Sandhoff disease

Sandhoff disease is a lysosomal disorder within the GM2 gangliosidosis family that primarily affects the nervous system. It is caused by biallelic pathogenic variants in the HEXB gene, leading to deficient enzyme activity and subsequent accumulation of GM2 gangliosides. Although the clinical presentation can vary, many individuals present in infancy with early neurological symptoms and developmental challenges. The condition is rare, affecting roughly 1 to 9 individuals per million in the population.

Characteristic clinical features of Sandhoff disease include an exaggerated startle response, a cherry red spot of the macula, hyperreflexia, and reduced beta-hexosaminidase B activity, all of which are consistently observed. After a period of apparently typical early development, affected children experience a phase of developmental regression marked by loss of previously acquired skills, which is a defining aspect of the condition. Over time, additional features such as macrocephaly, spasticity, various seizure types including bilateral tonic-clonic and myoclonic seizures, hypotonia, hepatomegaly, and CNS hypomyelination may develop, though these are seen in a subset of individuals. Not all individuals experience all features, and severity varies considerably.

Sandhoff disease results from pathogenic variants in the HEXB gene, which are inherited in an autosomal recessive manner. The deficiency of the beta-hexosaminidase enzyme due to mutations in both copies of HEXB leads to the accumulation of GM2 gangliosides in the central nervous system. This condition is more common when parents share a common ancestor, as the likelihood of both carrying the same rare variant is increased. Genetic counseling is recommended to help affected families understand inheritance and implications for future family planning.

Currently, management of Sandhoff disease focuses on supportive care and symptom management, with treatment plans tailored to the individual's needs. As no treatments are specifically approved for this condition, a multidisciplinary team typically provides care that may include physical, occupational, and speech therapies, along with interventions to address seizures and other complications. Genetic counseling is also an integral part of care, helping families understand the disorder and explore available options. Patients should discuss treatment options with their healthcare team to determine the most appropriate approaches for their situation.

Sandhoff disease is a lifelong neurodevelopmental condition characterized by an initial regression, followed by a period of relative stabilization and, in some individuals, later motor decline. The clinical spectrum ranges from severe early impairment to a more variable course, with outcomes differing widely between individuals. Outcomes described in medical literature continue to evolve as standards of care improve, and with current supportive care many individuals achieve improvements in quality of life. Families often find it helpful to connect with genetic counselors, specialized care centers, and support groups to navigate the complexities of the condition.

Several clinical trials are currently investigating new treatment approaches for Sandhoff disease. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility for emerging therapies.