Contributor: Gordon K. Klintworth
Sandhoff disease (GM2-gangliosidosis type II, hexosaminidase ß-subunit deficiency, variant O, OMIM #268800) was first recognized when a disorder almost indistinguishable from Tay-Sachs disease was discovered in non-Jewish families with prominent visceral involvement that involved particularly the kidney. GM2 ganglioside and its asialo derivative, as well as GA2 globoside, sphingolipid (ceramide-glucose-galactose-galactose-N-acetylgalactosamine) accumulate within neurons and different viscera. This globoside does not accumulate in tissues of Tay-Sachs disease, but in Sandhoff disease it is found at levels 15x> normal, especially in the kidney. In Sandhoff disease hexosaminidase A and hexosaminidase B are both absent. All patients with Sandhoff disease have been of non-Jewish origin.
As in Tay-Sachs disease, a cherry-red spot in the macula is one of the most distinguishing features of this disorder. Transmission electron microscopic studies revealed somewhat different abnormalities. The membranous bodies in the retina are slightly different in the two disorders. Tay-Sachs disease has predominantly concentric lamellae and round or oval particles that are somewhat similar in size. In Sandhoff disease, the particles are more pleomorphic and frequently confluent.
Patients with a defect or absence of the ß-subunit of hexosaminidase due to a mutation in the HEXB gene on chromosome human chromosome 5 (5q13) and this causes a lack of activity of both of the both isoenzymes of hexosaminidase (hexosaminidase A and hexosaminidase B). This results in an accumulation of globosides, oligosaccharides in visceral tissues and GM2 ganglioside in neural tissues in individuals with Sandhoff disease. Mutations in HEXB result in a heterogenous group of clinical phenotypes: Sandhoff disease - infantile type, Sandhoff disease - juvenile type, Sandhoff disease - adult type, Sandhoff disease - chronic type. Similar to the mutations of the b-subunit, those of the ß-subunit are a heterogeneous group. However, to date, only four mutations have been characterized in HEXB. One of the more common mutations is a 16 kb deletion of exons 1-5 which precludes the production of hexosaminidase B mRNA. This was found at relatively high frequency (8 out of 30) among Sandhoff alleles. Two others involve a G -> A transition at intron 12 and duplication of a sequence located between intron 13 and exon 14. These mutations were found in milder juvenile type of Sandhoff disease.