A novel HEXB mutation and its structural effects in juvenile Sandhoff disease.

Mutations in HEXB, encoding the beta-subunit common to hexosaminidases A and B, cause the neurodegenerative condition, Sandhoff disease. A homozygous missense HEXB mutation (p. D459A) was discovered in six patients with a rare juvenile variant: we show that this disrupts a salt bridge between aspartate D459 and arginine 505 at the subunit interface; R505 mutations are reported in late-onset Sandhoff disease. Identification of D459A contributes to diagnosis and molecular understanding of attenuated Sandhoff disease variants.

Juvenile Sandhoff disease--nine new cases and a review of the literature.

Juvenile Sandhoff disease (McKusick 268800) is a rare lysosomal storage disorder with only 12 cases recorded in the literature. This condition is also referred to as the subacute form of hexosaminidase deficiency. We describe 9 new cases of Pakistani origin and compare these with the other published cases. Ataxia and speech abnormalities were the commonest presentation. Constipation and urinary incontinence were frequent and may be due to autonomic neuropathy. Cherry-red spot was not noted in any of our cases. Increased lower limb reflexes were the commonest physical finding. Significant delay in diagnosis may be due to the nonspecific presentation of this condition. Diagnosis was on the basis of hexosaminidase deficiency. Residual enzyme activity did not correlate with the clinical picture. Emerging therapies make early diagnosis of this disorder important.

Intellectual disability and cerebral palsy in a UK community.

OBJECTIVE: The northern English city of Bradford has a population of 370,000. In recent years the Pakistani community has gradually expanded in number, and in 2001 contributed 41.4% of births in the city. There is a very high level of consanguineous marriage in this community, and the main aim of this study was to assess the influence of community endogamy and consanguinity on major disabling childhood diseases. SUBJECTS AND METHODS: More than 300 children are referred to the Child Development Centre each year. Data on neurodegenerative disorders, microcephaly and cerebral palsy were collated and analysed by community of origin and mode of inheritance. RESULTS AND CONCLUSIONS: There was a striking variation in the prevalence of many disabling conditions, but in all cases the Pakistani community was over-represented, suggesting a high prevalence of inherited disease. The large numbers of affected children present a challenge, and adequate resources are needed to improve the delivery of counselling, treatment and care to the community. As child health in Pakistan improves, our experience with the UK Pakistani community suggests that the genetic causes of disability and disease in childhood will assume greater importance.