From Diagnosis To Early Treatment Of Alpha-mannosidosis (AM)

Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the alpha-mannosidase enzyme. The condition is multisystemic, often presenting with mild to moderate intellectual disability, skeletal abnormalities, recurrent infections due to immunodeficiency, coarse facial features, and progressive hearing loss. Onset typically occurs in the first two years of life, but diagnosis is often delayed for up to five years due to its non-specific symptoms.

Dr. Lagler categorizes disease severity into three clinical types but emphasizes that AM exists on a spectrum. Type 3 (severe) presents in early infancy with rapid progression; Type 2 (moderate) shows symptoms before age 10; and Type 1 (mild) manifests after age 10 with slow progression. Early symptoms such as speech delay, hearing loss, and motor difficulties often overlap with other disorders, leading to misdiagnosis or diagnostic delays.

Diagnosis relies on enzymatic assays (measuring alpha-mannosidase activity), urinary oligosaccharide screening, and confirmation by MAN2B1 gene sequencing. Dr. Lagler underlines that once AM is suspected, targeted diagnostic testing is straightforward and should be initiated without delay.

The session explores two primary treatment options: hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) with velmanase alfa. Dr. Lagler discusses the strengths and limitations of each, noting that HSCT can address central nervous system symptoms if performed early, while ERT helps reduce somatic symptoms but does not cross the blood–brain barrier. A case study is presented demonstrating the effectiveness of initiating ERT before HSCT to optimize clinical outcomes—a strategy borrowed from MPS management protocols.

Comprehensive care involves multidisciplinary teams including neurologists, immunologists, ENT specialists, orthopedic surgeons, pain specialists, and speech therapists. Dr. Lagler stresses the importance of early referral to specialized centers and structured transition programs for adolescents moving into adult care.

He concludes by advocating for newborn screening, increased awareness, and the use of digital tools such as symptom checkers to reduce diagnostic delays and improve outcomes through early intervention.