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Chronic GM₂ gangliosidosis masquerading as atypical Friedreich ataxia

Clinical, morphologic, and biochemical studies of nine cases

Division of Medical Genetics (Drs. Willner, Grabowski, and Desnick), and the Departments of Neurology (Dr. Bender), Pathology (Dr. Gordon), and Pediatrics (Drs. Willner, Grabowski, and Desnick), Mount Sinai School of Medicine, New York, NY.

A progressive spinocerebellar degenerative disorder was characterized in nine patients, aged 11 to 37 years, from four unrelated Ashkenazi Jewish families; affected individuals had markedly deficient ß-hexosaminidase A activity. Symptoms included early onset of cerebellar signs (tremor, incoordination, and dysarthia) and, with maturity, the development of upper and lower motor neuron disorders, marked dysarthria, and ataxia. Three older patients, aged 26, 32, and 37 years, had dementia or recurrent psychotic episodes. Membrane-bound lamellar cytoplasmic inclusions, consistent with lysosomal ganglioside accumulation, were observed in rectal ganglia. The activity of ß-hexosaminidase A was markedly deficient in all sources analyzed. Parents had activities consistent with heterozygosity, confirming autosomal-recessive transmission of the ß-hexosaminidase A-deficient gene and the adult variant disorder. Residual ß-hexosaminidase A activity, partially purified by anion-exchange chromatography from cultured skin fibroblasts of the affected individuals, was heat-labile and co-electrophoresed with normal ß-hexosaminidase A. These findings suggest that these patients were allelic for a new ß-hexosaminidase A mutation and may represent a genetic compound of this allele and the allele causing Tay-Sachs disease.

Address correspondence and reprint requests to Dr. Desnick, Mount Sinai School of Medicine, Fifth Avenue and 100 Street, New York, NY 10029.

This work was supported in part by a grant from the Muscular Dystrophy Association, Grant No. 5-281 from the March of Dimes Birth Defects Foundation, by Grant No. RR-00071 from the Division of Research Resources, General Clinical Research Center Branch, National Institutes of Health, and by Grants Nos. GM 25279 and AM 12434 from the National Institutes of Health. Dr. Bender is the recipient of an Academic Career Development Award (1 KO7 NS 2071, and Dr. Desnick is the recipient of a Research Career Development Award (5 KO4 AM 00451) from the National Institutes of Health.

Accepted for publication October 9, 1980.

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