Sandhoff disease

Sandhoff disease (also known as GM2 gangliosidosis type II, or hexosaminidase A and B deficiency) is a rare, autosomal recessive lysosomal storage disorder caused by pathogenic variants in the HEXB gene, which encodes the beta subunit of hexosaminidases A and B. The deficiency of both hexosaminidase enzymes leads to the progressive accumulation of GM2 ganglioside and related glycolipids in neurons and other tissues throughout the body. Sandhoff disease is clinically very similar to Tay-Sachs disease but is distinguished by the involvement of visceral organs in addition to the central nervous system, due to the deficiency of both hexosaminidase isoenzymes. The most common and severe form is the infantile variant, which typically presents between 3 and 6 months of age with progressive neurodegeneration. Key features include developmental regression, an exaggerated startle response (hyperacusis), progressive motor weakness, hypotonia followed by spasticity, seizures, vision loss, and the characteristic cherry-red spot on fundoscopic examination of the macula. Macrocephaly due to brain swelling may develop. Unlike Tay-Sachs disease, hepatosplenomegaly and bony abnormalities may also be present. The infantile form is rapidly progressive and typically fatal by age 3 to 5 years. Juvenile and adult-onset forms also exist, presenting with later onset and slower progression of neurological symptoms including ataxia, motor neuron disease, cognitive decline, and psychiatric manifestations. There is currently no cure or disease-modifying treatment for Sandhoff disease. Management is primarily supportive and symptomatic, including seizure control, nutritional support, respiratory care, and physical therapy. Investigational approaches including substrate reduction therapy, gene therapy, and enzyme replacement therapy are under active research. Genetic counseling is recommended for affected families, and carrier testing and prenatal diagnosis are available.

Common questions about Sandhoff disease