Investigating Sandhoff Disease in Saskatchewan

Abstract

Sandhoff disease is an autosomal recessive lysosomal storage disease caused by mutations in the HEXB gene detrimentally affecting the enzyme β-hexosaminidase. A high incidence of Sandhoff disease has been reported in northern Saskatchewan. The variant of the disease present in the province causes the death of infants before 4 years of age. In order to ameliorate the impact of this disease on the families and communities where it occurs the following steps were taken. Initially, genetic analysis of the HEXB gene from affected patients revealed a common variant shared among 4 individuals. That genetic information was used to develop a diagnostic molecular assay (Chapter 2). A novel synthetic substrate specific for the hydrolytic activity of β-hexosaminidase was obtained and used to develop a biochemical assay for measuring enzyme activity (Chapter 3). Finally, a retrospective study was designed using residual dried blood spots from the Saskatchewan Newborn Screening Program. The two assays were used to screen the dried blood spots for Sandhoff disease carriers in the northern Saskatchewan communities and the frequency of disease-causing alleles was estimated (Chapter 4). A high carrier frequency for Sandhoff disease causing mutations was found during the retrospective analysis coinciding with the high incidence of Sandhoff disease previously reported. As such the assays developed throughout this project may serve as the basis for a preventative carrier screening program for Sandhoff disease in Saskatchewan.