Adult Sandhoff's disease: R505Q and I207V substitutions in the HEXB gene of the first Japanese case

We describe a 31-year-old Japanese man with adult Sandhoff's disease presenting as spinocerebellar degeneration. There was a marked cerebellar atrophy on MRI, and proliferation of abundant PAS-positive foamy macrophages in the rectal mucosa. The activities of total β-Hex, β-Hex A, and β-Hex B in leucocytes of the patient were 14%, 15%, and 6% of control values, respectively. However, oligosacchariduria or ultrastructural storage materials in liver tissue were nil. Direct sequencing of cDNA and genomic DNA, and restriction digestion revealed two different homozygous base substitutions in the HEXB gene: the G 1514→A substitution (R505Q) and the A 619→G substitution (I207V). The parents were consanguineous. His healthy mother, an enzymatic heterozygous carrier, was homozygous for I207V, but heterozygous for R505Q mutation. Thus, the patient is probably homozygous for both base substitutions and a R505Q mutation may be linked to the phenotype of adult Sandhoff's disease.