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GM1 gangliosidosis is a rare lysosomal storage disorder characterized biochemically by deficient beta-galactosidase activity and clinically by a wide range of variable neurovisceral, ophthalmological and dysmorphic features.
ORPHA:354Classification level: Disorder
The disorder is panethnic but worldwide prevalence is not known. Prevalence at birth is estimated to be approximately 1:100,000 to 200,000 live births. High prevalence has been found in Malta and Brazil, and in the Cypriot and Roma populations.
There are three types of GM1 gangliosidosis based on the age of onset: a severe rapidly progressive infantile form with onset before six months of age (type 1 GM1 gangliosidosis), a late infantile or juvenile form with onset between seven months and 3 years of age with delayed motor and cognitive development (type 2 GM1 gangliosidosis), and an adult, chronic form with late onset between 3 and 30 years of age (type 3 GM1 gangliosidosis) characterized primarily by generalized dystonia (see these terms). Disease severity appears to be related to the level of beta-galactosidase activity.
The disorder is caused by mutations in the GLB1gene (3p22.3) coding for beta-galactosidase. To date, more than 165 mutations have been identified. Deficient enzyme activity leads to toxic accumulation of gangliosides in body tissues, and particularly in the central nervous system (CNS).
Diagnosis may be difficult due to the wide clinical spectrum of the disease. Clinical suspicion is based on signs of storage such as facial coarsening, hypertrophic gums, cherry-red macula, visceromegaly, dysostosis and psychomotor delay. Peripheral blood smear (testing vacuolated lymphocytes) and urine oligosaccharides are good orientation tests. Gaucher-like foam cells have been reported on bone marrow examination. Diagnosis is confirmed by biochemical assay of beta-galactosidase activity and/or by molecular genetic testing. A secondary combined defect of both GLB1 and neuraminidase (NEU1) (causing galactosialidosis; see this term) has to be excluded.
Differential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).
Prenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells, if mutations are identified in an index case.
GM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.
Management and treatment
Treatment for patients with GM1 gangliosidosis is symptomatic and supportive. Substrate reduction therapy is a potential approach for clinical trials in late-onset forms.
Prognosis depends on the type of GM1 gangliosidosis and is extremely poor in the severe infantile form and variable in the chronic adult form of the disease.