Contributor: Gordon K. Klintworth
Sandhoff disease (GM2-gangliosidosis type II, hexosaminidase ß-subunit deficiency, variant 0, OMIM #268800) was first recognized because 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. A cherry-red spot in the macula is a prominent clinical distinguishing feature. Patients have a defect or absence of the ß-subunit of hexosaminidase due to a mutation in the HEXB gene and this causes a lack of activity of both of the both isoenzymes of hexosaminidase (hexosaminidase A and hexosaminidase B). The designation GM2-gangliosidosis variant 0 stems from the fact that affected individuals lack both 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. 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 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. The main entity in the differential diagnosis is Tay-Sachs disease, which has an almost identical clinical course and similar ocular manifestaions (cherry-red spot in the macula). In contrast to Tay-Sachs disease visceral involvement, particularly in the kidney, is a prominent feature and almost all, if not all, patients with Sandhoff disease have been of non-Jewish origin. Transmission electron microscopic studies have also disclosed slightly different intracytoplasmic membranous bodies in the in the retina and other neurons 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 often confluent.