GM1 gangliosidosis is a neurodegenerative disease characterized by the accumulation of GM1 gangliosides. There are three types of GM1 gangliosidosis. The infantile form (type I) begins within the first three months of life with progressive encephalopathy and amaurosis. Hepatosplenomegaly appears at onset, along with cutaneomucous infiltration (causing coarse facies), and deformations of the skeleton (including kyphoscoliosis). Developmental retardation or arrest, followed by progressive neurological deterioration usually occurs during the first 6 months of life. In 50% of cases, cherry red spots are found on the macula. Urinary oligosaccharide levels are high. Onset of the juvenile type (type II) occurs between ages 1 and 5. The main symptom is locomotor ataxia, ultimately leading to a state of decerebration with epileptic seizures. Viscera are only slightly affected. In adult forms (type III or chronic GM1 gangliosidosis), onset may be variable, sometimes juvenile, but diagnosis is not made until adulthood. Clinical signs are similar to those found in juvenile forms of Parkinson`s disease, atypical spinocerebellar degeneration, or dystonia. Viscera are not affected and there are no cherry red spots. Intellectual deficit can initially be mild or absent but progresses over time. GM1 gangliosidosis is caused by a deficiency in lysosomal beta-galactosidase (beta-gal). It is transmitted as an autosomal recessive inherited trait. The causative gene is located on chromosome 3 (3p21-33). A dozen mutations have been identified. They prevent the phosphorylation of the beta-galactosidase precursor, which is consequently secreted instead of being routed to the lysosomes. Beta-galactosidase deficiency and GM1 accumulation seem to induce the indirect activation of a neuronal apoptotic pathway. Diagnosis can be confirmed by skin biopsy and demonstration that the enzymatic activity of the beta-galactosidase is very low in leucocytes and cultured fibroblasts. Screening of heterozygous individuals and prenatal diagnosis can be performed. Prognosis depends on the age at onset of the gangliosidosis. Life expectancy does not extend beyond the age of two in the infantile form, and rarely goes beyond the age of 20 years in the juvenile form. In adult type gangliosidosis, the phenotype is variable, but the progressive neurological sequellae usually shorten life expectancy. For the slowly progressive forms, a treatment aiming at inhibiting ganglioside synthesis (Miglustat) is currently being tested.
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