heat shock proteins [43,103].

Almost counterintuitively, chemical chaperone technologies use competitive inhibitors to enhance residual enzyme activity, with the technology having a plausible theoretical basis in the conformational memory of proteins. CCT uses competitive inhibitors of lysosomal enzymes at subinhibitory concentrations in order to facilitate the transition of poorly folded lysosomal enzymes otherwise caught in the ER/proteasomal degradation machinery to the lysosomes [106]. The technology has seen widespread development with a number of programs in current clinical trials, but recent clinical data have highlighted the difficulties in using inhibitors in already severely compromised enzymatic systems. The most recent setback being reported only recently as initial data from a Phase III randomized, placebo-controlled study of migalastat in Fabry disease including 67 patients showed that the study did not meet its primary end points [108].

A major aid to any clinical trial and a significant advancement to the understanding of LSDs will be the development of tests/biomarkers that accurately predict the disease outcomes and aggressiveness. Tools for better and early diagnosis are also needed as the often irreversible degeneration and pathology observed for many of these diseases prompt an early and efficient intervention in order to have the highest likelihood of significantly improving the clinical outcome. The development of these tools will be important not just for the understanding of the diseases and their progression but will hopefully allow for better clinical trial designs and a better definition of subpopulations of patients that will have better or poorer responses to therapies.

As early intervention is generally considered a prerequisite for the prevention of irreversible complications in any LSD, the development of suitable biomarkers is of significant importance as their absence makes it difficult to support presymptomatic pharmacological therapy without the capacity to monitor consequences of the intervention. Of course, early lifesaving interventions are completely unethical to withhold in for example, infantile Pompe, Krabbe and Niemann--Pick type A disease, but when should one intervene in more gradually developing diseases? As the current therapies are not benign and have not only medical but also social and economical implications for the patient in terms of insurability and employability, the initiation of therapy needs very careful consideration which will also be the case for the therapies in development. However, progress in biomarker characterization is being made for a number of diseases such as Gaucher disease, Fabry disease, the MPS and Niemann--Pick type C disease [149-151].

No doubt the number of emerging therapies for LSDs is encouraging, with a lot of exciting biological mechanisms being explored as potential drug targets. This is however, also necessary as the complex nature of the diseases almost certainly demands a combined effort targeting not only general or specific pathology but rather aims at a shot-gun approach for treatment utilizing a battery of therapeutic modalities to deal with the intricate molecular pathology underlying these devastating diseases.

Importantly, the significant cost of therapy for these very rare diseases has to be considered not only at an individual level, but also by physicians and society at large as we seek to improve the life of patients with LSDs. This consideration becomes of particular relevance in the case of combination therapies, which will most likely be the future way to improve the life of patients who by odd chance have developed such devastating diseases.

Declaration of interest The author is employed by and holds shares in Orphazyme ApS, which develops therapies for lysosomal storage diseases.



Thomas Kirkegaard

Informa Healthcare



The success of the first enzyme replacement therapy (ERT) for a lysosomal storage disease (LSD) and the regulatory and commercial incentives provided by authorities for orphan and rare diseases has spawned a massive interest for developing drugs for these intriguing but devastating genetic disorders. The potential for new drugs in this arena is vast, as not only a high number of LSDs have no available therapy, but also alternative therapeutic approaches for diseases with existing treatment are much needed as a number of challenges facing the existing therapies have become very obvious. A significant unmet medical need is therefore apparent for most, if not all of the LSDs and the development of new therapies based on the increasing knowledge of the pathophysiological mechanisms involved in these devastating diseases is therefore anticipated with great interest from all stakeholders.

Areas covered:

The reader will be introduced to the intricate biological processes involved in lysosomal regulation and how these are exploited for current and emerging therapies. Therapies utilizing these processes will be thoroughly reviewed with regard to their mechanism of action, their clinical status and the challenges they are faced with and/or are aiming to address. For this review, a literature research has been undertaken that covers the years 1955 -- 2012.

Expert opinion:

The interest in lysosomal biology and disease has surged over the past decade not only in the halls of science but also of pharmaceutical companies. As the complexity of the LSDs increasingly become revealed, so do novel therapeutic targets continuously nurturing the development of new candidate drugs for these devastating diseases. Among this multitude of approaches, the ERTs still account for the vast majority of approved therapies but a number of exciting alternative approaches are emerging targeting various components of the pathophysiological cascade. This evolution of the field is much needed as the presently available treatments are unable to address all clinical aspects of these multifaceted diseases. Future therapy will most likely consist of combinations of these established and emerging approaches as well as other yet to be discovered concepts as the complexity of the diseases demands a certain degree of humbleness to the expectations for a cure based on a single therapy.

Keywords: chaperone, enzyme replacement, Fabry disease, Gaucher disease, glycosphingolipids, lysosomal storage disease, lysosomes, substrate optimization, substrate reduction, therapy

Thematic stream: 
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Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

BACKGROUND The lysosomal storage diseases (LSDs) comprise a heterogeneous group of almost 50 disorders that are caused by genetic defects in a lysosomal acid hydrolase, receptor, activator protein, membrane protein, or transporter, causing lysosomal accumulation of substrates that are specific to each disorder. The accumulation is progressive, ultimately causing deterioration of cellular and tissue function. Many disorders affect the central nervous system (CNS) and most patients have a decreased lifespan and significant morbidity. The LSDs are often categorized according to the type of substrate stored (i.e., mucopolysaccharidoses, oligosaccharidoses, sphingolipidoses, gangliosidoses, etc.).1

Most lysosomal proteins are the products of housekeeping genes expressed throughout the body, but storage occurs only in those cells with an available substrate (e.g., GM2 ganglioside is present predominantly in the CNS and deficiency of hexosaminidase A, which acts on the GM2 ganglioside and can be measured in the blood, causes Tay Sachs disease, a CNS condition). In all cases, the diagnosis must be established by specific enzyme assays and by mutational analysis. Urinary mucopolysaccharides and oligosaccharides, although useful for screening, can be normal and increased nonspecifically in healthy neonates.2

Although each disorder is rare, LSDs as a group have a frequency of one in 7000–8000 live births.3,4 The frequency estimate may be low as more individuals with mild disease and/or adult-onset forms of the diseases are being identified. All LSDs are inherited in an autosomal recessive fashion, except for Fabry, Hunter (mucopolysaccharidosis type II [MPS II]) and Danon diseases, which are X-linked. Some disorders are more prevalent in certain geographic areas or among particular population groups (e.g., Gaucher, TaySachs, Niemann-Pick type A, and mucolipidosis IV are more common in Ashkenazi Jews), largely as a result of ancestral founder mutations.5–7 For many diseases, such as Fabry, most kindreds have private mutations.

Highly effective preconception carrier screening programs for populations at risk for Tay-Sachs disease have been in place since 1971,6,8 leading to a great reduction in the number of affected children born. Carrier screening of Ashkenazi Jews has been expanded to include several other hereditary disorders found at higher frequency in this group.9

A single clinically defined disorder may be caused by more than one enzymatic defect, such as Sanfilippo disease (MPS III), that can be caused by a deficiency in any one of four hydrolases. Conversely, a disorder caused by a single enzyme deficiency usually gives rise to a spectrum of manifestations depending on the amount of residual enzyme activity and currently unknown modifiers. The age of onset, severity of symptoms, organ systems affected, and CNS manifestations can vary markedly, sometimes even within families. Although specific mutations or types of mutations can be associated with certain outcomes, genotype-phenotype correlations are typically not strong as with Gaucher disease (GD) patients with the same mutations who may present in childhood or be asymptomatic throughout adult life.10 For women with X-linked lysosomal storage disorders such as Fabry disease, the severity and extent of disease manifestations may be determined primarily by the degree of X-chromosomal inactivation,11 although evidence of random inactivation has been shown.12

Diagnosis and ascertainment Probands are typically ascertained because of clinical signs and symptoms, often after the disease is advanced and interventions less efficacious. Presymptomatic individuals, the subject of this article, may be ascertained through screening of family members of the proband, carrier screening, prenatal testing, populations at risk for a genetic disorder, or newborn screening (NBS). As will be discussed for each disorder, diagnosis depends on enzymatic or molecular definition of mutations, or both

Treatment of LSDs Because of their wide-ranging medical and psychosocial ramifications, LSDs require an ongoing multidisciplinary, team approach to treatment. Comprehensive management generally combines disease-specific therapy (if available) with symptomspecific measures. The team leader should be someone (generally a biochemical geneticist) who is experienced in treating LSDs, is aware of disease-specific complications and nuances of therapy, and keeps up to date with recent advances. Each patient’s team should include other relevant medical specialists familiar with LSDs. Once a diagnosis is established, genetic counseling is essential to provide patients and their families with an understanding of mode of inheritance, identify at-risk family members, and discuss recurrence risks. Patient and parent support groups are invaluable sources of emotional support and practical advice.

Hematopoietic stem cell transplantation (HSCT) has been used successfully in the management of some LSDs. The rationale behind HSCT is that a reconstituted hematopoietic system from a healthy, matched donor will contain stem cells that can produce the missing enzyme. The small amounts of secreted enzyme are available to be taken up by mannose-6-phosphate receptors on other cells, endocytosed, and delivered to the lysosome. The major drawback to HSCT is its high morbidity and mortality, although both have improved over time, particularly with the use of refined conditioning regimens and cord blood as a stem cell source. Graft failure is more common in HSCT for some of the LSDs. The advantage of HSCT is that cells can integrate into many tissues, including the CNS. The disadvantages include the low level of correction and the time required for integration of the cells into other tissues, factors that currently preclude HSCT from being curative

Specific treatments for LSDs are evolving rapidly with the involvement of an expanding number of biotechnology companies. Most widely used is enzyme replacement therapy (ERT), which supplies the missing enzyme exogenously through repeated intravenous infusions. With ERT, larger doses of enzyme can be administered than are attainable through HSCT; however, the blood-brain barrier (BBB) cannot be crossed, precluding the use of ERT for CNS disease. Even in patients with significant CNS involvement, ERT may be useful for reducing the morbidity associated with the somatic manifestations. The usefulness of ERT in the pre- and peri-HSCT period is being studied, and intrathecal ERT is being tested for MPS I and II. ERT is currently commercially available for Gaucher, Fabry, MPS I, II, VI, and Pompe diseases (PDs) and is undergoing clinical trials for MPS IVA and Niemann-Pick type B. ERT is not without its challenges. Many patients do not produce native enzyme (and are cross-reacting immunologic material [CRIM]-negative) or make native enzyme that differs significantly from administered enzyme, and consequently make antibodies to the exogenous enzyme, which may reduce efficacy and often causes adverse infusion reactions. Fortunately, the infusion reactions are usually easy to treat, many patients develop tolerance over time, and allergic reactions are rare

Oral therapies are available for two LSDs and more are being tested. Cysteamine is used successfully to preserve renal function in cystinosis.13–15 Substrate reduction therapy (SRT) with N-butyldeoxynojirimycin (OGT-918, miglustat, Zavesca; Actelion, Basel, Switzerland) reduces production of glycosphingolipids by inhibiting glucosylceramide synthase, the first step of their biosynthesis. SRT is approved for use in GD, although side effects preclude its more widespread use,16,17 and NiemannPick type C in Europe. A new-generation agent (Genz-11638; Genzyme Corporation, Cambridge, MA) is being tested that may have fewer side effects. For SRT to reduce lysosomal storage, there must be residual enzyme activity, which is always the case in GD but not in other disorders. Unfortunately, SRT does not reduce substrate turnover, resulting in cellular depletion of these evolutionarily conserved (and presumably important) glycolipids, a fact that may ultimately limit the utility of this therapeutic approach.

Oral small molecule chaperones are compounds that improve the folding and trafficking of lysosomal proteins with specific missense mutations. Clinical trials for Fabry disease are underway (Amicus Therapeutics, Camden, NJ). PTC124 (Ataluren, PTC Therapeutics, South Plainfield, NJ) causes the ribosome to read-through nonsense codons and yet allows the ribosome to end translation normally at the correct stop codon. This drug, currently in testing for other conditions, could be useful for some patients with LSDs caused by nonsense mutations.

