G_M2-Gangliosidoses

G_M2-gangliosidoses are neurodegenerative storage diseases, associated with intraneuronal G_M2-ganglioside accumulation. Intralysosomal G_M2-ganglioside hydrolysis requires the concerted action of β-hexosamidase A (HexA) and its cofactor G_M2 activator protein. Thus, disease can occur as a consequence of mutations in either the gene which encodes subunits of HexA (α and β) or its cofactor, each of which is mapped to independent loci. There is significant overlap in clinical presentation among these three clinical subtypes, encompassing Tay-Sachs disease (α-mutations), Sandhoff disease (β-mutations), and the AB variant (cofactor defect), all of which are inherited in an autosomal recessive fashion. The majority of affected individuals display a rapid degenerative course in childhood, and there are late-onset forms associated with life extending into decades. Ongoing studies of underlying pathogenesis implicate neuroinflammatory processes. There are investigations of various therapeutic approaches, including substrate reduction therapy, the use of pharmacologic chaperones and gene therapy. However, no specific treatment has been introduced that has altered what is ultimately a poor prognosis. Prevention has been achieved through carrier testing in populations at risk and prenatal diagnosis.