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The HUE-MAN Project

Information about Alpha-Mannosidosis

Children with alpha-mannosidosis

Summary

Disease characteristics.Osteolysis of the foot bones (MR) Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three clinical subtypes include a mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1); a moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2); and a severe form manifested as spontaneous abortion or early death from progressive central nervous system involvement (type 3). Individuals with a milder phenotype have mild-to-moderate mental retardation, psychiatric symptoms, reduced hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease, mainly cerebellar involvement causing ataxia. Associated medical problems include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; individuals may live into the sixth decade.

Diagnosis/testing. The diagnosis of alpha-mannosidosis relies on demonstration of deficient acid alpha-mannosidase enzyme activity in peripheral blood leukocytes or other nucleated cells such as fibroblasts. Carrier testing by this method is unreliable because of overlap of enzyme activity between carriers and non-carriers. MAN2B1 is the only gene associated with alpha-mannosidosis. Targeted mutation analysis of the most frequent MAN2B1 mutations is available on a clinical basis. In families in which the disease-causing mutations are known, molecular genetic testing can be used to accurately identify carriers.

Management.X-ray of a hydrocephalus Treatment of individuals with alpha-mannosidosis is aimed at preventing complications and optimizing quality of life and may include early use of antibiotics for bacterial infections, hearing aids for individuals with sensorineural hearing loss, insertion of pressure-equalizing tubes if fluid accumulates in the middle ear, physiotherapy, use of a wheelchair, orthopedic intervention, and shunting as needed for hydrocephalus. Educational considerations include use of sign language for individuals with hearing loss, early educational intervention for development of social skills, speech therapy, and special education to maximize learning. Surveillance includes medical history and physical examination every six to 12 months and specific otolaryngology, audiometry, ophthalmologic, neuropsychological, and skeletal examinations, along with blood tests and CT scans of the brain. Testing of at-risk newborn sibs assures that affected children will benefit from early intervention.

Genetic counseling. Alpha-mannosidosis is inherited in an autosomal recessive manner. Each pregnancy of a couple in which both partners are heterozygous for a disease-causing mutation of the MAN2B1 gene has a 25% chance of producing an affected child, a 50% chance of producing an unaffected child who is a carrier, and a 25% chance of producing an unaffected child who is not a carrier. Prenatal testing for pregnancies at 25% risk is available and relies upon assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing when the family-specific MAN2B1 mutation(s) is (are) known.