Gene therapy holds the promise of a cure for LSDs. However, many hurdles must be overcome before gene therapy can be applied to the LSDs including delivery to the correct cells, random integration, sustained expression, and immune reactions.

There is currently great variability in clinical practice for LSD treatment both within and among countries. Specific areas of controversy include when (and even if) to start specific therapies, what dose to use, how to monitor patients, when to stop treatments, and what adjunctive therapies should be used. Some of the variability is based on legitimate financial concerns given the expense of many specific therapies, but much has to do with the lack of long-term longitudinal studies with sufficient numbers of patients. Many available data comes from case reports, case series, clinical trials involving small numbers of patients, and voluntary patient registries as part of industry’s postmarketing commitments to the drug regulatory agencies.

For many countries, expense is a large consideration in the treatment of LSDs. Insurance plans may have a lifetime cap for drug expenses that can be rapidly exhausted with most of the available therapies. Some health systems demand that each new therapy be demonstrated to be cost-effective, a difficult challenge for these rare disorders. Some have designed special funding programs for rare disease treatments. Less affluent countries are unable to afford the drugs or routinely use a low dose. Some help is provided to many patients without resources by assistance programs from the drug companies; however, most individuals worldwide receive supportive and palliative care, at best.

Caring for presymptomatic individuals, however, diagnosed highlights the current limitations in our diagnostic evaluations and decision making. In part, the difficulty is due to the often poor correlations of residual enzyme activity and genotype with the clinical phenotype. HSCT is a consideration for some disorders that may have CNS involvement. To be effective, HSCT has to be performed well before evidence of CNS involvement. Because phenotype-genotype correlations are imperfect, it will always be uncertain whether a particular newborn will need HSCT or not. Because HSCT has significant associated mortality and long-term morbidity, deciding if and when to transplant will be a major area of clinical difficulty, as discussed in the context of the individual disorders. Other areas of difficulty include the often variable clinical response to therapy, the long time required for improvement or stabilization to be evident for those who become affected, and the general lack of large natural history studies for comparison. Most disorders lack useful and accepted biomarkers for therapeutic decision making.

Newborn screening Early detection of LSDs can be important for patients and their families and constitutes a major rationale for instituting NBS. For several disorders, it is clear that earlier initiation of therapy can make a substantial difference in outcome. The LSDs are sufficiently rare that most practitioners are unaware of their signs and symptoms, leading to diagnostic odysseys and delayed diagnoses. By the time patients are diagnosed, they may have suffered irreversible damage, limiting the effectiveness of treatment. Many patients remain undiagnosed. A second affected child is often born before the first is diagnosed. There is much to be learned about what can be realistically achieved with earlier detection (e.g., the response of skeletal disease in MPS VI) as well as the true incidence and extent of each disease.

Testing from dried blood spots (DBSs) is now possible for several LSDs using the same blood spot sample and highthroughput platforms, making population screening technically feasible (Table 1).

However, only few data are available that address sensitivity and specificity of these assays. Nevertheless, the Centers for Disease Control and Prevention has already produced freely available quality control DBS material for several LSDs,21 making high-throughput screening programs feasible. NBS for some LSDs has or will begin shortly as pilot programs (Pompe and Fabry diseases in Taiwan and Fabry disease in Washington State) or as additions to established NBS programs (Krabbe disease [KD] in New York State and Krabbe, Fabry, Pompe, Niemann-Pick, and Gaucher diseases in the States of Illinois and Missouri; Austria has piloted two studies on Fabry and Pompe diseases, respectively). At the same time, Pompe and Krabbe diseases were nominated to the US Advisory Committee on Heritable Disorders of Newborns and Children for inclusion in NBS. The Advisory Committee on Heritable Disorders of Newborns and Children did not consider the evidence to be sufficient to be able to recommend their inclusion at the current time.

As with any screening program, there are many ethical considerations in screening for LSDs. Variants of uncertain significance will certainly be identified. Adult-onset variants will be identified, perhaps in greater numbers than the early infantile forms of these diseases, and some patients with these may never develop symptoms or require therapy. Identification of both novel and adult-onset variants can lead to problems with insurability, labeling someone as vulnerable from birth, excluding from military service, etc. Consumers vary in their desire to detect late-onset disorders in the neonatal period and the acceptance of anxiety that some will face during a diagnostic evaluation for a positive screen. However, experience suggests that parents of patients and older patients with delayed diagnoses are almost universal in their support for early detection. Legislative changes will be needed to protect identified individuals from discrimination and ongoing counseling and support for patients and families will be required to minimize the psychosocial effects of early detection for adult onset LSDs. In this regard, in the United States, the Genetic Information Nondiscrimination Act provides legal protection against discrimination for health insurance or employment for individuals with a presymptomatic genetic condition.22,23

Any NBS system requires an organized network of centers for definitive diagnostic tests, genetic counseling, and treatment. Generally, care of LSD patients is coordinated by biochemical geneticists or metabolic disease specialists at centers equipped to handle the complex, multidisciplinary needs of LSD patients. Such trained individuals and centers are currently in short supply. Large geographic regions are entirely lacking in the necessary expertise. Even within centers, caring for LSD patients is time consuming, often requires expertise and facilities for the treatment of children and adults, and involves a significant amount of unreimbursed time from physicians and their staff. Many private payers will not authorize follow-up visits at LSD centers, under the erroneous belief that any physician is capable and willing to deal with complex therapies and their side effects, coordinating multidisciplinary care and dealing with anxious families. Even if the patient can be seen by the appropriate specialist, they may only make recommendations for testing and treatment that is then up to the primary care physician to arrange, something many are ill-equipped or unwilling to do. Many patients must travel great distances to receive weekly or biweekly drug infusions, even if a local infusion center is available and long after home therapy could be appropriate.

Another essential component of a LSD screening program is an experienced laboratory for rapid and accurate enzymatic and molecular testing. The laboratory must incorporate appropriate quality assurance and proficiency testing programs including sample sharing between laboratories. There are currently only a few laboratories around the world with the required expertise and experience.

A final important part of a NBS program is a well-designed, monitored, longitudinal follow-up program. This will allow definition of natural history and response to therapies, providing answers to the many outstanding questions not addressed by small pilot programs, case series, and industry-sponsored registries. Such a follow-up network should have a biological repository of samples to serve as a resource for identification and validation of biomarkers and modifier genes. These are precisely the charges of the new American College of Medical Genetics (ACMG)/National Institutes of Health (NIH) Newborn Screening Translational Research Network.

Purpose This guideline is intended as an educational resource. It highlights current practices and therapeutic approaches to the diagnosis and management of individuals who may have a LSD that is identified by NBS, family screening through a proband, or because of carrier testing in at-risk populations and subsequent prenatal or postnatal testing. Rather than discussing all LSDs, this guideline focuses on select LSDs for which a NBS test and some specific treatment are available or may become available in the near future. The goal is to provide some guidance for confirmatory testing and subsequent management as well as to define a research agenda for longitudinal studies, such as the Newborn Screening Translational Research Network being initiated by the ACMG with funding from NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. Target audience This guideline is directed at a wide range of providers, although care is commonly provided by metabolic disease specialists/biochemical geneticists and neuromuscular experts.


Consensus development panel

An international group of experts in the (a) clinical and laboratory diagnosis, (b) treatment and management (cardiac, respiratory, gastrointestinal/dietary, musculoskeletal, neurologic, psychosocial, general medical, and supportive and rehabilitative), (c) NBS, and (d) genetic aspects of LSDs was assembled to review the evidence base and develop a guideline on the diagnosis and management of the presymptomatic LSD patient.

Following a meeting during which published material and personal experience were reviewed by the panel, experts in the various areas reviewed the literature (predominantly English language identifiable with a PubMed search) in these areas and drafted their appropriate guideline sections. All members of the panel reviewed and approved the final guidelines. Consensus was defined as agreement among all members of the panel. For the most part, the recommendations must be considered as expert opinion because additional levels of evidence were not available in the literature. Where available, evidence from clinical trials is used to guide recommendations. The guideline was reviewed by the ACMG Board and approved on August 23, 2010.


Pompe disease or glycogen storage disease type II (OMIM# 232300)

Synonyms Acid maltase deficiency, acid -glucosidase (GAA) deficiency.


PD is due to intralysosomal accumulation of glycogen secondary to deficiency of GAA (EC The resulting clinical phenotypic spectrum ranges from infantile to adultonset. PD was first recognized by Dr. Pompe in a 7-month-old infant24 and later named as PD.25 PD was the first inborn error of metabolism to be recognized as a LSD.26 The overall prevalence of PD is estimated to be approximately 1:40,000 in the Netherlands and in New York City.27–29 The prevalence of infantile-onset PD is estimated to be 1:138,000 births in the Netherlands, 1:33,000 in Taiwan based on NBS, and it seems to be more frequent overall in the Chinese and Afro-American populations.27,28,30,31

Clinical phenotype All patients with PD have variable but progressive, intralysosomal glycogen storage in skeletal, heart, and smooth muscles with resulting organ damage and ultimate organ failure. The rate of glycogen accumulation depends on residual enzyme activity, environmental factors (nutrition), muscle fiber type, physical activity, and as yet unknown genetic modifiers.32 Patients with the same haplotypes around the mutant gene may in fact exhibit different clinical phenotypes.33 Although PD is often classified into two separate categories—infantile-onset and late-onset— based on age of onset of symptoms, PD is a clinical disease spectrum.34–37

Infantile-onset PD. Patients with infantile (classic) PD present with progressive left ventricular hypertrophy and generalized muscular hypotonia (floppy infant) and typically die within the first year of life because of cardiorespiratory failure.38–41 Significant cardiomyopathy may already be present in utero and readily detected by prenatal ultrasound. In addition, the electrocardiogram (ECG) may show conduction abnormalities including a short PR interval, characteristic tall QRS complexes, and Wolf-Parkinson-White syndrome in some patients.34,37,40,42 Additional symptoms include macroglossia, hepatosplenomegaly, and feeding difficulties.34,35,43 Patients usually present with disease symptoms at approximately 3 months of age and death occurs at a median age of 6.0–8.7 months.40,43

Late-onset PD. The leading clinical symptom in patients with late-onset PD (“nonclassic” childhood, juvenile, or adult-onset) is progressive muscle weakness due to initial involvement of the muscles of the proximal lower limbs and the paraspinal muscles. There is a significant early involvement of the diaphragm and accessory respiratory muscles, which leads to respiratory failure necessitating assisted ventilation, in some instances, even when patients are still ambulatory.41 Occasionally, respiratory failure may be the presenting clinical symptom associated with frequent upper airway infections, orthopnea, sleep apnea, and morning headaches.37,41 Cardiac involvement is typically not observed in late-onset PD although some patients do have rhythm abnormalities due to underlying Wolf-Parkinson-White syndrome and cardiac hypertrophy can be noted in some.44–46 Vascular involvement of large intracranial blood vessels due to glycogen storage in smooth muscle cells leading to cerebral aneurysms has been reported.37,47,48

Current diagnostics

Biochemical markers. The use of acarbose to inhibit activity of the isoenzyme maltase glucoamylase made it possible for the first time to measure GAA activity reliably in leukocytes and DBSs.49–51 GAA activity can be either measured using fluorometry or tandem mass spectrometry (MS/MS).49,50,52,53 Although there is a correlation between GAA activity in fibroblasts and clinical phenotype, the clinical phenotype may not be readily predicted through enzyme analysis in different tissues.54

Serum creatine kinase, transaminases, and lactate dehydrogenase are increased in most patients with PD but may occasionally be within normal limits in those with adult-onset PD.34 Muscle biopsies for primary diagnostic purposes are obsolete as the false-negative diagnostic rate may be significant.34,41 Urinary hex 4 is a breakdown product of glycogen and is typically increased in the majority of patients with PD. Levels of excretion are higher in infants and those with significant disease burden. Levels have correlated with muscle biopsy glycogen content. It is useful for monitoring the clinical response to treatment.55,56

Molecular analysis.

