betahexosaminidase

Beta-hexosaminidase is a lysosomal enzyme that cleaves N-acetylhexosamine residues from the non-reducing ends of glycoconjugates, including glycolipids and glycoproteins. In humans it exists mainly as two isoforms: hexosaminidase A (HexA) and hexosaminidase B (HexB). HexA is a heterodimer composed of an alpha subunit (encoded by HEXA) and a beta subunit (encoded by HEXB), whereas HexB is a homodimer of beta subunits. Both enzymes belong to the beta-hexosaminidase family and function best in the acidic environment of lysosomes.

GM2 ganglioside degradation is a key substrate pathway for beta-hexosaminidases. HexA, in conjunction with the GM2 activator protein, removes an N-acetylgalactosamine residue from GM2 to form GM3, enabling further degradation. HexB can act on other substrates, but it does not efficiently hydrolyze GM2 in the absence of HexA. Defects in these enzymes cause GM2 gangliosidosis, a group of lysosomal storage disorders.

Clinical and genetic aspects: Tay-Sachs disease results from deficiency of HexA (often due to mutations in HEXA) and is characterized by progressive neurodegeneration, developmental delay, seizures, and early mortality. Sandhoff disease arises from HexB deficiency (mutations in HEXB) and affects HexA and HexB activities, typically presenting with more severe and earlier-onset symptoms, including hepatosplenomegaly. Diagnosis is based on enzymatic activity measurements in blood or leukocytes and genetic testing of HEXA, HEXB, and GM2A (GM2 activator) genes.

There is no widely available cure; management is supportive, and research into enzyme replacement and gene therapies continues.