Not All Alpha-Mannosidosis Look Severe: Recognizing Mild and Attenuated Forms in Everyday Pediatric Practice

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Introduction

Dr Karolina Stepien: Welcome to the next EiP webinar, dedicated to attenuated forms of alpha-mannosidosis. Today I'm here with Dr João Durães from Portugal. First, some housekeeping: please don't take screenshots, and please don't reproduce any of the slides, content or images without the express written permission of the speaker. The webinar will take 50 to 60 minutes — presentations followed by questions and answers. Questions can only be submitted via the chat, not asked verbally, and you can post them at any time during the presentations; we will answer them at the end. The webinar is recorded and will be available on the website.

My name is Karolina Stepien. I'm an adult metabolic consultant at Salford in Greater Manchester, and I'm here with Dr João Durães, an adult neurologist from Coimbra in Portugal.

What alpha-mannosidosis is

I would like to start by reminding you what alpha-mannosidosis is. It is an autosomal recessive lysosomal disorder caused by deficiency of the enzyme alpha-mannosidase. Deficiency of this enzyme affects the degradation of glycoproteins and causes progressive accumulation of mannose-rich oligosaccharides in various tissues and organs, primarily the central nervous system. This leads to impaired cell function and cell death (apoptosis).

The condition is very heterogeneous, and patients may manifest different symptoms, but all patients described so far have had a degree of intellectual disability. They may also manifest neurocognitive dysfunction and hearing problems — these are the primary, most prevalent features in childhood. Coarse facial features become more prevalent later in childhood and adolescence. Patients may have motor symptoms, which can be what leads to the diagnosis, as we'll discuss later. They may present with muscle weakness or large-joint problems, and hepatosplenomegaly can be seen as well.

The diagnosis is usually made by enzyme activity, which is reduced in leukocytes or other nucleated cells. It can also be supported by light microscopy showing vacuoles in lymphocytes, but the absence of this feature does not preclude the diagnosis. What is relevant for the cases we present is easy access to genetic testing, which may identify biallelic pathogenic variants in the MAN2B1 gene — genetic testing can be key to the diagnosis in these patients. Although a clear genotype–phenotype correlation has not been described, there have been studies attempting to correlate MAN2B1 variants with cognitive dysfunction, motor dysfunction and central nervous system pathology.

Three types — and a continuum

There are three main types of alpha-mannosidosis, although from a clinical and practical point of view it may be difficult to distinguish between them. Type 3 is the more severe form, with rapidly progressive central nervous system disease; patients may be diagnosed in infancy or early childhood, have severe and recurrent infections, and it often leads to death in childhood.

At the other extreme is a very mild form. Patients present well above ten years of age, with very slowly progressive muscle weakness and balance problems, and they may have skeletal abnormalities, with motor dysfunction coming later. There is also a moderate type, where patients develop symptoms overlapping types 3 and 1 around or before the age of ten, with a degree of skeletal abnormality. But the condition is clearly described as a continuum, because there is no clear distinction in symptoms or age of onset between the types. Hearing impairment and speech delay are hallmark symptoms of the severe and moderate forms early in childhood, while motor impairment and psychiatric symptoms are typical of the mild forms and more prevalent later, in adulthood.

Prevalence and differential diagnosis

The prevalence is estimated at one in 500,000 live births; according to other sources it can be as rare as one in a million. What is relevant is the atypical presentation — atypical clinical manifestations that may overlap with other diseases. A study by Nathalie Guffon looked at the differential diagnosis of alpha-mannosidosis, which may be misdiagnosed as mucopolysaccharidosis types I, II or III, sialidosis, free sialic acid storage disease and many others. Certain features overlap with other lysosomal storage diseases — ataxia, intellectual disability, coarse facial features, dysostosis multiplex. The point is that alpha-mannosidosis should be considered in the differential diagnosis of patients with these clinical features, and further investigations, including biochemical and genetic testing, should be considered.

