GM2gangliosidoses

GM2 gangliosidoses are a group of autosomal recessive lysosomal storage disorders caused by deficient activity of beta-hexosaminidase A (Hex A) or by defects in the GM2 activator protein, leading to accumulation of GM2 ganglioside in neurons. In some cases, deficiency of both Hex A and Hex B underlies disease (Sandhoff). The condition encompasses Tay–Sachs disease (Hex A deficiency), Sandhoff disease (Hex A and Hex B deficiency), and GM2 activator protein deficiency (AB variant).

Clinical features vary by onset. Infantile forms present in early infancy with hypotonia, feeding difficulties, rapid neurodevelopmental deterioration, seizures, and vision loss; cherry-red macula is typical. Sandhoff disease tends to be more severe and may include hepatosplenomegaly and earlier death; later-onset forms may present with ataxia or psychosis and slower progression.

Diagnosis relies on biochemical and genetic testing. Hex A activity is markedly reduced or absent in Tay-Sachs, whereas Sandhoff shows reduced activities of both Hex A and Hex B; GM2 activator protein deficiency yields low GM2 activation with normal hexosaminidase levels. GM2A, HEXA, and HEXB gene testing confirms the diagnosis. Neuroimaging may show cerebral atrophy; characteristic macular cherry-red spot can be observed on eye exam.

Management is supportive, focusing on symptom control, seizures, nutrition, and respiratory care; multidisciplinary teams provide care. There is no widely approved disease-modifying therapy. Research into substrate reduction, enzyme replacement strategies, and gene therapy is ongoing, but none established as standard care. Prognosis depends on subtype and onset; infantile Tay-Sachs and Sandhoff variants are usually fatal in early childhood, whereas later-onset forms may progress more slowly.

Epidemiology: carrier frequencies are higher for HEXA mutations in Ashkenazi Jews, contributing to disease prevalence in that population; Sandhoff and GM2 activator protein deficiency are rarer and occur in diverse populations.