Two hundred eighty-nine different pathogenic mutations in GAA are known including nonsense, missense, small deletions, insertions, and nonpathogenic mutations. Details on mutations and associated phenotypes can be found at

A new tool that estimates the severity of a particular GAA sequence variant has been introduced. The severity of a given GAA sequence variant is reflected in the quantity and quality of GAA precursor (110 kD) and modified precursor molecules (95 kD, 76 kD, and 20 kD) following transfection of COS cells.57,58

Molecular testing is the preferred technique for prenatal diagnosis, provided the genotype of the index patient is known. Alternatively, enzyme analysis in chorionic villi may be used.41

Ascertainment A PD NBS pilot program in Taiwan used acarbose and 4-methylumbelliferyl-b-D-glucuronide (4-MUG) to measure GAA activity in DBS.59 The screening program covers approximately 45% of the Taiwanese population, and the same laboratory provides Pompe diagnostic services for all of Taiwan. Between October 2005 and March 2007, more than 130,000 newborn infants were screened, and PD was diagnosed in four infants during their first month of life. In contrast, three infants were diagnosed during the same time period based on clinical symptoms alone between the age of 3 and 6 months. All infants except one in the screening group had infantile-onset PD and were started on ERT.59 The recall rate for repeat blood tests was 0.82% and for clinical recall 0.091%.59,60

The use of MS/MS for enzyme analysis in DBS for the diagnosis of Fabry, Gaucher, Krabbe, Niemann-Pick, and Pompe diseases, respectively, has been evaluated.51–53 The MS/MS technique for GAA analysis in DBS was further evaluated and validated on more than 10,000 anonymous newborn infants in Austria and 29 known patients with PD.52 The recall rate in this study was 0.03%.52

Antibodies against epitopes of lysosomal proteins including GAA have also been used for detection in neonatal screening samples, although a formal validation on a larger number of samples has not been done.61 Patients with PD and structurally intact epitopes may not be readily detected by this method.

Therapy Alglucosidase alfa (recombinant GAA [rhGAA], Myozyme/ Lumizyme; Genzyme Corporation) has been shown to be effective in the treatment of patients with early- and late-onset PD.18,35,36,62–65 The individual response to ERT may vary due to development of rhGAA specific antibodies, age of presentation, rate of progression of disease, muscle fiber type, defective autophagy, and underlying genotype.32,35 The development of rhGAA antibodies may be more frequent in patients with absent GAA protein (CRIM-negative) and have an impact on the prognosis of patients with infantile-onset PD.32 Induction of immune tolerance to reduce rhGAA antibody formation has been evaluated in GAA knockout mice.66,67 Success with a tolerance-inducing regimen including treatment with anti-CD20 monoclonal antibody (rituximab) plus methotrexate and intravenous gamma globulin has been reported in a CRIM-negative infant.68 Clinical trials are ongoing in infants

Neurological symptoms in infantile-onset PD were not readily observed due to early death within the first year. The advent of ERT and the increased survival rate in infants treated early have uncovered neurological manifestions of PD related to cochlear dysfunction and delayed myelination, and bulbar involvement.69–71 The long-term outcome of surviving infants on ERT is unfolding.

Recommended follow-up procedures

Diagnostic confirmation. A suggested diagnostic algorithm is presented in Figure 1.

1. Confirm the diagnosis by demonstrating GAA deficiency in a blood-based assay (DBS, leukocytes, and lymphocytes) or fibroblasts. Enzyme analysis in a blood-based assay is preferred due to the faster turnaround, lower costs, and reduced invasiveness.

2. Assess CRIM status by Western blot/mutation analysis for patients with infantile presentation (cardiac involvement in infancy).

3. Mutation analysis of the GAA gene.

Clinical follow-up and intervention.

1. Laboratory tests including serum creatine kinase, transaminases, lactate dehydrogenase, and urinary hex4.

2. Chest radiograph, ECG, and 2D echocardiogram.

3. Clinical evaluation including swallow, pulmonary, and neurological examination.

4. Prompt initiation of ERT in patients with infantile PD.

5. Evaluations every 6–12 months in the remaining patients.

It is important to identify patients with infantile PD as early as possible because ERT needs to be initiated as early as possible. The management of patients with infantile PD should be done at specialized centers with the appropriate expertise and back-up facilities. Under no circumstances should ERT be given at home or in peripheral potentially understaffed hospitals. Infantile patients are an anesthesia risk for infusion port placement and could develop airway problems should an infusion-related reaction occur. Close cardiology follow-up is required as cardiac remodeling occurs with ERT. A frank discussion with the parents is warranted regarding poor outcomes in CRIM-negative patients who typically do poorly on ERT alone.72 The role of immune modulation in tolerance induction is emerging and data look promising.68 Longterm issues should also be discussed.

Fabry disease (OMIM# 301500) Synonyms Anderson-Fabry Disease, angiokeratoma corporis diffusum, -galactosidase A (-gal A) deficiency.


Fabry disease is a X-linked inherited lysosomal storage disorder caused by deficiency of the enzyme -gal A (E.C. Affected patients have insufficient ability to degrade the membrane glycosphingolipid ceramide trihexoside (GL-3). The subsequent deposition of GL-3 in body tissues leads to the symptoms of the disease. No ethnic predilection exists for Fabry disease, which occurs in approximately 1:40,000 male births.3 However, studies from select populations have shown a Fabry disease prevalence of 1:100–1:1000 male dialysis patients, 1:20–1:30 of “idiopathic” hypertrophic cardiomyopathy cases, and 1:20 male (1:40 female) patients with cryptogenic strokes.74–79

Clinical phenotype

Fabry disease causes significant morbidity and mortality in both hemizygous males and heterozygous females. The mean age of presentation for affected boys is 6–8 years; the typical presenting symptom is acute, episodic pain crises followed by chronic acroparesthesias.80–82 GL-3 accumulation in the vascular endothelium and other cells leads to hearing loss, myocardial microvascular ischemia, dysrhythmias, hypertrophic cardiomyopathy, valvular insufficiency, gastrointestinal symptoms, hypohidrosis, temperature and exercise intolerance, dysregulation of vascular tone and autonomic functions, obstructive lung disease, progressive renal insufficiency leading to kidney failure, and increases the risk of cerebrovascular accidents and myocardial infarctions.83–93

Early death in hemizygotes occurs typically in the late fifth to early sixth decade from kidney failure, strokes, and cardiac events.94–95 Heterozygous females, previously thought to be asymptomatic “carriers,” can have significant symptomatology, generally at a later age than hemizygous men.96–98 There is a “cardiac variant” of attenuated Fabry disease with hypertrophic cardiomyopathy as the predominant symptom, although these patients may develop milder symptoms in other organ systems.99

Current diagnostics

Biochemical markers. Reduced leukocyte -gal A enzyme levels will be found in hemizygotes. As GL-3 storage begins prenatally, boys will have increased GL-3 levels in plasma and urinary sediment. LysoGL-3 may be a useful biomarker for the monitoring of treatment efficacy.100 Heterozygote leukocyte enzyme activity and tissue GL-3 levels vary, are often in the “normal” range, and do not correlate with presence or severity of Fabry symptoms.98,101

Molecular analysis.

Most pathogenic GLA mutations are “private” and nonrecurrent; more than 300 mutations have been described. In general, mutations that result in prematurely truncated -gal A, which are approximately 45% of those reported, will result in a classical Fabry phenotype in a hemizygote.102 Missense mutations that result in very low leukocyte -gal A levels will also result in a classical phenotype. Because Fabry disease shows marked intrafamilial variability, predicting symptom severity, age of onset, and rate of progression is quite difficult even for a hemizygote with a mutation known to cause a classical phenotype. Mutations with residual -gal A enzyme activity thought to consistently produce an attenuated phenotype (e.g., N215S)103,104 have been reported in patients with classical disease.105 For heterozygotes, intrafamilial variability, lack of correlation between biochemical markers and phenotype, and lyonization make presymptomatic prediction of phenotypic severity impossible. One pseudodeficiency allele, D313Y, has been described with low plasma -gal A activity and slightly reduced leukocyte enzyme activity.106 One study estimated the frequency of the D313Y allele to be 1 in 220 X-chromosomes, implying a 1 in 660 frequency in males.107


Variant forms of Fabry disease with significant residual enzyme activity, including those who may not develop any symptoms, may be particularly common in NBS, up to 1:3,100– 1:4600 male births, in one study.108 Taiwan has also established a NBS program for Fabry disease and identified 42 male and 3 female infants with -galactosidase mutations of 110,027 screened for a prevalence of 1:2400 live births and 1:1600 male births.109 No data have been published regarding the sensitivity, specificity, false-positive rate, and positive predictive value of NBS for Fabry disease.

Therapy Enzyme replacement therapy. Two versions of recombinant human -galactosidase A (rhGAL): alfa (Replagal; Shire, Cambridge, MA) and beta (Fabrazyme; Genzyme Corporation) have been developed. Results for clinical trials conducted on both versions have been published; in the United States, only rhGAL beta was approved for treatment of Fabry disease, whereas, both forms are available in Europe, Australia, and Canada.110–113 ERT with rhGAL is the standard of care for symptomatic patients with Fabry disease.86,114

ERT with rhGAL significantly reduces plasma GL-3 and tissue GL-3 storage in myocardium, kidney, and skin. Those treated with rhGAL also demonstrated significant reduction in pain scores.115 Subsequent studies have indicated that ERT also stabilizes renal function if initiated in patients with urinary protein excretion 1 g/24 hours. ERT also slows progression of renal insufficiency in those with significant proteinuria, improves pulmonary and gastrointestinal symptoms, and reduces renal, cardiac, and CNS events.116–122 Women treated with ERT demonstrated reduced left ventricular hypertrophy as well as plasma and urinary GL-3123. ERT in children also reduced plasma and urinary GL-3 levels.124 However, ERT cannot completely mitigate valvular disease, acroparesthesias, and risk for cerebrovascular accidents.

Adjunctive therapies such as statins and aspirin for reduction of thromboembolic risk factors, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers for treatment of proteinuria and hypertension, and various antiepileptic medications for the treatment of neuropathic pain are recommended as part of the comprehensive care of a patient with Fabry disease.86

Pharmacologic chaperone therapy. Clinical trials are being conducted in selected patients with missense GLA mutations using a competitive inhibitor of the -gal A enzyme. In low concentrations, this inhibitor stabilizes misfolded (but functional) -gal A as the enzyme is synthesized in the endoplasmic reticulum of the cell, allowing for transport into the lysosome where it can properly degrade GL-3.

Recommended follow-up procedures

Diagnostic confirmation.

A suggested diagnostic algorithm is presented in Figure 2.

1. NBS will detect primarily hemizygotes; because of the variability in -gal A enzyme activity in heterozygotes, it will likely fail to detect a substantial percentage (40– 60%) of female infants with Fabry disease.98,125

a. Because of this variability, any females identified by NBS will need molecular testing for confirmation.

b. A male infant who screens positive for Fabry disease should have confirmatory testing performed by analyzing leukocyte -gal A enzyme activity.

2. If the enzyme activity is low (in males) or a GLA mutation is found (in females), the infant should be referred for evaluation and genetic counseling at a metabolic center.

3. Confirmatory GLA sequencing should be performed in any male infant with low -gal A enzyme activity, given the predicted high frequency of the D313Y pseudodefi- ciency allele.

a. A detailed pedigree should be constructed to determine at-risk family members and testing offered, because most mutations are familial. If a mutation is not identified, pedigree analysis, measurement of biomarkers such as urinary GL-3, and molecular examination for deletions may clarify the patient’s status.

Clinical follow-up and intervention.

Management recommendations for ERT initiation and multidisciplinary follow-up have been published for both pediatric and adult Fabry patient.86,126 Once the diagnosis of Fabry disease has been confirmed:

1. Baseline diagnostic studies (ECG, echocardiogram, ophthalmologic examination, renal function tests, plasma and/or urine GL-3) should be obtained. Affected members identified as a result of screening should also undergo identical evaluations; adults should also undergo additional testing as recommended.86

2. In global practice, there is wide variability in the usage of ERT even for hemizygotes, with some starting therapy at a young age even without symptoms and others waiting until end organ damage is evident. The decision to initiate ERT should be made according to the clinical judgment of the managing metabolic physician in conjunction with the family of the patient.