Delayed diagnosis versus late-onset disease

Today we are focusing on attenuated, mild forms, and it is worth distinguishing between delayed diagnosis and late-onset disease. Delayed diagnosis refers to patients who have had symptoms and clinical manifestations for a long period of time, but for some reason the diagnosis was delayed. In a late-onset form, symptoms appear for the first time in adulthood — and that is less relevant for alpha-mannosidosis.

Diagnostic delay in rare diseases has an impact not only on the life of the individual, but on families and society as a whole. The average time from symptom onset to diagnosis has been estimated at four to five years, and in some cases as long as a decade. These patients often face a diagnostic odyssey, with very extensive and expensive work-ups in different institutions and hospitals.

Published evidence on diagnostic delay

Zielonka and colleagues have looked at diagnostic delay in alpha-mannosidosis in a quantitative study of 111 previously published cases. The main outcomes were age at symptom onset, diagnostic delay and survival; the authors also looked at residual enzyme activity and its correlation with survival and clinical outcomes. They found that symptoms can start as early as 12 months of age, whereas the median diagnostic delay was six years. At the age of 41, three quarters of the patients were still alive. Enzyme activity was available for at least a third of them: where it was as low as 4.5% in fibroblasts, survival was rather poor, whereas patients diagnosed somewhat later — above seven years of age — with much higher enzyme activity could have a normal life expectancy into adulthood.

Given that we now have easier access to whole-genome sequencing and genetic testing, milder phenotypes — particularly patients with very atypical presentations and no striking features — may be diagnosed later in life, but the diagnostic delay should be reduced. In this study, the prevalent symptoms, in descending order, were cognitive impairment, hearing loss, organomegaly, short stature, bone anomalies, respiratory tract infections and ear infections, hernias, muscular hypotonia, cardiovascular features, dysmorphism and ataxia.

An adult cohort: attenuated versus non-attenuated cases

I would like to discuss the results of our study, in which we identified 25 adult patients above the age of 16 — patients with attenuated, milder forms, but also patients with severe and moderate forms in whom the diagnosis had been missed — and compared their age at diagnosis, age at symptom onset and outcomes. There were 14 attenuated and 11 non-attenuated cases across seven countries. All the patients in this cohort had hearing impairment and intellectual disability in the first decade of life, whereas the milder forms were diagnosed much later, in the third, fourth or fifth decade. They were diagnosed because of progressive motor dysfunction, progressive ataxia, swallowing problems, and becoming more dependent on care or a wheelchair.

As expected, patients with attenuated forms experienced a longer diagnostic odyssey: the diagnostic delay was 26.8 years on average in attenuated cases, compared with 19.7 years in more severely affected patients. This confirms what has been seen in other studies. Patients in the attenuated group were also significantly older at diagnosis — 33.4 years, compared with 20.6 years in non-attenuated cases — so at least ten years' difference between the groups.

We also looked at genotypes. They were classified into group 1, patients with two null variants; group 2, genotypes leading to MAN2B1 protein localisation to the endoplasmic reticulum; and group 3, genotypes leading to MAN2B1 localisation to the lysosome. Most patients with moderate and severe forms were in group 2, but group 2 also included patients with mild forms, and some patients were classed in group 1. The cohort was probably too small to draw conclusions about correlation, but work is ongoing.

Those with attenuated forms had relatively normal family lives and were relatively independent. They had support from a carer or parent, but they were able to attend primary and secondary education; one patient completed a university course, and some did unskilled or voluntary work.

Case: an attenuated presentation diagnosed in adulthood

Patients with attenuated forms often have very subtle symptoms, and I want to present one case briefly. The patient was born at term, with a birth weight of 2.6 kg; there was meconium aspiration, but otherwise her early childhood and development were initially normal. She required a hernia operation at the age of three. When she went to primary school she struggled with her speech and was moved to a special needs school. She needed hearing aids for sensorineural hearing loss. Her mother said she always struggled with infections: she had recurrent ear infections, needed a grommet in childhood, and had a tonsillectomy. Her height in childhood was 148.5 cm. There was possible prognathism, possibly low-set ears and possibly mild pes cavus, but no obvious peripheral neuropathy.

