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    Velmanase alfa for treating alpha-mannosidosis

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    2 The condition

    2.1 Alpha-mannosidosis is an ultra-rare lysosomal storage disorder caused by inheriting a faulty copy of the MAN2B1 gene from both parents. This impairs production of the enzyme alpha-mannosidase, leading to systemic accumulation of mannose-rich oligosaccharides in various tissues, especially in the central nervous system, liver and bone marrow.

    2.2 The clinical presentation is associated with a very wide range of impairments with varying degrees of severity. Signs and symptoms of alpha-mannosidosis can occur at a very young age. The most severe forms occur during infancy (before 5 years) and are associated with rapid progression, leading to early death. More moderate forms are characterised by slower disease progression with people surviving into adulthood. These more moderate forms are associated with a very wide range of impairments, complications and comorbidities that increase with time. The impairments include:

    • facial and skeletal deformities (especially scoliosis and deformed hips and feet)

    • speech and language deficiencies

    • mental health difficulties

    • bone deterioration, and joints and muscle weakness (leading to pain)

    • reduced lung function because of an enlarged liver and spleen, and spinal abnormalities

    • immunodeficiency with recurring infections (mainly respiratory and ear).

    2.3 The overall prevalence of alpha-mannosidosis is estimated to be between 1 in 500,000 and 1 in 1,000,000. At the time of the evidence submission, the Society for Mucopolysaccharide Diseases (MPS Society) estimated that there were 25 people with alpha-mannosidosis in England.

    2.4 There are currently no pharmacological treatments for alpha-mannosidosis that alter the disease course. Treatments aim to manage symptoms and improve quality of life. They include walking aids, physiotherapy, infection management, ventilation support, general treatment of comorbidities, supportive measures at home and major surgical interventions (for example, ventriculoperitoneal shunts, cervical spine decompression, joint replacement). An allogeneic haematopoietic stem cell transplant from a matched sibling or matched umbilical cord donor is an option for some people when clinically indicated, but is associated with significant risks.

    2.5 Alpha-mannosidosis is managed in UK lysosomal storage disorder specialist centres. These centres have experience of administering enzyme replacement therapies by infusion for other related conditions.