Sandhoff disease

Sandhoff disease is a rare lysosomal storage disorder resulting in severe neurodegenerative sequelae. It is characterized by the progressive accumulation of GM2 ganglioside within the lysosomes of nerve cells. This accumulation leads to widespread neurodegeneration, resulting in severe physical and mental deterioration.

Epidemiology

Sandhoff disease is a rare condition, with an estimated incidence ranging from 1 in 130,000 to 1 in 400,000 live births globally ^1,7. Unlike some other lysosomal storage diseases, Sandhoff disease does not have a strong ethnic or geographic predilection and can occur in various populations worldwide ¹.

Most individuals present in infancy (most before nine months of age), with adult-onset (typically third and fourth decades) being reported but rare ⁹.

Clinical presentation

Infants with Sandhoff disease typically present with hypotonia, motor weakness, and an exaggerated startle response to noise. As the disease progresses, affected infants experience developmental regression, loss of acquired skills, and increasing neurological impairment ⁴.

Over time, the disease leads to more severe symptoms, including vision loss, hearing loss, seizures, and spasticity. Most children with Sandhoff disease do not survive beyond early childhood due to the progressive and debilitating nature of the disorder ^5,9.

Rarely, individuals remain essentially asymptomatic until early adulthood (third and fourth decade) ⁹. In this group, cerebellar and lower motor neuron dysfunction are most common as well as symptoms of autonomic dysfunction ⁹.

Screening

Genetic testing is important for diagnosing Sandhoff disease, particularly in families with a known history of the condition. HEXB gene mutations can be identified through molecular genetic testing ¹.

Prenatal diagnosis of Sandhoff disease is possible through chorionic villus sampling or amniocentesis. ¹.

Pathology

Sandhoff disease results from mutations in the HEXB gene, which encodes the beta-subunit of the hexosaminidase enzymes. The mutation causes a deficiency in both hexosaminidase A (Hex-A) and hexosaminidase B (Hex-B), leading to the accumulation of GM2 ganglioside and related glycosphingolipids in neurons, particularly in the central nervous system ².

The accumulation of GM2 ganglioside within the lysosomes of neurons disrupts normal cellular function, leading to progressive neuronal damage and loss. This is the primary mechanism driving the severe neurodegenerative symptoms observed in patients ³.

Radiographic features

CT

Brain CT scans may reveal cerebral atrophy and increased density in the thalami, indicative of lysosomal storage material accumulation. However, CT scans may not be sensitive enough to detect early changes ^6,7.

MRI

MRI is more effective in detecting the characteristic brain changes of Sandhoff disease, including white matter abnormalities and thalamic hyperintensities on T2-weighted images. These imaging findings correspond with the progressive neurodegenerative nature of the disease and can assist in the diagnosis ^6,7.

In the adult onset form of Sandhoff disease, MRI of the brain may be normal initially, or demonstrate progressive cerebellar atrophy ⁹.

Treatment and prognosis

There is currently no cure for Sandhoff disease, and treatment is primarily supportive. Management focuses on alleviating symptoms, such as controlling seizures, managing feeding difficulties, and providing respiratory support as the disease progresses ³.

Ongoing research into potential treatments includes enzyme replacement therapy, gene therapy, and substrate reduction therapy. These experimental approaches aim to address the underlying cause of the disease by either replacing the deficient enzymes or reducing the accumulation of harmful substrates, though they are not yet widely available ³.