At the age of 20 she started stumbling over things. She developed progressive ataxia and had to walk holding on to furniture. At 27 she was referred to a neurogenetic clinic for ataxia screening. Her initial provisional diagnosis was Niemann–Pick type C because of the ataxia, and for the first few years she was simply monitored, with no progression of her symptoms. However, she developed large-joint problems and pain, which limited her quality of life and required steroid injections.

When she was enrolled in the 100,000 Genomes Project, the diagnosis was confirmed: she was a compound heterozygote for two known variants — a frameshift variant known to cause loss of protein function, and a missense variant previously described in patients with type 1 and type 2 alpha-mannosidosis. We confirmed this with biochemical and functional studies: she had classical urinary oligosaccharide changes, with a trisaccharide band, very low enzyme activity, and slightly raised creatine phosphokinase.

When we saw her in clinic she was in her third decade of life and had only been known to the neurogenetic clinic because of ataxia. Then all her other health problems became unmasked. She had osteoarthritic changes on X-ray and CT, and required hip replacement surgery. She developed secondary amenorrhoea and swallowing problems, and she now has heart valve disease. This shows that attenuated patients, particularly once the diagnosis is confirmed, may need input from many members of the multidisciplinary team — in keeping with other attenuated cases, whose condition becomes apparent later in life and who develop different health problems later.

Barriers to diagnosis

To touch on barriers to diagnosis in our cohort: these patients manifest very subtle or atypical symptoms, which delay the diagnosis. They may be seen by various clinicians and misdiagnosed, or carry a provisional diagnosis for many years, and some are not referred to genetic or metabolic clinics in time. We know they all present with hearing impairment and learning disability in the first decade of life, so early genomic investigation of intellectual disability is likely to shorten the diagnostic delay.

A study from the US looked at undiagnosed cases of possible lysosomal storage diseases and the reasons for delayed diagnosis, and its findings are very much in keeping with ours. Patients may have multi-organ involvement or very isolated organ involvement — for example, more and more retinal phenotypes of lysosomal storage diseases are being described. Their symptoms may mimic other conditions, and as a result patients are seen in the wrong clinics for long periods; in some of these cases the delay was as long as 15 years. Poor characterisation of possible disease phenotypes, milder symptoms that delay patients seeking medical attention, and poor awareness of lysosomal storage diseases among adult providers were identified as the main causes of delay.

So the referral pathway is really relevant. Many of these patients are seen in neurology, medical genetics or paediatric neurology for many years, and neurocognitive decline, balance problems and motor dysfunction are the main reasons clinicians start investigating them. They may have symptoms in childhood but not seek medical attention for a long time if those symptoms are not progressing rapidly. There may also be other factors in certain ethnic subgroups that need further attention.

Conclusions

In conclusion, the diagnostic pathway in attenuated alpha-mannosidosis is often very complex. Patients manifest subtle, non-specific symptoms, which are the main cause of delayed diagnosis. Patients with attenuated phenotypes may unpredictably develop accelerated disease with organ damage, and early diagnosis maximises the opportunity for them to be treated, or at least to be offered the best supportive care. The therapeutic goals for attenuated cases still need to be investigated further. Despite growing awareness of alpha-mannosidosis and improved diagnostic methods, there are gaps, and knowledge of the natural history is limited and needs further study. I'd now like to hand over to Dr Durães.

Three cases: how timing of diagnosis shapes outcome

Dr João Durães: Thank you, Dr Stepien, for the wonderful introduction and for clearly defining what we are talking about today. I have chosen some of the cases we follow here in Coimbra to illustrate how delayed diagnosis can affect prognosis and therapeutic options, and why we should always strive for the earliest possible diagnosis, even in attenuated cases. We will review three patients, starting with the one who was diagnosed earliest.

Case 1: early referral and early treatment

This patient is currently 22 years old. At four months of age he developed chronic nasal obstruction and difficulty breathing — the first symptoms. His parents were worried, and three months later, at seven months, he had his first paediatric assessment. The paediatrician found macrocephaly and facial dysmorphism; in the three months between the first symptoms and the assessment there had been two episodes of otitis, and the examination also showed mild hepatomegaly and mild lumbar kyphosis.

