A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype

We describe two adult siblings who had had mild GM₂ gangliosidosis since childhood. They presented with spinal muscular atrophy and dysarthria, and one sibling also had mental disturbances. Laboratory studies established the diagnosis of the B1 variant of GM₂ gangliosidosis, because the hexosaminidase (Hex) A deficiency was not present upon testing with the unsulfated synthetic substrate 4-methylumbelliferyl N-acetylglucosaminide. HEXA gene analysis proved that the patients are compound heterozygotes for the previously identified G⁵³³→A mutation and for a new mutation, G¹¹⁷¹→A, at exon 11. This new mutation affects a conserved amino acid and results in a Val→Met substitution at position 391 of the HEXA gene. Full sequence of the α-subunit cDNA of Hex A revealed no other mutation. Assays for Hex A activities in patients suspected of having GM₂ gangliosidosis should be performed with the sulfated substrate 4-methylumbelliferyl N- acetylglucosamine 6-sulfate.