DeCure for Sandhoff disease

Sandhoff disease is a rare lysosomal storage disorder inherited in an autosomal recessive pattern, with a reported prevalence of 1 in 384,000 live births. The disease results from a deficiency of beta-hexosaminidase A and B, caused by mutations in the HEXB gene, which encodes the β-subunit of the enzyme. This deficiency leads to accumulation of GM2 gangliosides within lysosomes in visceral cells and the central nervous system. Three phenotypes are described based on age of onset: acute infantile Sandhoff disease, with onset before 6 months; subacute juvenile Sandhoff disease, with onset at 2–5 years; and late-onset Sandhoff disease, with onset in late teens or young adulthood.

Case reports describe a 9-month-old boy who presented with rapid psychomotor deterioration, seizures beginning at 2 months, loss of motor skills, feeding difficulties, increased startle response, red maculas, decreased vision, and head circumference above the 95th centile, with no organomegaly. A 14-month-old male child presented with macrocephaly, regression of developmental milestones, seizures, and a macular cherry red spot on fundus examination; enzyme studies confirmed reduced beta-hexosaminidase A and B. A 10-year-old boy with progressive deterioration of intellectual functioning, ataxia, and hemiplegia was found to have absent serum hexosaminidase activity, and skin biopsy showed axonal accumulations of dense osmiophilic deposits; this was reported as an atypical juvenile case. A 10-year-old female child with subacute juvenile Sandhoff disease had attained normal developmental milestones until about age 4, then exhibited regressive changes around 4.5–5 years, becoming progressively slow and unsteady; diagnosis was made by MRI, whole-exome sequencing, and biochemical genetic testing.

In one family, after diagnosis of an affected 14-month-old child, the mother was offered prenatal diagnosis in a subsequent pregnancy. That fetus was found to have the same enzyme deficiency, and the pregnancy was medically terminated. The authors note that early identification of the disorder helped prevent the birth of further affected children in that family. The 2025 case report concludes that not much literature has been published on how subacute juvenile Sandhoff disease impacts daily life and function, and recommends multidisciplinary involvement including physiotherapy, speech therapy, and psychiatry to monitor prognosis and manage supportive care.

What is still missing are treatments that alter the course of the neurodegeneration; no therapy is described in these reports. There is no mention of any drug being tested or repurposed for Sandhoff disease in these abstracts. The evidence consists entirely of small numbers of individual case descriptions, with no controlled trials, no biomarker validation for progression, and no systematic data on survival or functional outcomes. Funding for natural history studies and for preclinical or clinical testing of potential therapies remains absent from this literature.