So at this point there were already some hallmark signs. The paediatrician recognised them and made a fast referral to the metabolic unit, where an immediate diagnostic work-up began: screening for storage disorders showed normal glycosaminoglycans but an abnormal oligosaccharide pattern, which led to measurement of alpha-mannosidase activity. This was clearly reduced, and genetic testing later confirmed a pathogenic variant usually associated with more moderate presentations.

Because the diagnosis was early, there was close monitoring and follow-up. The child began to develop hearing loss and mild developmental delay, mainly involving language, but always with a normal neurological examination. After careful discussion with the parents and with reference centres, it was decided to proceed with haematopoietic stem cell transplantation at the age of two. There were no significant peri-procedural complications.

In the twenty years since, enzyme activity has remained in the lower range of normal. Urinary oligosaccharides still show an abnormal pattern, but cognitive findings have been relatively stable over time. The patient finished secondary school and is looking for a stable paid job. His neurological examination remains normal, without significant ataxia, and there have been no further severe infections or orthopaedic complications. The main concern now — and one of the limiting factors in his education — is hearing loss.

His most recent brain MRI, at 20 years old, shows no significant supratentorial cortical atrophy. There are cerebellar changes, which the neuroradiology department thinks are more likely hypoplasia than atrophy, and they do not seem to be progressing significantly — but it is something to be alert to. The CT scan shows no significant thickening of the skull bones.

The key points from this case: even with mild symptoms and mild clinical findings, early suspicion and referral to metabolics or genetics is always important, and we should strive for easy, fast access to the complete diagnostic work-up, including genetic testing. Even when the diagnosis can be made on enzyme activity, genetic testing can help guide some decisions. Early diagnosis allows close monitoring and intervention as early as possible — here, haematopoietic stem cell transplantation was done before any significant cognitive or neurological involvement.

Case 2: overlooked infections, a later diagnosis

We move from this first patient, where everything was smooth and fast, to a second patient where things are more complicated. He is currently 25 years old. In his clinical file, the age of onset is recorded as five years, with mild intellectual disability. When we think about age of onset, people usually mean the symptoms that led to the first medical consultation. But when we reviewed his past medical history, he had already had episodes of otitis since the age of three. There was mild facial dysmorphism, with arched eyebrows and frontal and occipital flattening; hearing loss; episodes of tonsillitis and dental abscesses; and trigger finger.

At around six or seven years of age he was referred to the genetics unit. Although some symptoms had been overlooked by his parents or by other physicians, from this point the referral was fast and the same diagnostic work-up was applied: urinary oligosaccharides were abnormal, alpha-mannosidase activity was reduced, and genetic testing confirmed the same pathogenic variant. By then, at six to seven years old, it was deemed too late for haematopoietic stem cell transplantation, so he received the best medical management and follow-up.

Over time he developed mild intellectual disability and attended secondary school with an adapted curriculum. He had facial dysmorphism not very different from the case Dr Stepien presented, and he developed obesity, frequent infections and significant bone pain that really limited his daily activities and quality of life. In adolescence he developed mild gait ataxia, without appendicular ataxia, no signs of myopathy, and an otherwise normal neurological examination.

Things changed when he was 20, with the approval of enzyme replacement therapy for alpha-mannosidosis in Portugal; at that time it was obtained through an early access programme. In the five years since starting enzyme replacement therapy, there has been significant improvement in bone pain, with a subsequent improvement in quality of life and no significant infections. He maintains a mild ataxia that has not progressed much in five years, and significant hearing loss.

His brain MRI, at a similar age to the first patient, is different: there is mild cerebral atrophy, more in the parietal regions, and significant cerebellar atrophy, mildly progressing on subsequent scans. There are also non-specific periventricular white matter changes — not the occipital or occipitoparietal white matter changes typically described in alpha-mannosidosis — and the CT shows thickening of the skull bones.

