Late-onset G(M2) gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (Tyr¹⁸⁰→His) in the Hex A α-chain gene

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 β-hexosaminidase A (Hex A) in this form of G(M2) gangliosidosis has been invariably associated with the presence of the Gly²⁶⁹→Ser substitution in the α-chain. We found two siblings of Ashkenazi Jewish descent diagnosed with late-onset G(M2) gangliosidosis who were negative for the Gly²⁶⁹→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→C, resulting in the missense Tyr¹⁸⁰→His. Expression studies in COS-7 cells suggested that the effect of this mutation was to decrease the stability of the α-chain at physiologic temperatures and therefore to indirectly affect the formation of mature Hex A.