Last update: 06/06/2006

Background to disease

OMIM 228800 (gene OMIM 606873)

Sandhoff disease is a progressive neurodegenerative disorder characterised by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease. Motor weakness begins in the first 6 months of life and is progressive. Patients have an exaggerated startle reaction to sound, early blindness, progressive mental and motor deterioration, doll-like face, cherry-red spots and enlargement of the heart. Death usually occurs by 3 years of age.

Sandhoff disease is inherited in an autosomal recessive manner. Estimates of the incidence of Sandhoff disease are about 1/1000 in Jews and 1/600 in non-Jews. The disease is caused by mutations in the gene (HEXB gene) coding for the beta subunit of the hexosaminidase A and B enzymes. The HEXA gene codes for the alpha subunit. Hexosaminidase A is comprised of alpha and beta subunits whereas hexosaminidase B is made from beta subunits only. Mutations in the HEXB gene result in a lack of both hexosaminidase A and B and this causes Sandhoff disease. Mutations in the HEXA gene result in a lack of hexosaminidase A which causes Tay-Sachs disease. Sandhoff disease and Tay-Sachs disease are clinically indistinguishable however enzyme analysis allows differentiation of the two diseases.

The HEXB gene is located at 5q13. HEXB has 14 exons and encodes a protein of 556 amino acids. A number of mutations have been reported in HEXB – see HGMD. Missense, nonsense, splicing, small deletions, small insertions and gross deletions have been described. The mutations are spread across the gene although there are only a few mutations described 5’ to exon 5.

Patients can be diagnosed clinically by biochemical assays to detect hexosaminidase A and B activity. This approach is not reliable for carrier detection.

Laboratory Analysis

Contact scientists: Kim Flintoff and Teresa Patrick

	Test	Target reporting time (working days)
1.	*Sequencing of the 13 exons of the HEXB* gene**	40

* Prenatal = 3 working days to report

Tests performed: mutation analysis for known cases and diagnostic queries, carrier tests, prenatal tests.