3. The infant should be seen by the metabolic specialist at 6-month intervals and monitored for onset of Fabry symptoms.

Gaucher disease


GD type 1, Nonneuronopathic GD (OMIM# 230800); GD type 2, acute neuronopathic GD (OMIM# 230900); GD type 3, chronic or subacute neuronopathic GD (OMIM# 231000); acid- -glucosidase deficiency.


GD is the most common lysosomal storage disorder, characterized by lysosomal accumulation of undegraded glucosylceramide because of deficiency or insufficient activity of the enzyme acid- -glucosidase (glucocerebrosidase, glucosylceramidase, EC GD is a pan-ethnic disorder. Estimates concerning disease prevalence in the general population vary between 1:40,0003 and 1:60,000.128 In the Ashkenazi Jewish population, particularly, a high number of patients are observed with a calculated disease prevalence of approximately 1:800.10 As a very rare variant, GD can also be caused by a deficiency of the nonenzymatic sphingolipid activator protein SAP C (or saposin C).129–132 

Clinical phenotype

Based on characteristic patterns of clinical signs and age of onset, GD is subdivided into three main disease variants: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic).10 Although this categorization facilitates clinical management to a certain degree, it is important to realize that GD, like other lysosomal storage disorders, consists of a continuous spectrum of disease variants with “asymptomatic” and less severely affected type 1 patients at one end and severely affected type 2 and lethal in utero forms at the severe end of the clinical scale.1,3 A detailed list of subtype- and system-specific disease manifestations of GD is given in Table 2.

In general, the type 1 patients who present in childhood tend to have more pronounced visceral and bony disease manifestations than those that present in adulthood.127 Type 1 patients can experience growth retardation, delayed puberty, leukopenia, impairment of pulmonary gas exchange, and destruction of vertebral bodies with secondary neurologic complications.10 There is an increased risk for multiple myeloma133 and Parkinson disease.134

Some authors have proposed a subdivision of type 3 GD into three variants, depending on the most prominent disease symptoms. Variant 3a is characterized by rapidly progressive neurological manifestations (oculomotor apraxia, cerebellar ataxia, spasticity, refractory myoclonic seizures, and dementia) with variable visceral symptoms, whereas the 3b variant shows more pronounced visceral and bony symptoms with less severe, slowly progressive CNS involvement. A “3c” variant has been reported primarily in patients of Druze descent, with mild visceral disease, slowly progressive neurological manifestations, and unique to this subtype, cardiac valvular calcifications and corneal opacities.10,127

Current diagnostics

Biochemical markers. GD is most commonly diagnosed by demonstrating insufficient acid--glucosidase enzyme activity in peripheral blood leukocytes or DBSs on filter paper. Alternatively, cultured skin fibroblasts or, in the case of prenatal diagnosis, amniotic fluid cells and chorionic villi can be used as tissue source.10 The measurement of -glucosidase cannot reliably predict the disease phenotype or identify heterozygotes for GD.10,127 In addition, patients with saposin C deficiency will be missed by determination of -glucosidase enzymatic activity.129,131,135 

Abnormally low enzymatic test results can be further corroborated by the demonstration of increased glucosylceramide levels.136 Reflecting the high levels of macrophage activation in GD patients, chitotriosidase137 and CCL18/ PARC/MIP-418138 show moderate to massive elevations in almost all patients. Although these biomarkers are not specific for GD and cannot be used to predict the subtype, their increase is usually far more pronounced than in other disorders with macrophage involvement. Apart from their role as supportive diagnostic tool, they can be used to monitor the efficacy of specific therapies (see below), although the correlation between the level of each biomarker and severity of active disease is limited or at least a matter of debate.10 However, 5–6% of all GD patients are homozygous for a common 24-bp deletion in exon 10 of the chitotriosidase gene, which renders the enzyme inactive.139 Alternative ancillary biomarkers comprise increased activities/concentrations of tartrate-resistant acid phosphatase, angiotensin converting enzyme, and plasma ferritin.10,128

Molecular analysis. Sequencing of the GBA gene is the definitive method to diagnose GD. Within the Ashkenazi Jewish population, four common mutations (p.N370S, p.L444P, c.84insG, and c.IVS2 1) account for 90% of the disease-causing alleles; these same mutations account for 50–60% of disease causing alleles in non-Jewish patients.10 The p.L444P mutation accounts for nearly all disease-causing alleles in the Norrbottnian Swedish population, and the p.D409H mutation is responsible for the GD type 3c found in Druze kindreds. Recombinant (Rec) alleles contain several point mutations (including p.L444P) that arise as a result of gene rearrangements between GBA and a nonfunctional GBA pseudogene. Therefore, targeted mutation analysis of the p.L444P mutation cannot distinguish between isolated p.L444P mutations and Rec alleles, potentially leading to errors in genotype designation. A more detailed list of genotype-phenotype associations is given in Table 3. There are no known pseudodeficiency alleles for acid -glucosidase. 

Ascertainment NBS programs for GD are expected to begin this year in at least two states in the United States. Given the high carrier frequency in Ashkenazi Jews, population-based prenatal carrier screening and testing of at-risk individuals in GD pedigrees have identified children and even identified older, currently “asymptomatic” GD type 1 individuals.


GD type 1. To date, two options are available for the specific therapy of patients with GD type 1. The reference treatment is ERT and it was GD that served as model disease to establish the efficacy of this therapeutic approach.10 The proof of concept studies date back to the early 1990s and used a modified human placental enzyme (alglucerase) to restore GBA activity in patients with GD.140–142 In 1993, the recombinant successor enzyme (imiglucerase; recombinant human GBA; Cerezyme, Genzyme Corporation) was introduced and numerous studies document safety and efficacy concerning major peripheral symptoms within the first year of treatment, whereas the response to bone abnormalities is less effective and may take at least several years.10,143–145 Approximately 15% of treated patients develop IgG antibodies against the recombinant enzyme and approximately half of these patients show mild to moderate allergic adverse events, particularly during the first year of treatment.10 In the majority of patients, antibodies disappear when ERT is continued with the same dosage,126,146,147 and only a few patients develop therapy-limiting inhibitory antibodies.10 A second form of ERT for Gaucher was recently approved for use (velaglucerase alfa, VPRIV; Shire, Wayne, PA).148 Finally, a third ERT product is being studied (taliglucerase alfa, UPLYSO; Protalix Biotherapeutics, Carmiel, Israel).149

An alternative to ERT is SRT with N-butyl-deoxynojirimycin (Miglustat; Zavesca; Actelion Pharmaceuticals, Basel, Switzerland).16,17 SRT was shown to be effective concerning hepatosplenomegaly, anemia, and thrombocytopenia; by contrast, improvements of bone disease were delayed and limited.144,150 Comparison of independent dose finding studies of both drugs suggest that SRT is similarly effective as a low-dose treatment with ERT, but less effective than standard- or high-dose enzyme replacement.127 Therefore, SRT is currently only recommended as second-line therapy for adult patients with GD type 1, which either show severe side effects on ERT or refuse to receive ERT at all and have mild to moderate disease.127 The profile of adverse effects on SRT comprises mild to moderate diarrhea (85–90% of patients), which usually resolves within the first year of treatment and is amenable to dietary changes and drug treatment, an initial weight loss of 6–7% (60% of patients), (sensory) peripheral neuropathy, transient tremor (30%), and possibly cognitive impairment.

GD types 2 and 3. Because of its rapid clinical progression, there is no specific therapy available for patients presenting with a GD type 2 phenotype. For patients with GD type 3, several therapeutic approaches have been tested in the past. In the pre-ERT era, a number of patients underwent HSCT, but long-term results have been poor.10,151 In conjunction with the significant mortality risk associated with this treatment, HSCT is no longer recommended or performed for type 3 GD

When ERT was established, studies with standard and highdose treatment were performed despite the fact that only trace amounts of the currently used enzyme preparation cross the intact BBB, if at all.152 The results were heterogeneous: some authors observed beneficial effects and an overall deceleration of mental and neurological deterioration,153 whereas others could not demonstrate any significant therapeutic influence on the natural course of the neurological symptoms.154,155 Notably, no study showed any advantage of high-dose regimens when compared with the standard treatment.154,156 Finally, studies combining ERT and SRT were initiated, based on the rationale that miglustat passes the BBB.157 Again, the results were ambivalent. Two case studies revealed stabilization158 or even improvement153 of neurological signs in symptomatic patients with GD type 3 and, over a 3-year observation period, demonstrated prevention of further neurological manifestations in a young child whose only initial manifestation was disturbed saccadic eye movements.158 By contrast, a multicenter study investigating the efficacy of a combination treatment in a bigger patient cohort was recently terminated ahead of schedule as a result of disappointing intermediate results.

Future therapeutic approaches

Phase II clinical trials of a small molecule chaperone for acid -glucosidase (Amicus Therapeutics, Camden, NJ) were recently completed, with disappointing results. A phase II clinical trial with another SRT (Genz-112638; Genzyme Corporation) aims to reduce the profile of side effects and has recently completed its primary endpoint. Further studies are ongoing.

Recommended follow-up procedures

Diagnostic confirmation. A suggested diagnostic algorithm is presented in Figure 3.

1. Leukocyte acid -glucosidase enzymatic activity repeated.

2. If the GBA activity is low on the repeat specimen, GBA molecular confirmation and further evaluations should occur at a metabolic center as per the published recommendations159–163 (

Clinical follow-up and intervention. Guidelines for the treatment of pediatric, adult, and female pregnant patients with GD type 1, and patients with GD type 2 have been published159–163 (https:// After confirmation of, and genetic counseling regarding the GD diagnosis:

1. Evaluations for anemia/thrombocytopenia, hepatosplenomegaly, and bony involvement should be performed.

2. For patients predicted to have neuronopathic GD, or for patients whose genotype cannot accurately predict phenotype, the degree of neurological impairment should also be assessed.

3. Gaucher biomarker and anti-GBA antibody levels should be measured before initiation of ERT.

a. Type 3 GD patients should be started on treatment immediately;

b. Treatment in type 1 GD patients should begin if two or more manifestations listed in the Table 2 are present.159

c. Because of the lack of currently effective treatment for type 2 GD, only supportive care is recommended at this time.

4. Infants should be monitored at regular intervals (at least quarterly) to assess response to treatment and for development of additional Gaucher manifestations that may require additional interventions.

Krabbe disease (OMIM# 24520)

Synonyms Globoid cell leukodystrophy.