The key points from this patient: frequent infections are often overlooked. He had recurrent otitis from the age of three, but his first contact with a paediatrician was at five, for developmental delay. Although the ages are similar to the first patient, this later diagnosis limited access to haematopoietic stem cell transplantation, which led to a significantly different outcome. Enzyme replacement therapy has improved his quality of life — sometimes in measures that are not assessed as often, such as bone pain or activities of daily living — but, as with every enzyme replacement therapy for lysosomal storage disorders, the long-term neurological outcome, particularly the progression of ataxia, remains to be seen.

Case 3: an "attenuated" form diagnosed at 20

The third patient is a woman, older than the previous two — currently 53. She was referred to neurology at 19 because of frequent falls. There was a family history of consanguinity. Looking back at her history, pregnancy and delivery were normal, but she had a severe respiratory infection at 19 days old and then a mild developmental delay that was attributed to that infection. In late childhood — later than the two previous patients — she developed recurrent otitis with chronic otitis media, hearing loss and scoliosis. At the time this was not considered important enough to refer to a specialised centre, and she continued regular follow-up.

In adolescence she developed behavioural problems and many orthopaedic problems, including knee instability with frequent subluxations, ligament tears, and gait impairment with frequent falls. When she was assessed in our neurology clinic she showed some impulsive behaviour, severe language impairment, facial dysmorphism with macroglossia, a mild tetraparesis with a myopathic pattern and, importantly, a severe gait ataxia — a marked midline ataxia with truncal involvement, but relatively mild or negligible appendicular ataxia.

Because some of these findings pointed to a lysosomal storage disorder, even if the team did not know which one, they did a full metabolic screen. This revealed abnormal oligosaccharides; further investigation led to measurement of alpha-mannosidase activity and genetic testing, which confirmed a homozygous pathogenic variant.

She was 20 years old at the time. There was no indication for haematopoietic stem cell transplantation — the parents did not even entertain the idea — and velmanase alfa, the enzyme replacement therapy, was not yet available. She went on to have severe behavioural problems requiring high doses of neuroleptics, with the resulting motor adverse effects. The ataxia progressed, though she could walk with support. She needed three knee surgeries for detachment of the knee tendons and ligament reconstruction. She developed severe deafness with both sensorineural and conductive components.

As often happens in this type of disease, her behaviour has since normalised and she is currently without any medication. She is mute but able to follow simple commands — for example, she raises her arms when asked — and fully dependent in her activities of daily living, with a mild tetraparesis; there is some myopathic involvement, but it is not the most complicated part of the picture. She has severe gait ataxia and is wheelchair-bound.

What can we learn from this third patient? Frequent infections are often overlooked; so-called attenuated forms can be deceiving; and late neuropsychiatric involvement and ataxia can be important clues — but a diagnosis at that point limits management. We need to diagnose early.

Conclusions from the cases

In conclusion, it cannot be emphasised enough that developmental delay and intellectual disability should always have a clear, confirmed etiology, and that early pattern recognition and referral are essential. The clinical findings of alpha-mannosidosis are recognisable, even in attenuated forms. Multidisciplinary discussion, referral networks and referral pathways are essential to improve the diagnostic pathway. I'll hand back to Dr Stepien for the discussion.

Discussion: obesity and joint pain

Dr Karolina Stepien: Thank you very much — fascinating cases, with slightly different phenotypes and different ages at diagnosis. I'd like to start the discussion, and I encourage delegates to type their questions in the chat. In your second case you mentioned obesity. Do you think it was related to the large-joint problems and joint pain? Was the patient using a wheelchair or walking?

Dr João Durães: He was able to walk, with difficulty, and it was mild obesity — a BMI between 32 and 35. I think it was mostly due to hypomobility. He had severe bone pain and was not keen to use any kind of support, so he tried to manage without it, which led to hypomobility rather than a metabolic dysfunction as such.

Recurrent infections as a red flag

Dr Karolina Stepien: Thank you. You mentioned that infections were overlooked, which is a very relevant point. Recurrent chest and ear infections are common in children, but in patients with lysosomal storage diseases such as alpha-mannosidosis they are a striking feature and have been included in various diagnostic algorithms for this condition. So this is about raising awareness among paediatricians, including community paediatricians: they should really consider screening for other conditions. Even if a child doesn't have developmental delay or striking facial features, recurrent ear infections should be investigated further.

