Case of late-onset Sandhoff disease due to a novel mutation in the HEXB gene

Sandhoff disease is one of a group of autosomal recessive conditions known as the GM2 gangliosidoses. Normal breakdown of GM2 gangliosides is performed by the enzyme beta-hex-osaminidase A. This enzyme consists of 2 subunits (alpha and beta), which are encoded by the HEXA and HEXB genes, respectively. Mutations in either of these genes result in buildup of the GM2 gangliosides, with HEXA mutations producing a phenotype of Tay-Sachs disease and HEXB mutations causing Sandhoff disease. The classic form of Sandhoff disease presents in infancy with symptom onset between ages 2 and 9 months. Symptoms include progressive weakness, intellectual disability, vision and hearing impairment, exaggerated startle response, seizures, and death usually before age 3. Late onset forms of Sandhoff disease have been described but are much rarer. Adult-onset cases can present with a wide spectrum of symptoms, including spinocerebellar ataxia, motor neuron disease, sensorimotor neuropathy, tremor, dystonia, and psychosis.(1) Specifically, in reviewing cases with the motor neuron disease phenotype, most reports describe predominant lower motor neuron features, with few cases showing both upper and lower motor neuron findings similar to amyotrophic lateral sclerosis.(2,3) More recent reports have identified an increasing number of novel sequence variants (often compound heterozygous point mutations) that are associated with the motor neuron disease phenotype,(4,5) although the mechanism by which these variants produce this specific phenotype is not well understood.