KD is caused by the deficiency of galactocerebrosidase (GALC; EC, a lysosomal -galactosidase that is responsible for cleavage of galactosyl moieties from a variety of substrates including galactosylceramide, monogalactosyldiglyceride, and psychosine.164 The name “globoid cell leukodystrophy” derives from the storage of myelin fragments and galactosylceramide in multinucleated macrophages (globoid cells) around blood vessels of affected white matter. KD is inherited as an autosomal recessive trait and more than 70 mutations, including missense, nonsense mutations, and small deletions in the GALC gene have been identified to date.164,165 The resulting clinical phenotype is due to progressive damage of the white matter of the peripheral and CNSs and comprises a spectrum from early infantile KD (EIKD) to late-onset KD (LOKD).166 The incidence of KD in Europe and the United States is estimated to be 1:100,000 newborns.166,167 Based on these data before the onset of NBS for KD in New York, it was estimated that close to 90% of patients with KD may have the infantile form of disease. However, based on the data from the New York State NBS Program, the overall incidence of KD is approximately 0.91:100.000 and 0.26: 100,000 for EIKD based on the New York State case definition criteria (personal communication, JJ Orsini, 2009).168

Clinical phenotype

Early infantile-onset KD. Infants with EIKD typically present within the first months of life with progressive irritability, spasms upon noise stimulation, recurrent episodes of unexplained fever, blindness, and deafness.166,169 The disease course is rapidly progressive, leading to frequent seizures, hyperpyrexia, hypersalivation, complete loss of social contact, and loss of bulbar functions. Death typically occurs within the first 2 years of age because of respiratory complications.166 Peripheral neuropathy is always present in EIKD but may not be observed in LOKD. A detailed description of the natural history of KD from the Hunter’s Hope Krabbe Family Database has been recently reported.170

Late-onset KD. Visual impairment, ataxia, and irritability, respectively, may be the first presenting symptoms in LOKD although age of onset may be highly variable.171 All patients with EIKD show abnormal nerve conduction studies (NCSs), whereas approximately 90% of patients with EIKD have abnormal brainstem auditory evoked responses (BAER), 65% have an abnormal electroencephalogram, and 53% have abnormal flash visual evoked potentials (VER).169,172 In contrast, only a small percentage of patients with LOKD show abnormal neurophysiologic studies.172 Cranial magnetic resonance imaging (MRI) may show demyelination of white matter without any sign of peripheral nerve involvement.173 Diffusion tensor imaging studies may help to identify early involvement of motor tracts in asymptomatic neonates with KD.174

Current diagnostics

Biochemical markers. Diagnosis of KD is made by demonstration of low GALC activity in leukocytes or DBSs.164 Molecular analysis. Confirmation of the diagnosis can be made by molecular analysis of the GALC gene.164,165 Genotypephenotype correlation is limited and may only be possible if the clinical impact of a particular genotype is known in a larger set of patients with KD.165,175 In principle, homozygosity for the 30-kb deletion may predict EIKD.166 Occasionally, patients with LOKD carry two severe mutations that abolish enzyme activity completely.176 There is variability in presentation even with the same genotype.167


New York State Laboratories, Wadsworth Center Albany, New York, started NBS for KD using MS/MS technology in August 2006. Through June 2009, 769,853 newborn infants were screened (personal Communication, JJ Orsini, 2009).51,177,178 Out of a total of 140 recalls (recall rate 0.018%), two infants were identified to have EIKD and were transplanted; one died of transplant complications. Five additional infants were confirmed to have low enzyme activity but were not transplanted and are currently followed up very closely. An additional 13 and 36 infants were found to have moderately low or borderline low enzyme activity, respectively. All infants identified with low enzyme activity are being followed up by the Krabbe Disease Consortium in New York State.178


The only therapy at present is early allogeneic hematopoietic stem cells (HSCs) or cord blood transplantation.179,180 Escolar et al.180 reported on the use of cord blood transplantation after myeloablative chemotherapy in 11 asymptomatic newborns and 14 symptomatic infants with EIKD. Presymptomatic infants before transplantation continued to show psychomotor development and gain of milestones. Symptomatic infants only showed minimal neurologic improvement after transplantation.180 A review of 25 cases of presymptomatic infants transplanted for EIKD from different transplant centers from the United States and Canada demonstrated an overall mortality rate of 15%.168 Despite successful engraftment, most transplanted infants developed signs of neurological disease related to KD.168

Recommended follow-up procedures

Diagnostic confirmation. The diagnosis should be confirmed by demonstrating (1) GALC deficiency in leukocytes and (2) mutation analysis of the GALC gene. Clinical follow-up and intervention

1. Early (preferably younger than 30 days of age) bone marrow/stem cell transplantation from cord blood should be considered in any case predicted to have EIKD (e.g., homozygosity for the 30-kb deletion, compound heterozygosity for the 30-Kb deletion, and another severe mutation with very low GALC activity). In most cases, the genotype cannot predict phenoytype.

2. Other individuals requires follow-up at regular, 6–12 monthly intervals.

3. Although there are no data on the appropriate follow-up studies, they could reasonably include the following: (a) neurologic examination, (b) cranial MRI, (c) neurophysiologic studies (BAER, VER, electroencephalogram, and NCS), (d) lumbar puncture (for cerebrospinal fluid protein), if subtle neurological signs are present, and (e) diffusion tensor imaging studies that may help to identify early involvement of motor tracts in asymptomatic neonates with KD.174

Metachromatic leukodystrophy (OMIM# 250100)

Synonyms Arylsulfatase A (ARSA) deficiency.


Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by insufficient enzymatic activity of ARSA (E.C. This enzymatic defect results in moderate to massive accumulation of sulfated glycolipids, in particular, galactosylceramide-3-O-sulfate (sulfatide), in the brain, peripheral nervous system, and kidneys.181,182 Although the age of onset and dynamics of disease progression vary, MLD is primarily characterized by progressive neurodegeneration of the central and peripheral nervous systems.

MLD is a panethnic disorder; depending on the population studied, incidents estimates for the most common subtype, late infantile MLD, vary considerably between 1:40,000 (Sweden, Washington State) and 1:170,000 live births (Germany).183 Of note, certain ethnic populations show significantly higher incidence rates such as the Habbanite Jewish population (1:75), Alaskan Eskimos (1:2500), and Navajo Indians (1:6400).183

Two other biochemical defects have been identified that result in a MLD or MLD-like phenotype. Several patients described with a MLD phenotype were found to have a defi- ciency of the nonenzymatic sphingolipids activator protein saposin B (OMIM# 249900).184–186 Multiple sulfatase deficiency (MSD), caused by mutations in the sulfatase activator enzyme sulfatase modifying factor 1 (SUMF1) (OMIM# 272200), not only results in progressive demyelination of the central and peripheral nervous systems but is also accompanied by ichthyosis and features of MPS.182,183

Clinical phenotype

Based on age of disease onset, MLD has been divided into three main subtypes: late infantile, juvenile, and adult MLD. As in other lysosomal storage disorders, this classification facilitates clinical management but ignores the fact that MLD comprises a phenotypic continuum. The phenotypes and natural histories of each subtype are summarized in Table 4. Although disease progression in late infantile MLD is more uniform in both presentation and dynamics, the juvenile and adult forms are considerably more variable. Patients with the latter two types may manifest with primarily neurologic symptoms of clumsiness, gait disturbance, worsening of coordination, and fine motor skills, or with primarily psychiatric symptoms of bizarre behaviors, emotional lability, personality changes, or even psychotic episodes. Although disease progression toward complete loss of all cognitive skills and function is observed in most patients, some experience periods of disease stability punctuated by episodic deterioration.182

Sulfatide deposition occurs in the gallbladder, leading to papillomatous transformation that can be noted on abdominal ultrasound. Cerebrospinal fluid protein levels are generally increased, exceeding 50 mg/dL, in most MLD cases except the adult onset type. BAER and VER testing demonstrate impairment of hearing and vision. NCS velocities are slowed, reflecting peripheral demyelination and neuropathy. Demyelination of the CNS is evident on brain MRI initially as symmetric, nonenhancing periventricular and subcortical T2 white matter prolongation. With disease progression, cortical atrophy and ventriculomegaly become apparent. A scoring system for MRI has been developed for MLD.187

Current diagnostics

Biochemical markers. Deficient or insufficient residual activity of ARSA in peripheral blood leukocytes or cultured fibroblasts are a necessary, but not sufficient, condition for the diagnosis of MLD. ARSA “pseudodeficiency” is a relatively common variant that is found in 1–2% of the European and Euro-American individuals who have 5–15% of normal ARSA enzymatic activity but no sulfatide excretion or evidence of pathologic storage. These individuals never develop any disease-related clinical symptoms throughout their lives.188,189 Because of the high prevalence of ARSA “pseudodeficiency,” any positive biochemical test result must obligatorily be corroborated by a second analytical test system, such as ARSA sequencing or measurement of urinary sulfatides (or molecular analysis), because patients with all types of MLD excrete increased levels of these compounds.182,190,191 Enzymatic assays using artificial substrates are inappropriate to predict possible disease phenotypes.183 Although MLD can usually be distinguished from MSD based on phenotype alone, the measurement of a second sulfatase enzyme activity should be considered. In contrast to other lysosomal storage disorders, no other biomarkers are currently available for MLD.

Molecular analysis. The diagnosis of MLD can also be con- firmed by molecular genetic analysis of the ARSA gene. To date, more than 140 disease relevant mutations have been identified (for details, see the Human Genome Mutation Database http:// ARSA). Several recurrent mutations have been observed that account for up to 60% of disease-relevant alleles in certain populations.182,183,192 ARSA mutations characterized in more detail have been divided into two groups: (1) “null alleles” such as c.459 1ga (25% of disease alleles) and c.1204 1ga that result in complete loss of enzymatic activity and (2) “R alleles” such as p.P426L (25% of disease alleles) and p.I179S (12.5% of disease alleles) that allow the synthesis of ARSA enzyme with residual catalytic activity of up to 5% of normal.182,193 Based on this classification, genotype-phenotype correlations have been proposed194 and further corroborated192,195,196 to predict, in limited fashion, the clinical presentation and natural history (see Table 5). Although the predictive value of this correlation is excellent for patients homozygous for two null alleles, patients with one and two R alleles show considerable phenotypic variability, implicating other genetic and/or environmental factors that contribute to the disease course.182,183,192 Consequently, reliable prognostication in these cases is not possible.  

To date, two pseudodeficiency-related sequence variations have been identified that can occur independently or together in cis. One, c.*96AG, destroys the polyadenylation signal 95 bp downstream of the translation termination codon197,198 and results in a markedly decreased synthesis of a catalytically normal enzyme. The other, p.N350S, abolishes the N-glycosylation site of the ARSA enzyme and causes aberrant targeting of the protein away from the lysosome.198

Ascertainment To date, one high-throughput screening system for the reliable detection of ARSA deficiency in DBS has been proposed, but no NBS programs have actually begun to screen for MLD.199 A high false-positive rate is anticipated as a result of the high prevalence of pseudodeficiency alleles in many populations and will be problematic for any MLD NBS program. Given the high frequency of pseudodeficiency alleles, a homozygous pseudodeficient genotype is approximately 400 times, and a MLD/pseudodeficient genotype 30–50 times more common than a true MLD/MLD genotype.182


Late infantile MLD. Therapeutic options are at present very limited in MLD. For late infantile MLD, no approved specific therapy exists at all and treatment efforts are restricted to palliative and/or supportive measures including the prevention or delay of secondary complications.181,183,193 Early HSCT at a presymptomatic stage is completely ineffective and is not recommended.193,200

Juvenile and adult MLD. Because of the less rapid disease progression, HSCT has been established for several years as the only specific therapeutic option for juvenile and adult forms of MLD.181,201,202 Notably, HSCT harbors substantial risks and its real long-term effects are still unknown182,183. According to the current experience, when performed before onset of clinical symptoms, HSCT is able to stabilize cerebral demyelination and arrests or slows, disease progression in later-onset forms of MLD.182,201,202 On the other hand, HSCT does not arrest or ameliorate disease progression in the peripheral nervous system,201,202 and patients with successful HSCT have developed severe, peripheral neuropathy-related motor deficits several years after transplantation.193

Future therapeutic approaches

A number of alternative therapeutic concepts are currently being developed and investigated. Phase I studies of intrathecal recombinant human ARSA have been completed, and phase II studies are recruiting patients at the time of this writing. Other modalities include cotransplantation of HSC and mesenchymal stem cells,203,204 umbilical cord blood transplantation,205,206 ex vivo HSC gene therapy, in vivo and cell-based gene therapies, and coexpression strategies with recombinant ARSA and the formylglycine-generating enzyme.181,193

Recommended follow-up procedures

Diagnostic confirmation. The high frequency of pseudodefi- ciency alleles must be kept in mind when counseling a family whose newborn has been screened positive for MLD or an individual detected because of a prior affected family member/ carrier screening in high-risk populations. Consequently, con- firmation of the diagnosis must include (1) analysis of urinary sulfatides and (2) ARSA gene sequencing.

Clinical follow-up and intervention.

1. Presymptomatically identified MLD patients should be followed at regular intervals by both a neurologist and a metabolic physician.

2. Those predicted to have juvenile and late-onset MLD should be referred for a HSCT evaluation, recognizing that even early HSCT is ineffective for peripheral demyelination.

3. Periodic brain MRI imaging to monitor the status of CNS demyelination should be performed to allow for scoring and monitoring of response to therapy.

Care of late infantile MLD patients is currently limited only to palliative and supportive measures. Given the frequency of null alleles and the lack of treatment for the potentially high percentage of newborns to be identified with the late infantile type, it is questionable whether NBS should be considered for this disorder at the present time.

