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

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Abstract

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 G1514→A substitution (R505Q) and the A619→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.

Introduction

Sandhoff's disease (MIM 268800) (McKusick et al., 1994) is a rare autosomal recessive disease caused by mutations of the β-hexosaminidase (β-Hex) β-subunit gene on chromosome 5q13, and it involves both β-hexosaminidase A (β-Hex A, αβ) and β-hexosaminidase B (β-Hex B, ββ) deficiencies (Gravel et al., 1995). A deficiency of these lysosomal isoenzymes leads to accumulation of GM2 ganglioside and related glycolipids, particularly in neurons. Three clinical phenotypes have been delineated by the dominance of the encephalopathy and the relative importance of lifespan rather than age of onset. An infantile form of classical Sandhoff's disease is fatal before age 4 years and central nervous system involvement is extensive and severe. Juvenile patients (Wood and MacDougall, 1976, Cashman et al., 1986, Mitsuo et al., 1990, Wakamatsu et al., 1992) reveal less severe manifestations such as cerebellar ataxia, mental retardation, spinal muscular atrophy, and local panatrophy and they are likely to die later, usually between childhood and early adulthood. Patients with the adult form presenting as spinocerebellar degeneration (Oonk et al., 1979) or motor neuron disease (Barbeau et al., 1984, Federico et al., 1986, Gomez-Lira et al., 1995) have a more prolonged survival. Thus, the clinical phenotype in this disorder varies widely, whereas the phenotype/genotype relationship or specific mutation for the late-onset form seems to be undetermined.

We describe here the first Japanese patient with adult Sandhoff's disease to present as spinocerebellar degeneration. To elucidate the phenotype/genotype relationship in this form, clinicopathologic and genetic investigations were done.

Section snippets

Case report

The patient is a 31-year-old Japanese man, whose parents are consanguineous; their mothers are sisters. He had normal motor and mental performance until adulthood except for slight dysarthria. After completing junior college, he worked at an electric factory as an assemblyman. He was in good health until five years before evaluation, when the family noticed that he had slight unsteadiness on walking. Deterioration with respect to hand writing, speaking, and thinking followed thereafter. On

Ultrastructural studies

For electron microscopy, biopsied rectal mucosa under fiberscopy and liver tissue obtained from the patient by needle biopsy were immediately fixed in 2.5% glutaraldehyde, and postfixed in 2% osmium tetroxide. The tissues were embedded in Epon 812 and sectioned as reported previously (Uyama et al., 1992).

Enzyme assays

Total β-Hex (mainly β-Hex A and β-Hex B) activity in blood leucocytes was measured by a fluorometric assay using 4-methylumbelliferyl (4MU)-β-N-acetyl-d-glucosamine (Nacalai Tesque, Kyoto,

Ultrastructural studies

In the rectal mucosa, most of the macrophages possessed many moderately electron-dense and -lucent vacuoles, ranging from 1.3 to 3.5 μm, which were delimited by a single unit membrane (Fig. 2B). Membranous cytoplasmic bodies were not found. In biopsied liver tissue containing hepatocytes, Kupffer cells, and endothelial cells, there were no intracytoplasmic abnormal ultrastructures suggesting storage materials.

Enzyme assay

The results of enzyme assay using blood leukocytes as samples are summarized in Table 1

Discussion

The diagnosis of Sandhoff's disease in our patient was confirmed by combined deficiency of β-Hex A and β-Hex B in leukocytes, and the proliferation of abundant PAS-positive foam cells in rectal mucosa. In this patient, a low but considerable amount of β-Hex A activity (15% of the control mean) was found while it is almost deficient (<3% of the control mean) in a classical Sandhoff's patient. The residual activity of β-Hex A may be associated with late-onset mild clinical features in our

Acknowledgements

We wish to thank Ms Y. Kuroki for a technical assistance, and Ms M. Ohara for reviewing the manuscript. This work was supported by grants from the Ministry of Education, Science, and Culture of Japan.

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