Sandhoff disease is a rare, inherited neurodegenerative disorder. It belongs to a group of conditions known as lysosomal storage diseases. These disorders occur when lysosomes, cellular compartments responsible for waste breakdown, do not function correctly. Sandhoff disease primarily affects the brain and spinal cord, leading to progressive damage.
The Genetic Basis of Sandhoff Disease
Sandhoff disease stems from changes within the HEXB gene. This gene contains instructions for producing components of two related enzymes: beta-hexosaminidase A and B. Mutations in the HEXB gene result in a significant reduction or complete absence of these enzymes.
Hexosaminidase A and B break down a fatty substance called GM2 ganglioside. Without these enzymes, GM2 ganglioside accumulates to toxic levels in neurons of the brain and spinal cord. This buildup destroys nerve cells, causing neurological symptoms. Sandhoff disease follows an autosomal recessive inheritance pattern, meaning an individual must inherit two copies of the mutated HEXB gene, one from each parent, to develop the condition. Parents carrying one mutated gene copy typically do not show symptoms.
Signs and Progression
Sandhoff disease symptoms vary by form, categorized by age of onset. The classic infantile form is the most common and severe, with symptoms appearing between 3 and 6 months. Infants often experience a loss of previously acquired motor skills, such as the ability to sit or crawl, and exhibit an exaggerated startle response to loud noises. Seizures commonly develop as the disease progresses, and a distinctive “cherry-red spot” on the retina can often be identified during an eye examination.
The juvenile form of Sandhoff disease presents later, usually between ages 1 and 10, with a slower progression of symptoms. Children may experience difficulties with coordination, muscle weakness, and challenges with speech. In the late-onset or adult form, symptoms appear even later in life and progress at a much slower pace. These individuals might experience clumsiness, muscle weakness, and psychiatric symptoms.
Diagnosis and Medical Evaluation
Sandhoff disease is suspected when characteristic clinical symptoms are present. The definitive diagnostic test involves a biochemical enzyme assay, which measures the activity levels of hexosaminidase A and B enzymes. This test is typically performed using a blood sample or a skin biopsy. In individuals with Sandhoff disease, the activity of both hexosaminidase A and B enzymes is found to be severely reduced.
To confirm the diagnosis and identify the specific genetic cause, molecular genetic testing is performed. This testing analyzes the HEXB gene to pinpoint the exact mutations responsible for the enzyme deficiency. For prospective parents with a family history of the disease, prenatal diagnosis through amniocentesis or chorionic villus sampling is available to determine if the fetus is affected. Additionally, carrier screening can identify individuals who carry one copy of the mutated gene, informing family planning decisions.
Management and Supportive Care
Currently, there is no curative treatment for Sandhoff disease, and management focuses on alleviating symptoms and enhancing the quality of life for affected individuals. A multidisciplinary team approach addresses the diverse needs arising from the disease’s progression. Nutritional support, including feeding tubes, ensures adequate caloric intake and prevents aspiration pneumonia.
Physical therapy helps manage muscle stiffness and maintain mobility, while occupational therapy assists with daily living activities. Medications, such as anticonvulsants, control seizures, a common neurological symptom. Respiratory care manages lung infections and breathing difficulties, which can become more pronounced as the disease progresses. Researchers continue to explore potential therapies, including gene therapy and enzyme replacement therapy, offering hope for future treatment options.