Niemann-Pick disease, types A (OMIM# 257200) and B (OMIM# 607616)


Lysosomal acid sphingomyelinase deficiency, sphingomyelin lipidosis


Deficiency of lysosomal acid sphingomyelinase (ASM; E.C., encoded by the sphingomyelin phosphodiesterase-1 (SMPD1) gene, results in types A and B Niemann-Pick disease (NPA and NPB, respectively). Undegradeable sphingomyelin accumulates primarily in CNS neurons and reticuloendothelial cells. Collectively, both types occur in approximately 1 in 250,000 live births; NPA is seen more frequently and NPB less so in the Ashkenazi Jewish population with an incidence of 1:40,000 live births, whereas NPB is more common in individuals of Northern African descent.207

Clinical phenotype

Full details regarding symptomatology of NPA and NPB are given in Table 6. In general, NPA is characterized by neonatalonset disease, neurodegeneration, and early death.208 NPB has a more variable presentation, but age of onset is typically in later childhood or adulthood. Primary symptoms are related to hepatosplenomegaly and impaired pulmonary function due to accumulation of sphingomyelin in reticuloendothelial and pulmonary tissues.208,209 With a few rare exceptions, cognition is spared.211

Current diagnostics

Biochemical markers. ASM activity assayed from fibroblasts or leukocytes is 5% of normal controls in NPA patients and between 2% and 10% of normal in those with NPB.212 Because of the overlap in enzymatic activity between NPA and NPB, enzyme assay alone is unreliable in predicting phenotype. For similar reasons, enzyme activity cannot differentiate carriers from normal individuals. Postmortem studies in brains of patients with Niemann-Pick disease demonstrate markedly increased sphingomyelin levels in NPA and normal sphingomyelin in NPB.213

Affected patients may have increased serum transaminases, reduced fasting levels of high-density lipoprotein cholesterol, and increased low-density lipoprotein. Patients also demonstrate progressive anemia and thrombocytopenia. The characteristic finding in biopsy specimens from liver, lung, or bone marrow is the “foam cell,” a large cell of histiocytic origin that is swollen with stored lysosomal lipid. Infiltration and accumulation of foam cells into body tissues leads to the visceromegaly, pulmonary compromise, and marrow dysfunction seen in both forms of the disorder.

Molecular analysis. Sequencing of the SMPD1 gene is the most reliable method to confirm a diagnosis of NP. In the Ashkenazi Jewish population, three founder mutations p.R496L, p.L302P, and fsP330 account for more than 95% of mutant alleles and are associated with the NPA phenotype.207 Non-Jewish NPA patients generally have “private” SMPD1 mutations. NPB occurs in all ethnic backgrounds but is rarer in Ashkenazi Jews and more frequent in Northern Africans. The p.[Delta]R608 mutation predicts a NPB phenotype, even when found in trans with a NPA mutation,214 and is thought to be protective against cognitive impairment. A few other mutations are also thought to be neuroprotective.211 Individuals with at least one p.Q292K mutation had later-onset neurologic abnormalities such as mental retardation, expressive language delay, areflexia, and abnormal retinal findings.211 This mutation seems to be more prevalent in the Czech and Slovak populations.215 Ascertainment Early ascertainment is currently only through prenatal carrier or family-based testing. No pilot NBS programs have been established for NPA/NPB.


Hematopoietic stem cell transplantation. Allogeneic or cord blood stem cell transplantation is ineffective at preventing neurocognitive regression in NPA, despite full donor engraftment.216,217 Allogeneic stem cell transplantation was reported in three NPB patients.93,219–221 Significant transplant-related complications were reported in all patients: poor linear growth, inadequate weight gain, and chronic graft-versus-host disease requiring immunosuppressive therapy. One patient experienced hepatic veno-occlusive disease with her first HSCT, developed graft failure, and required a second HSCT.93 Although all three patients had normalization of leukocyte ASM enzyme activity, another patient experienced stagnation and regression of developmental milestones. At the time of the report, she was 18 years old, wheelchair bound, gastrostomy feeding dependent, with no verbal communication.219 All three showed resolution of pulmonary involvement and hematopoietic abnormalities and incomplete improvement in visceromegaly.

Enzyme replacement therapy. Clinical trials are in progress to determine the efficacy of ERT with recombinant human acid sphingomyelinase in patients with NPB (Clinical trials identi- fication number NCT00410566).

Recommended follow-up procedures

Diagnostic confirmation. A suggested diagnostic algorithm is presented in Figure 4. An infant with a positive newborn screen for NP should first have leukocyte ASM activity, transaminases, bilirubin levels, and lipid profile assayed. The infant and family should then be referred for evaluation and genetic counseling at a metabolic center. If the ASM activity is low, then SMPD1 gene sequencing should be obtained to determine the causative mutations. Mutations with clear phenotypic correlations will allow for prediction of type A or B disease. SMPD1 targeted gene sequencing should be recommended for any identified at-risk family members.

Clinical follow-up and Intervention. Once NP has been confirmed, the infant should be evaluated by an ophthalmologist with a dilated funduscopic examination. Plain radiographs of the chest and abdominal ultrasound should be performed at regular intervals to document the extent of pulmonary involvement and hepatosplenomegaly. The metabolic physician should evaluate the infant on a monthly basis, documenting weight gain, linear growth, pulse oximetry, and developmental progression. Eventually, the infant will need evaluation and regular follow-up by neurology and pulmonology as the disorder progresses. Because no curative treatment currently exists, only symptomatic and supportive care can be provided. Lipid lowering drugs (e.g., statins) are ineffective.

MPS type I

Synonyms MPS I-H, Hurler syndrome, severe MPS I (OMIM# 607014); MPS I-HS, Hurler-Scheie syndrome, intermediate MPS I (OMIM# 607015); MPS I-S, Scheie syndrome, attenuated MPS I (OMIM# 607016).


MPS I is caused by a deficiency of -L-iduronidase (EC, encoded by the IDUA gene. -L-iduronidase participates in the degradation of heparan and dermatan sulfate, two glycosaminoglycans (GAGs) found in nearly all body tissues. Consequently, -L-iduronidase deficiency results in a disease that involves multiple organ systems resulting from the accumulation of undegradable GAG material throughout the body. The population frequency of MPS I is estimated to be approximately 1 in 100,000 births, with MPS I-H the most common and MPS I-S the rarest of the subtypes.222,223 MPS I-H is especially common in the Irish Traveler population, with an incidence of 1 in 371 live births.223

Clinical phenotype

Disease manifestations of MPS I span a continuum of severity and age of onset, with Hurler syndrome representing the most severe end of the clinical spectrum with the earliest onset and presence of neurocognitive regression, Scheie syndrome the attenuated end of the clinical spectrum with later age of onset, and Hurler-Scheie syndrome used to describe patients with intermediate disease severity and symptom onset. A detailed list of subtype and system-specific disease manifestations of MPS I is given in Table 7. Emphasis must be made on the nonuniform nature of symptom severity; in other words, a patient with “intermediate” MPS I based on lack of cognitive involvement may have severe orthopedic disease and cardiac valvular dysplasia, for example.

Current diagnostics

Biochemical markers. -L-iduronidase activity in MPS I is markedly reduced compared with normal controls. As a general rule, patients with MPS I-H have undetectable -L-iduronidase activity whereas patients with MPS I-HS and MPS I-S have residual -L-iduronidase activity. Evidently, as little as 0.4% of normal enzyme activity is sufficient to produce a mild phenotype.224 Enzymatic activity alone is unreliable for prediction of phenotype because some MPS I-H patient fibroblasts had more enzyme activity than those from MPS I-HS patients; similarly, there were MPS I-HS cell lines with more activity than MPS I-S cells.224,225 Enzymatic analysis is also insufficient for carrier testing because of overlap in activity between normal individuals and heterozygotes.19

Molecular analysis. Certain IDUA mutations allow for prediction of the phenotype. Homozygosity or compound heterozygosity for the p.Q70X and p.W402X nonsense mutations predict a MPS I-H phenotype. p.Q70X and p.W402X are also the two most common mutations in Caucasian MPS I patients, accounting for 60–70% of mutant alleles in those populations.226 The presence of two nonsense mutations is predictive of a MPS I-H,226 although one 20-year-old homozygous p.W402X patient was described as having MPS I-S without further description of her phenotype.227 The p.R89Q missense and the c.678-7ga (IVS5-7ga) splice site mutations predict a mild phenotype.228–232 All three subtypes of MPS I have been reported in patients with the homozygous p.P533R mutation; both MPS I-H and MPS I-HS have been reported with p.P533R compound heterozygotes with other “severe” mutations.226 A rare p.A300T pseudodeficiency allele has been reported in one family.233 


Early ascertainment is currently only accomplished through family-based testing. As of yet, no NBS programs for MPS I have been established.


ERT for MPS I-HS and I-S. Results for clinical trials with recombinant human -L-iduronidase (laronidase) (rhIDU, Aldurazyme; Genzyme Corporation) have been published.234,235 Weekly ERT with 0.58 mg/kg/dose of rhIDU improved forced vital capacity and reduced symptoms of airway obstruction, apnea/hypopnea index, and duration of nighttime desaturation episodes. Exercise tolerance was increased, as patients receiving laronidase had significant improvement in the distance traveled during the 6-minute walk test compared with placebo. Liver and spleen volumes were reduced to near normal levels. Patients also demonstrated improvement in weight gain and linear growth velocity. Some improvement was also seen in restriction of joint mobility.234 A similar efficacy profile was noted in MPS I-H patients receiving ERT.235 Urinary GAG excretion was reduced by 55–60% to levels at or below the upper limit of normal.235,236 ERT does not seem to adequately treat the orthopedic manifestations of MPS I, especially with regard to spinal cord compression and vertebral dysplasia. Clinical trials are underway to determine whether intrathecal rhIDU infusion is effective for these manifestations (Clinical Trials identification number NCT00215527). Nearly all patients developed IgG antibodies to laronidase. Development of antibody was not associated with changes in urinary GAG levels, and titer levels decreased with continued infusions. Adverse effects of laronidase infusion were usually infusion reactions (flushing, fever, and headache) or anaphylactoid reactions (urticaria, rash, nausea, abdominal pain, and edema) and were managed by temporary reduction in infusion rate and administration of antihistamine and antipyretic medication.

ERT and HSCT for MPS I-H. Multiple studies documenting neurodevelopmental and somatic disease outcomes after HSCT for MPS I-H have been reported.237–245 Although HSCT creates significant morbidity stemming from postconditioning immunocompromise, pneumonitis, graft-versus-host disease, and hepatic veno-occlusive disease, and is subject to graft failure or chimerism, it is currently the only known treatment modality that prevents mental retardation. Survival and engraftment rates have steadily improved to 85–90% in recent series.240–245 One series saw no effect of pre-HSCT ERT on survival or engraftment,244 whereas another noted a reduction in pulmonary complications and successful engraftment and survival of all seven patients treated with combined therapy.245 Other groups eschew ERT before transplant unless the patient has significant cardiopulmonary disease, citing the possibility of anti--iduronidase antibodies interfering with successful engraftment.

HSCT performed before 24 months of age and the onset of significant developmental delay (developmental quotient 70) has the highest probability of rescuing neurocognitive outcome; engrafted survivors may experience speech delay and learning disability.238–241,246 Good developmental outcomes have been reported in “late” transplants, and some “early” transplant patients have significant developmental delay. Stem cell transplant from donors without IDUA mutations seems to correlate with higher levels of posttransplant -L-iduronidase activity, GAG clearance, and better developmental outcomes than stem cells from heterozygous MPS-I donors.239,247

In addition to improvement of neurocognitive outcomes, HSCT successfully eliminates hepatosplenomegaly and glycosaminoglycanuria, improves joint mobility, slows development of cardiac valvular dysfunction, and reduces airway obstruction and frequency of otitis media.238,240 Coarse facial features “soften” with time. Outcomes for other parameters are mixed. Hearing loss remained in approximately half of patients. Some demonstrated resolution of corneal clouding, but others required corneal transplantation. Glaucoma developed in some patients as well.238,240 HSCT does not adequately treat the orthopedic complications of MPS I-H, presumably because of poor penetration of -L-iduronidase into growth plate cartilage. Cervical spine instability, progressive kyphosis, spinal cord compression, carpal tunnel syndrome, and painful hip dysplasia were present in nearly all transplanted patients and required orthopedic surgery intervention.238,240 Growth velocity is initially normal and slows down due to persistent vertebral body dysplasia.238,240,241 The final adult height is usually 1–3 standard deviations below the mean.238

Recommended follow-up procedures

Diagnostic confirmation. A suggested diagnostic algorithm is presented in Figure 5.

