Alpha-mannosidosis is a very rare lysosomal storage disorder caused by deficiency of lysosomal alpha-mannosidase (MAN2B1) (E.C. 188.8.131.52). The birth prevalence is around 1 in 500.000. Based on this estimation 20-30 patients might be expected to live in the Netherlands. The true clinical prevalence, however, is lower with 7-8 living patients currently identified in the Netherlands.
Establishing a deficiency of alpha-mannosidase enzyme activity in leukocytes or fibroblasts is the gold standard for the diagnosis. Molecular genetic testing of MAN2B1 and the identification of two disease-causing alleles can confirm the diagnosis. Detection of a genetic variant in the MAN2B1 gene should always be followed by biochemical testing for enzyme activity to confirm pathogenicity. There is no clear genotype/phenotype correlation, which hampers prediction of clinical outcome.
Pathophysiology and phenotypes
The clinical expression of the disease (OMIM 248500) varies widely, as is almost always the case for lysosomal storage disorders. While the phenotypes should be viewed as part of a continuum, there are roughly three clinical types (mild, moderate, and severe) that can be distinguished. Most patients fit into the moderate type.
- Type 1. Mild form: clinically recognized after the age of ten years, with myopathy, slow progression, and absence of skeletal abnormalities
- Type 2. Moderate form: clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities
- Type 3. Severe form: with obvious progression, leading to early death from primary central nervous system involvement or infection
General features of the disease are typical appearance of a storage disorder (as in the mucopolysaccharidoses) with coarse facial features, a relatively large head and frontal bossing. Hearing loss is frequently observed. Frequent infections may be partially explained by immunological disturbances, which are incompletely understood.
Skeletal disease also resembles the mucopolysaccharidoses with evidence of dysostosis multiplex leading to skeletal complications such as osteonecrosis. Osteoporosis may also occur.
The neurological and psychiatric features are the most debilitating of the disorder: these affect cognition (patients all have intellectual disabilities) and speech. Development of motor function is frequently delayed or, after initial development of milestones, deteriorates. Patients frequently suffer from hypotonia. This further impacts their mobility. A large proportion of patients exhibit psychiatric symptoms, ranging from psychotic episodes to autistic behavior and depression.
Finally, frequent infections (primarily pulmonary) have been reported in alpha-mannosidosis patients. The natural disease progression is variable. Patients can remain stable for very long periods of time, although systematic large cohort studies are lacking.
Supportive care is the cornerstone of treatment: orthopedic interventions, antibiotics for infections, physical therapy and use of hearing aids or wheelchairs etc, as well as psychiatric support are all important. Families may need support as well, as the multisystemic impairment of patients may pose a heavy burden on family life.
Early studies have tried hematopoietic stem cell transplants (HSCT) as a therapeutic option with variable results. In general, patients cannot be cured, but HSCT may allow better mental development although scientific evidence in large studies is currently lacking.
Enzyme replacement therapy
The EMA recently authorized Lamzede as treatment for long-term enzyme replacement therapy in patients with alpha-mannosidosis (marketing authorisation under exceptional circumstances to Lamzede on 25 January 2018).
Lamzede is indicated for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis.
In the Netherlands, treatment will be available for a restricted group of patients as laid down in a Managed Access Protocol. This protocol is supervised by an Indication Committee consisting of experts from the lysosomal expert centers in the Netherlands (Amsterdam UMC, SPHINX and Erasmus MC, center for lysosomal and metabolic diseases).
Amsterdam UMC and Erasmus MC
The Amsterdam UMC and Erasmus MC are the lysosomal expert centers in the Netherlands. Both centers are involved in the diagnosis and follow-up of patients with alpha-mannosidosis.