Sandhoff Disease

Clinical characteristics: Sandhoff disease comprises a phenotypic continuum encompassing acute infantile, subacute juvenile, and late-onset disease. Although classification into these phenotypes is somewhat arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span.

1. Acute infantile Sandhoff disease (onset age <6 months). Infants are generally normal at birth followed by progressive weakness and slowing of developmental progress, then developmental regression and severe neurologic impairment. Seizures are common. Death usually occurs between ages two and three years.

2. Subacute juvenile Sandhoff disease (onset age 2-5 years). After attaining normal developmental milestones, developmental progress slows, followed by developmental regression and neurologic impairment (abnormal gait, dysarthria, and cognitive decline). Death (usually from aspiration) typically occurs in the early to late teens.

3. Late-onset Sandhoff disease (onset older teen years or young adulthood). Nearly normal psychomotor development is followed by a range of neurologic findings (e.g., weakness, spasticity, dysarthria, and deficits in cerebellar function) and psychiatric findings (e.g., deficits in executive function and memory). Life expectancy is not necessarily decreased.

Diagnosis/testing: In a proband, the diagnosis of Sandhoff disease is established by: (1) enzymatic testing that identifies abnormally low activity of the enzymes beta-hexosaminidase A (HEX A) and beta-hexosaminidase B (HEX B) combined with an increased contribution from HEX A; and (2) identification biallelic pathogenic variants in HEXB on molecular testing.

Management: Treatment of manifestations: Treatment is symptomatic. Supportive care in acute infantile Sandhoff disease focuses on providing adequate nutrition and hydration, managing infectious disease, protecting the airway to reduce aspiration risk, controlling seizures, supporting motor development, and preventing deformities. Supportive care in subacute juvenile and late-onset Sandhoff disease focuses on maximizing motor function and speech and language as well as providing aids for activities of daily living and communication.

Surveillance: Periodic multidisciplinary evaluations to monitor existing disease manifestations and identify new manifestations requiring modification of supportive care.

Agents/circumstances to avoid: In acute infantile Sandhoff disease, avoid positioning that increases aspiration risk during feedings; and seizure medication dosages that result in excessive sedation. In subacute juvenile Sandhoff disease, avoid situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility; and circumstances that increase the risk of falling. In late-onset Sandhoff disease, avoid situations that increase the risk of falling (e.g., walking on uneven or unstable surfaces); and psychiatric medications that have been associated with worsening disease in late-onset Tay-Sachs disease, a similar disorder (e.g., haloperidol, risperidone, chlorpromazine).

Genetic counseling: Sandhoff disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a HEXB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the HEXB pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.