One of your cases was treated with enzyme replacement therapy, which improved quality of life. We have previously looked at treatment modalities — patients treated with haematopoietic stem cell transplantation, patients on enzyme replacement therapy, and treatment-naive patients — and the long-term impact on pain, mental health and mobility. Those who have been treated, particularly since childhood, may respond, and their self-reported quality of life was significantly better.

Transition from paediatric to adult services

We have a question from the chat: many of these patients end up in adult neurology with ataxia before anyone thinks of a metabolic cause. What does a good transition and referral pathway between paediatric and adult services look like in your country?

Dr João Durães: If there is already a diagnosis, we have a structured transition within our metabolic reference centre. That is the exception — there are no clear national guidelines for transition in every specialty, and in adult neurology, for example, patients are sometimes just sent to our clinics without a fully established transition process. But for metabolic patients we have reference centres for metabolic disorders, with an organised transition: the adult physician attends the paediatric consultations, followed by a smooth handover of records. I think this is really important.

Dr Karolina Stepien: And who looks after adult patients — adult neurologists or geneticists?

Dr João Durães: It depends on the type of pathology. If there is neurological involvement, it is the neurologist. We also have internal medicine physicians who follow patients with mainly genetic metabolic disease, so the transition can be to either specialty.

Dr Karolina Stepien: So from paediatric neurology to adult neurology. And are these patients followed by geneticists as well?

Dr João Durães: We have geneticists in our reference centre, but they are mostly involved in the diagnostic phase rather than general long-term follow-up and management.

Dr Karolina Stepien: In the UK we have a well-established transition service. Patients are followed by tertiary metabolic and genetic departments and transition from paediatric metabolic services to the relevant adult metabolic centre long term, and these specialties coordinate referrals to ENT, anaesthetics, orthopaedics, neurology and neuropsychiatry as needed. So this is a very good point about transition. But attenuated cases are often missed in childhood and may present after the point of transition. Apart from a community paediatrician in childhood, they may not have been seen by a clinician for a long time, and then suddenly present with progressive neuromotor or neurological symptoms and be referred to the relevant centre.

Is improving behaviour a warning sign?

Next, a question about the behavioural problems in patient three, which eventually resolved without medication, although she became mute. Is the psychiatric phase followed by a burnout stage of disease progression — should clinicians read improving behaviour as a warning sign rather than a good one?

Dr João Durães: I think it is always a warning sign of disease progression — clearly a mechanism of progression. In terms of managing symptoms it is easier for the family and the physician, but it is always a sign of disease progression, and this is the stage we don't want to reach with a treatable disease.

Dr Karolina Stepien: That is our experience as well. Your patient was diagnosed at around 19, relatively mildly affected and not followed by anyone for long periods, but then needed input from psychiatry and neurology. We also see patients in their fourth or fifth decade decline suddenly — to the extent that families often suspect a coexisting condition. They feel the alpha-mannosidosis has been stable for many years, and then the patient declines, stops communicating, develops neurocognitive decline and swallowing problems, and becomes dependent on carers and parents. The progression can be rapid, within 12 to 18 months in some patients.

Hand signs: carpal tunnel and trigger finger

Another question: in your experience, are there small signs in the hands, such as carpal tunnel syndrome or trigger finger? Are they common, as in other storage diseases?

Dr João Durães: I believe they are not specific signs for alpha-mannosidosis. They can help if there is already some degree of suspicion, but I don't think they are enough for us to screen every young patient with carpal tunnel syndrome.

Dr Karolina Stepien: Carpal tunnel syndrome is seen in the MPS conditions and may also be observed in alpha-mannosidosis. But patients who are moderately or severely affected have intellectual disability, and very often, even if they have acroparesthesias, they may not be able to communicate it. They may be rather inactive and need support even with feeding, so they may not tell us there is a problem with their hands. Those who do have symptoms need follow-up by a hand surgeon to exclude pathology in the wrist. Oligosaccharides accumulate in tendons and muscles, which may result in muscle weakness, and ataxia and balance problems are possibly related to the CNS disease as well as to the effect of oligosaccharides on muscles and tendons. We need to bear in mind that patients with intellectual disability may not tell us — but they may point at the wrist or rub a limb, suggesting something is not right.