An infant who has a positive MPS I newborn screen should have the following: 1. Follow-up testing with leukocyte -iduronidase enzyme activity. If low -iduronidase activity, the infant should then be referred to a metabolic center for (a) further evaluation. (b) genetic counseling regarding the specific diagnosis, and (c) other subspecialty evaluations.

Clinical follow-up and intervention. Management of a MPS I patient requires a multidisciplinary approach; detailed, systemspecific guidelines for the treatment of MPS I have been published.248 In addition to regular follow-up by a metabolic specialist, patients should also have the following:

1. Evaluations from ophthalmology, otolaryngology, cardiology, orthopedic surgery, pulmonology, neurodevelopmental specialists, and pediatric neurosurgery as necessary.

2. Plain radiography will demonstrate a constellation of skeletal findings known as dysostosis multiplex: J-shaped sella turcica, “spatulate” ribs with anterior widening, wedge-shaped dysplastic biconcave vertebral bodies, shortened and rotated radius and ulna, proximal pointing of the metacarpals, and coxa valga. Severity of the dysostosis tends to correlate with disease severity.

3. Periodic audiometry.

4. Polysomnography.

5. Echocardiography.

6. Electrocardiography.

7. Abdominal ultrasound.

8. Imaging studies of the brain and spine.248

Follow-up and intervention of patients confirmed to have MPS I must ensure that those who are to develop severe disease receive HSCT early enough to preserve neurocognitive outcome, whereas those with milder disease do not receive HSCT unnecessarily.

Because α iduronidase enzyme activity level is unreliable for phenotypic prediction, and no current biomarkers are widely available for predictive purposes, treatment decision-making depends on genotype-phenotype correlations drawn from IDUA mutations. However, this method also has significant limitations. The p.P533R IDUA mutation accounts for 5–10% of mutant alleles; patients with p.P533R mutations have encompassed the entire MPS I disease spectrum. New IDUA mutations for which phenotypes have not been reported will also undoubtedly be discovered. These scenarios present a difficult challenge to management as secure prognostication of MPS I phenotype will be impossible. The experience gained from caring for patients in this category must be gathered to guide future treatment for future newborns diagnosed with unclear MPS I phenotypes

All confirmed infants with MPS I should have a detailed multidisciplinary initial evaluation as detailed in Muenzer et al.248 Further disease management is dependent on the predicted MPS I phenotype.

MPS I-H. If MPS I-H is predicted,

1. Hematology/oncology referral should be made to initiate the HSCT process.

2. Surgery referral, for implantation of a central venous catheter, should also be made.

3. Initiation of ERT should be made based on the clinical judgment of the coordinating metabolic specialist.

4. The infant should also have regular neurodevelopmental assessments performed to follow the developmental trajectory during and after the treatment process.

MPS I-HS and MPS I-S. Because the milder forms of MPS I have later symptom onset:

1. ERT does not need to be initiated immediately in the neonatal period.

2. Monitoring of the infant by the metabolic specialist at least every 3 months.

3. ERT should be initiated based on the clinical judgment of the specialist and discussion with the infant’s family. Similar to MPS I-H cases, ERT should be administered through peripheral venous access pending implantation of central venous access by the pediatric surgeon, if necessary. MPS I patients with mutations that are novel or unable to predict phenotype (such as p.P533R): 1. The infant should be monitored regularly by the metabolic physician and other subspecialists. 2. If possible, the patient should be evaluated for potential HSCT and, if a donor is found, “put on hold” for transplantation based on the developmental outcome of the patient. 3. Neurodevelopmental assessments should take place every 3–4 months.

4. HSCT performed if the infant is beginning to demonstrate markers of MPS IH such as developmental delay, severe organomegaly, and/or skeletal manifestations.

MPS type II (OMIM# 309900)

Synonyms Hunter Syndrome; iduronate sulfatase deficiency.


MPS type II is an X-linked MPS caused by a deficiency of iduronidate 2-sulfatase (IDS, EC, encoded by the IDS gene. Similar to -L-iduronidase, IDS is also involved in the breakdown of heparan and dermatan sulfate, catalyzing the enzymatic step prior to -L-iduronidase. Consequently, symptoms of MPS II are similar to MPS I, involving storage of GAG material in multiple organ systems. The population frequency of MPS II is estimated to be approximately 1 in 76,000–320,000 male live births.221,222

Clinical phenotype

Nearly all affected patients are male, but rare symptomatic females have been described.249 MPS II patients also display a spectrum of severity, but onset of symptoms is later and velocity of disease progression slower than MPS I. Patients with severe MPS II have cognitive regression and are typically diagnosed between 18 and 36 months. Attenuated patients are recognized between 4 and 8 years and have learning disabilities or normal intelligence, but no neurodegeneration.250,251 Patients with neurocognitive involvement tend to have difficult, aggressive behavior. Those with complex IDS gene arrangements are at higher risk for generalized tonic-clonic seizure disorders. Corneal clouding, if present, is visible only with slit-lamp examination and does not interfere with vision. Glaucoma is also a rare manifestation of MPS II. Patients may experience night blindness and papilledema due to GAG storage around the optic cup. A characteristic thickening of the skin with a “pebbly” appearance is seen in many patients. Ultimately, problems associated with upper airway obstruction, cardiopulmonary disease, and orthopedic sequelae are responsible for early death in MPS II patients.

Current diagnostics

Biochemical markers. The level of plasma IDS enzyme activity, while low in affected patients, cannot predict disease severity. Enzymatic analysis also cannot be used to determine carrier status.252,253 The enzyme requires activation via posttranslational modification of cysteine 59 to formyl-glycine. The enzyme that performs this modification is encoded by the SUMF1 gene; mutations in SUMF1 cause MSD. Therefore another sulfatase such as ARSA or arylsulfatase B (ARSB) should be concurrently assayed with IDS activity to assess for MSD.

Molecular analysis. The most common recurrent IDS mutations (20%) are gross rearrangements, most of which arise from recombination events with an IDS pseudogene.254–256 Most of these patients manifest the severe phenotype; those with extensive deletions demonstrate a contiguous-gene deletion phenotype and are more likely to develop seizures and other “atypical” symptoms.257

Very few recurrent point mutations have been reported; of those, genotype-phenotype correlations are difficult to draw due to the reports’ lack of complete phenotypic data and inconsistencies in defining severity of disease. Some reported “intermediate” patients as having mental retardation, whereas others did not.258,259 Individuals throughout the spectrum of phenotype severity have been reported for the p.A85T257,259–262 mutation. The p.P86L258,263 and p.R468Q258–260,262–265 mutations have all been reported with a “severe” phenotype. Although the p.R172X259,260,265–267 and p.R468W233,259,268,269 mutations are usually reported as “severe,” they have been associated with “intermediate”256 or “mild” phenotypes.270,271 The p.R443X mutation is generally reported as an “intermediate” phenotype, although the severity of cognitive involvement in most cases is uncertain.256,258,259,265,267,272,273


Hematopoietic stem cell transplantation. HSCT successfully eliminated hepatosplenomegaly, reduced cardiac valvular thickening, improved joint mobility, and normalized coarse facies.274–276 However, the major problem with HSCT for MPS II is its inability to preserve neurocognitive outcome277–282 and the high mortality rate. All HSCT cases for “severe” MPS II followed by the North American Storage Disease Collaborative Study Group demonstrated declines in IQ to below 50.283 These disappointing results, coupled with the development of ERT, do not make HSCT a currently acceptable treatment modality for any form of MPS II. However, citing the later age of the transplanted patients with “severe” disease, some groups are assessing the efficacy of early HSCT on MPS II patients whose older siblings manifested severe disease.

Enzyme replacement therapy. Results for clinical trials with recombinant human IDS (idursulfase, Elaprase™; Shire, Cambridge, MA) have been published.284,285 Weekly ERT with 0.5 mg/kg/dose of recombinant IDS improved forced vital capacity and increased exercise tolerance as measured by the 6-minute walk test. Of the patients with hepatosplenomegaly at baseline, 80% had normalized at the end of the 53-week trial. Overall, the weekly ERT group demonstrated 25% reduction in liver and spleen volumes. Significant improvement in elbow joint mobility was also demonstrated by those receiving weekly ERT. Urinary GAG excretion normalized in 40% receiving idursulfase, and the weekly group excreted 52% less from baseline. IgG antibodies to idursulfase developed in 47%. Although those with antibodies had a lower reduction in urinary GAG excretion, no differences in clinical outcomes were noted compared with those without antibodies. The percentage of patients with antibodies declined to 32% by the end of the pivotal trial. Infusion-associated reactions were similar to those experienced by MPS I patients receiving laronidase and also decreased in frequency after 12 weeks.


Early ascertainment is currently only through family-based testing. Currently, there are no NBS programs for MPS II.

Recommended follow-up procedures

Diagnostic confirmation. A suggested diagnostic algorithm is presented in Figure 6.

1. An infant who has a positive MPS II newborn screen should have confirmatory testing performed with simultaneous plasma IDS and leukocyte ARSA or ARSB enzyme activities. a. If only IDS is low, then genetic testing for MPS II should be performed. b. If both are low, then SUMF1 should be sequenced to confirm MSD.

2. Once a diagnosis of MPS II or MSD has been confirmed, then a metabolic evaluation with genetic counseling should be performed.

Identification of females. NBS programs will find female infants with low IDS activity. Confirmatory testing should also be performed:

1. To distinguish false positives from MPS II heterozygotes and MSD females.

2. Genetic counseling and careful review of the family pedigree to identify other at-risk family members should be performed.

3. MPS II heterozygotes should be followed periodically by a metabolic physician for reinforcement of recurrence risk counseling and monitoring for development of Hunter syndrome symptoms.

4. Because some heterozygotes have enzyme activity in the “normal” range, not all carrier females can be identified with NBS.253

Clinical follow-up and intervention. Management guidelines for patients with MPS II have been published.236

1. All confirmed MPS II boys should be referred for genetic counseling, multidisciplinary evaluations, and diagnostic studies similar to those for MPS I.

2. Regular neurodevelopmental assessments should be performed to follow the developmental trajectory.

3. The decision to initiate ERT should be made according to the clinical judgment of the metabolic specialist.

a. For a MPS II infant with severe disease, any discussion between specialist and parents about ERT initiation must include clear counseling about the inability to reverse cognitive outcomes. This is an extremely controversial issue, given the cost of ERT, its limitations, and the consequences of increasing mobility in a mentally retarded child with potential behavioral problems.

b. Clear parameters for discontinuation of ERT must also be delineated before initiation.

MPS type VI (OMIM# 253200)

Synonyms Maroteaux-Lamy Syndrome, ARSB deficiency.


MPS VI is caused by mutations in the ARSB gene that encodes N-acetylgalactosamine-4-sulfatase (ARSB, EC The incidence of MPS VI has been estimated to be approximately 1 in 300,000 live births.221 Affected individuals cannot adequately degrade GAGs that contain N-acetylgalactosamine-4-sulfate and consequently excrete increased levels of urinary dermatan sulfate.

Clinical phenotype

Age of presentation and velocity of disease progression are variable, but affected patients typically come to medical attention at 6–24 months of age with deceleration of growth velocity, macrocephaly, macroglossia, facial coarsening, and hepatosplenomegaly. Symptoms are similar to the somatic manifestations of severe MPS I, with progressive corneal clouding, openangle glaucoma, skeletal abnormalities, painful hip dysplasia, restriction in joint mobility, and cardiac valvular dysfunction. Otolaryngological complications include recurrent otitis media, conductive hearing loss, and upper-airway obstruction. Communicating hydrocephalus and spinal cord compression occur from accumulation of GAGs in the CNS.286 Cognitive development and intelligence are normal and primarily limited by physical impairment of motor skill acquisition and learning. Cardiopulmonary complications arising from infection or perioperative airway difficulties are the primary causes of premature death in early adulthood.

