Alpha-mannosidosis

Alpha-mannosidosis

• is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability
• is caused by lysosomal alpha-mannosidase deficiency
• is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12) (1)
• occurs in approximately 1 of 500,000 live births (1)
• children with alpha-mannosidosis are often born apparently normal, and their condition worsens progressively some children are born with ankle equinus or develop hydrocephalus in the first year of life
• is a progressive disorder showing as clinical features mental retardation, hearing loss, skeletal deformities, central nervous system involvement, and immuno defects
• can be classified into three groups (2):
  • Type 1 a mild phenotype:
    • clinically recognized after 10 years of age, without skeletal abnormalities and very slow progression
    • including hearing loss, learning disability, and survival into adulthood
  • Type 2 is a moderate form:
    • clinically recognized before 10 years of age
    • with skeletal abnormalities and slow progression with developmental of ataxia at age 20-30
    • most common type
• Type 3 is a severe form:
  • immediately recognized, with skeletal abnormalities and obvious progression, leading to an early death from primary central nervous system involvement or myopathy
• most severe forms occur during infancy (before 5 years) and are associated with rapid progression, leading to early death (3)
• diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells using artificial colorimetric of fluorimetric substrates (2)
• enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis (2)
  • NICE state that:
    • velmanase alfa ( an enzyme replacement therapy produced using recombinant DNA technology)
      • is recommended as an option for treating the non-neurological signs and symptoms of mild to moderate alpha‑mannosidosis
    • the NICE committee noted that "...clinical trial evidence suggests that velmanase alfa may lead to improvements in functions such as walking, stair climbing and lung capacity, and quality of life, for people with alpha‑mannosidosis.."
• other treatments aim to manage symptoms and improve quality of life and include:
  • walking aids
  • physiotherapy
  • infection management
  • ventilation support
  • general treatment of comorbidities
  • supportive measures at home
  • 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

Reference:

• Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis. 2008 Jul 23;3:21. doi: 10.1186/1750-1172-3-21. PMID: 18651971; PMCID: PMC2515294.
• Ceccarini MR, Codini M, Conte C, Patria F, Cataldi S, Bertelli M, Albi E, Beccari T. Alpha-Mannosidosis: Therapeutic Strategies. Int J Mol Sci. 2018 May 17;19(5):1500. doi: 10.3390/ijms19051500. PMID: 29772816; PMCID: PMC5983820.
• NICE (December 2023). Velmanase alfa for treating alpha-mannosidosis