Orthopaedic surgery and wound healing

There is also a question: is orthopaedic surgery successful for lower-limb skeletal problems, and can healing after surgery be a problem? This is a very difficult question. Speaking for my adult orthopaedic colleagues, they are quite reluctant to operate on adult patients with intellectual disability and other comorbidities, particularly heart problems. Nevertheless, we have had patients who had hip replacements and repeated foot surgery. We define success as resolution of pain, or no longer depending on a wheelchair or walking aids and being able to walk again. Healing can be a problem after surgery, and we are currently looking into this, because we have observed that wound healing can be prolonged and problematic in these patients.

Pregnancy and genetic counselling

There is also a question about guidance on pregnancy in alpha-mannosidosis, and what genetic counselling is offered to partners. In our centre, we refer patients to genetic counsellors for counselling and screening, and to estimate the risk of the partner being affected or being a carrier of the same variant.

Pregnancy is likely to be very complex and requires the whole multidisciplinary team, so we refer these patients to a high-risk pregnancy clinic from the very beginning. Ideally, we encourage patients to plan their pregnancy and let us know their plans well in advance, so that appropriate delivery plans can be made with the multidisciplinary team in case the airway is compromised — adult patients with alpha-mannosidosis may have a degree of airway disease, so anaesthetists and ENT teams may need to be involved. A few pregnancies have been documented in the literature, and we are aware of some other cases.

Dr João Durães: Just to clarify: it is important to have a multidisciplinary team with experience — the orthopaedic, obstetric and plastic surgery teams too. It has to be a team with experience of lysosomal storage disorders.

Dr Karolina Stepien: I completely agree — clinicians and specialists who have experience in managing complex cases of lysosomal storage disease.

Orthopaedic management once the diagnosis is known

There is a question about the case I presented: the patient was receiving steroid injections for hip problems before the diagnosis. Once alpha-mannosidosis is known, does orthopaedic management change, and are there interventions you would avoid? It's a very good point. The patient was initially managed conservatively with steroid injections, which eased the pain temporarily; she then decided to stop them and became dependent on walking aids. In her case, surgery was life-changing: she became mobile again and a happy person, and her quality of life improved. As for interventions to avoid, preparation for such surgery needs the involvement of the full multidisciplinary team — ENT, anaesthetic and airway assessment — and ideally these clinicians should be present during the surgery, because patients with alpha-mannosidosis, like those with mucopolysaccharidoses, may have airway disease that can be compromised. So surgery is worth considering if it is likely to be beneficial, but there are several steps of preparation. Any other comments, Dr Durães?

Newborn screening and earlier diagnosis

Dr João Durães: Only what you have already said. But I'd like to raise another important topic: newborn screening for lysosomal storage disorders and alpha-mannosidosis. How do we achieve an earlier diagnosis — education, artificial intelligence for earlier detection, newborn screening? I'd like to hear your opinion.

Dr Karolina Stepien: This is a very good point. Work is being done globally by various teams on newborn screening for lysosomal storage diseases in general, and we know that patients with alpha-mannosidosis would benefit from having the condition included in newborn screening programmes. In the UK there is the Generation Study, in which babies born now are screened for common pathogenic variants, so they are diagnosed very early, in the first few days of life, and are likely to be considered for therapy much sooner. We don't know yet, but in 20 to 30 years' time their outcomes are likely to be better — so it is a matter of watching and waiting. Hopefully newborn screening for alpha-mannosidosis will become available at some point in most countries globally.

Closing

I think that is the end of the questions from our delegates. Thank you very much for your time. If there are any other burning questions, we are very happy to follow up offline by email. Thank you for joining us today, and hopefully we'll see you again next time.

Dr João Durães: Thank you. Bye.

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