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Late-onset G sub M2 gangliosidosis

Ashkenazi Jewish family with an exon 5 mutation (Tyr sup 180 right arrow His) in the Hex A alpha-chain gene

From the Department of Neurology, New York University School of Medicine, New York, NY.
Supported in part by the Margaret Enoch fundG. is recipient of the H.I. Duggan Investigator Award from the Arthritis Foundation. S.B. is recipient of a fellowship from the Human Frontier Science Program Organization (HFSPO).
Received August 16, 1995. Accepted in final form December 4, 1995.
Address correspondence and reprint requests to Dr. E.H. Kolodny, Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.

Late-onset G_M2 gangliosidosis is a variant form of Tay-Sachs disease characterized by onset of symptoms and signs in adolescence or in early adult life. The deficiency of beta-hexosaminidase A (Hex A) in this form of G_M2 gangliosidosis has been invariably associated with the presence of the Gly²⁶⁹ right arrow Ser substitution in the alpha-chain. We found two siblings of Ashkenazi Jewish descent diagnosed with late-onset G_M2 gangliosidosis who were negative for the Gly²⁶⁹ right arrow Ser mutation. Analysis of the HEXA gene showed that they were compound heterozygotes for the functionally silent 4-bp insertion in exon 11, typical of the infantile form of the disease and for a novel mutation, T⁵³⁸ right arrow C, resulting in the missense Tyr¹⁸⁰ right arrow His. Expression studies in COS-7 cells suggested that the effect of this mutation was to decrease the stability of the alpha-chain at physiologic temperatures and therefore to indirectly affect the formation of mature Hex A.

NEUROLOGY 1996;47: 547-552

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