A severe neonatal form with coarse facies, dysostosis multiplex, and cardiac disease has been reported.287,288 Similarly, later-onset or attenuated forms of MPS VI have also been reported.289–291

Current diagnostics

Biochemical markers

Fibroblast or leukocyte ARSB activity in patients with MPS VI is generally 10% of the lower limit of normal, but amount of residual enzyme activity does not correlate with the severity of the phenotype.291 Enzymatic analysis permits the distinction between affected patients, mutation carriers, and normal individuals. ARSB requires posttranslational modification of cysteine 91 into formyl-glycine by sulfatase-modifying factor for catalytic activity. Therefore, activity of another sulfatase, generally ARSA and/or iduronate sulfatase, should be concurrently assayed with ARSB activity to exclude the possibility of MSD.

Molecular analysis

Although most patients carry at least one “private” ARSB mutation, some genotypes allow for prediction of phenotype. Patients with homozygous truncating mutations had severe phenotypes, as did patients with the p.R315Q, p.S384N, and p.L72R mutations, which accounted for 19.8% of all alleles discovered. Patients carrying at least one p.Y210C, p.C405Y, p.D83Y, p.R152W, or p.R434I mutation had attenuated phenotypes.292 No pseudodeficiency alleles are known.


Early ascertainment is currently only through familybased testing. No pilot NBS programs have been established for MPS VI.


Hematopoietic stem cell transplantation. Long-term follow-up of MPS VI patients who have undergone HSCT indicates efficacy in improving joint mobility, facial coarseness, obstructive sleep apnea, hepatosplenomegaly, cardiomyopathy, and possibly valvular thickening. No cervical cord compression was noted during the period of follow-up. The transplanted patients demonstrated progression of corneal opacity, continued short stature, and developed orthopedic complications (progressive kyphosis and carpal tunnel syndrome). HLA-identical donors were used in each case; all patients reported successfully engrafted, had reconstitution of leukocyte ARSB activity, and excreted less GAGs after transplant. Nonfatal graft versus host disease occurred in nearly all patients reported.293–295 Success with umbilical cord transplant has also been reported.296

Enzyme replacement therapy. Results of clinical trials for recombinant human arylsulfatase B (rhASB, Naglazyme; Biomarin Corporation, Novato, CA) have been published.297–299 The 1 mg/kg/week dose produced a greater reduction in urinary GAG excretion compared with the 0.2 mg/kg/week dose. Although visceromegaly in MPS VI is not as prominent as other types of MPS, the five (50%) patients with hepatomegaly in the 48-week open-label phase II trial demonstrated reduction in liver size, with four demonstrating normal age-weight adjusted liver size.298 In the same study, the three patients with the most severe abnormalities in nocturnal pulse oximetry experienced improvement in average oxygen saturation and decrease in time spent below 90% saturation. In the 24-week phase III doubleblind, randomized, placebo-controlled study, the rhASB group demonstrated a significant improvement in the 12-minute walk test distance compared with the placebo group. Urinary GAG excretion was reduced 75% from baseline in the rhASB group, whereas remaining essentially unchanged in the placebo group. Those treated with rhASB also demonstrated improvement in the 3-minute stair climb. No significant changes were observed in joint range of motion, energy level, and hand dexterity.299 Preliminary long-term rhASB observations show stabilization of left ventricular ejection fraction, reduced left ventricular wall thickness, and in patients initiated on rhASB therapy in the first year of life, improved linear growth. ERT does not seem to have an effect on corneal clouding or the development of cervical myelopathy (personal communication, P Harmatz, 2009).

Nearly all patients developed IgG antibodies to rhASB; one patient was found to have antibodies with neutralizing activity in vitro. Development of antibody was not associated with changes in urinary GAG levels. Adverse effects of rhASB infusion were usually infusion reactions (rigors, fever, and shortness of breath) or anaphylactoid reactions (urticaria, rash, nausea, abdominal pain, and edema) and were managed by premedication with antihistamines, antipyretics, or corticosteroids. One episode of apnea occurred that was attributed a combination of obstructive sleep apnea and sedation from diphenhydramine.

Recommended follow-up procedures

Diagnostic confirmation.   A suggested diagnostic algorithm is presented in Figure 7.

1. An infant who has a positive MPS VI newborn screen should have confirmatory testing with leukocyte ARSB and ARSA enzyme activity.

a. If ARSB activity is low and ARSA normal, ARSB gene sequencing should be performed to confirm the diagnosis of MPS VI.

b. If both sulfatase activities are low, MSD should be confirmed using molecular analysis of the SUMF1 gene.

2. Once the diagnosis of MPS VI or MSD has been con- firmed, the patient should then be referred to a metabolic center for evaluation and genetic counseling regarding the specific diagnosis.

Clinical follow-up and intervention.

Similar to the other types of MPS, a multidisciplinary approach is needed to care for a MPS VI patient.

1. All confirmed MPS VI infants should have a multidisciplinary baseline and follow-up evaluations as detailed in the management guidelines.300

2. A skeletal survey that includes flexion/extension views of the cervical spine, lateral view of the entire spine, and frog-leg view of the hips should be obtained.

3. An early orthopedic surgery referral should be made if a gibbus is present or imaging demonstrates vertebral anomalies that predict early development of kyphoscoliosis.

4. MRI of the brain and spine should be obtained to assess CNS involvement. Although airway compromise is less of a concern in an infant with MPS VI compared with an older child, the anesthesiologist or otolaryngologist securing the airway for the procedure must have experience in dealing with the potential airway challenges presented by the disorder.

5. The family should be counseled regarding the risks and benefits of HSCT versus ERT. If HSCT is desired, the patient should be referred to a hematology/oncology specialist for transplant evaluation. If they choose ERT, it should be initiated as soon as possible after confirmation of the diagnosis.

a. To obtain consistent venous access for the weekly rhASB infusions, the infant should be referred to a pediatric surgeon for placement of an indwelling central venous catheter.

b. While awaiting placement of central access, ERT using peripheral venous access should be given so that initiation of treatment is not delayed.

6. The infant should be followed regularly by the metabolic physician to document growth, development, and symptoms of MPS VI. Early identification of neonates with MPS VI involvement offers a unique opportunity to determine whether early initiation of treatment prevents or slows the progression of the serious somatic effects of the disorder.


Family-based studies and new technologies for NBS have made the diagnosis of presymptomatic individuals with LSD’s possible. These guidelines provide a framework for the initial evaluation and management of several disorders. There are significant limitations we faced in composing these guidelines. LSDs are rare and complex conditions. There is limited natural history data for most conditions and little long-term follow-up data on the efficacy of different therapeutic approaches. The evidence bases for these rare disorders are poorly organized and statistically weak. Efforts to capture diagnostic and long-term follow-up data to improve understanding are urgently needed. Biospecimen repositories are needed for future research studies of biomarkers, modifier genes, etc. In this regard, the creation of ACMG/NIH Newborn Screening Translational Research Network301 is timely and will play an important role in improving our knowledge base in the coming years. Patients with LSD often need multidisciplinary care that should ideally be provided through a team approach including medical genetics, hematology, cardiology, neurology, ophthalmology, anesthesiology, etc. As NBS for LSDs becomes more widespread, there will be an increasing need for physicians trained in the care of these patients, particularly biochemical geneticists. Laboratories used for enzymology and molecular diagnostics should be experienced and of high quality as evidenced by participation in quality assurance and proficiency testing programs. They should be capable of providing rapid turn-around of results (local laboratories are desirable).



Raymond Y. Wang, MD , Olaf A. Bodamer, MD, PhD , Michael S. Watson, MS, PhD and William R. Wilcox, MD, PhD

Lippincott, Williams and Wilkins


Disclaimer: This guideline is designed primarily as an educational resource for health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from this guideline.

Purpose: To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease. Methods: Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases. Results: Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI. Conclusion: These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic indivduals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network. Genet Med 2011:13(5):457– 484. Key Words: newborn screening, lysosomal storage disease, enzyme replacement therapy, presymptomatic, consensus guidelines

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Boutrid, Nada*; Rahmoune, Hakim; Bioud, Belkacem

Excellence in Pediatrics 2014


Introduction: Mucopolysaccharidosis type I is an autosomal recessive inborn error of metabolism characterized by accumulation of incompletely degraded glycosaminoglycans leading to systemic impairment. Our report presents the oro-dental and radiographic findings in 04 patients with MPS I.

Methods & Description: The examination of the Mucopolysaccharidosis type I affected children followed in our clinic reveals characteristic abnormalities such as hypoplastic peg-shaped teeth and dysplastic teeth and gingival hyperplasia. In all our patients, dental panoramic radiograph underlines these aspects.

Results & Discussion: The oral and dental findings of MPS I include hyperplastic gingiva, macroglossia, high-arched palate, short mandibular rami with abnormal condyles, spaced hypoplastic peg-shaped teeth with retarded eruption; and localized dentigerous cyst-like radiolucencies Guven et al.(Jan 2008) have investigated the ultrastructural and chemical properties of MPS I (Hurler) teeth: The dentin of the primary teeth was characterized by extremely narrow dentinal tubules with an irregular wave-like pattern. The enamel-dentin junction was poorly shaped, micro gaps occurred and the enamel displayed an irregular arrangement of prisms. The enamel and the dentin had an abnormal protein structure and the dentin protein content was low. The mucopolysaccharidoses (MPS) are a prominent subgroup among the lysosomal storage diseases. The intra-lysosomal accumulation of glycosaminoglycans (GAGs) in these disorders induces a cascade of responses affecting cellular functions and maintenance of the extra-cellular matrix.

Consclusion: As well as skeletal problems, mucopolysaccharidoses' patients have dental with specific deformities. Teeth involvement is highlighted, having an eye to the possibilities of reversing these oro-dental changes with enzyme replacement therapy .

University Hospital of Setif, Algeria

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Imrie, Jacqueline1; Mathieson, Toni*1; Evans, Miriam2; Green, Jim2

Excellence in Pediatrics 2014


An International Niemann-Pick Disease Alliance campaign to raise awareness amongst clinicians that may not be aware of the combination of symptoms that might suggest a diagnosis of NP-C. What is NP-C? Niemann-Pick Disease Type C is a progressive, irreversible and chronically debilitating lysosomal storage disease. It is caused by a defect in lipid transportation within the cell. This leads to intracellular accumulation of lipids in the brain, liver and spleen causing the symptoms of NP-C. NP-C is an inherited condition and can present at any age, affecting infants, children, adolescents and adults. The incidence of NP-C is approximately 1 in 120,000 live births. However, this is likely to be an underestimate due to a lack of clinical awareness of the disease and the difficulty in recognising NP-C because of its highly heterogeneous clinical presentation. NP-C is commonly undetected or misdiagnosed. This is often due to its highly variable clinical presentation characterised by a wide range of symptoms that, individually, are not specific to the disease. The journey to diagnosis can therefore be long and frustrating for patients and their families. The average delay in diagnosis is five to six years from onset of neurological symptoms. Why have a campaign? Currently Niemann-Pick type C disease (NP-C) takes, on average, five years to diagnose. However, NP-C is treatable and so this means that patients live for five years without treatment or access to support. Think Again. Think NP-C is a campaign led by the International Niemann-Pick Disease Alliance (INPDA), an alliance of non-profit Niemann-Pick disease patient support organisations across the world. Think again.Think NP-C The campaign will be launched in more than 10 countries with resources in more than 4 languages and involve International family support groups. The campaign aims to reduce the time to diagnosis by supporting healthcare professionals who are unfamiliar with NP-C to recognise the key signs and symptoms of the disease. This will help patients by speeding up diagnosis so patients can access treatment and support.

The campaign has an International advisory group from specialists in the field and is financially supported by Actelion  


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