Sandhoff disease

Infants with the classic form of Sandhoff disease typically appear normal until the age of 3 to 6 months when their development slows and muscles used for movement weaken. Affected infants typically lose motor skills such as turning over, sitting, and crawling. They may also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Sandhoff disease may experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified through an eye examination, is characteristic of this disorder. Some affected children also have an enlarged liver and spleen, frequent respiratory infections, or bone abnormalities.^[1][2] Children with the severe infantile form of Sandhoff disease usually live only into early childhood.^[1]

Forms of Sandhoff disease where the symptoms develop after infancy are very rare. Signs and symptoms can begin in childhood, adolescence, or adulthood and are usually milder than those seen with the infantile form. Characteristic features include muscle weakness, loss of muscle coordination (ataxia) and other problems with movement, speech problems, and mental illness. These signs and symptoms vary widely among people with late-onset forms of Sandhoff disease.^[1]

Sandhoff disease is caused by mutations in the HEXB gene. The HEXB gene provides instructions for making a protein that is part of two critical enzymes in the nervous system, beta-hexosaminidase A and beta-hexosaminidase B. These enzymes are located in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, these enzymes break down fatty substances, complex sugars, and molecules that are linked to sugars. In particular, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside.^[1]

Mutations in the HEXB gene disrupt the activity of beta-hexosaminidase A and beta-hexosaminidase B, which prevents these enzymes from breaking down GM2 ganglioside and other molecules. As a result, these compounds can accumulate to toxic levels, particularly in neurons of the brain and spinal cord. A buildup of GM2 ganglioside leads to the progressive destruction of these neurons, which causes many of the signs and symptoms of Sandhoff disease.^[1]

Sandhoff disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.^[1] 

Carrier testing is performed to identify individuals who have a gene mutation and may be at risk for having a child or other family members with the same mutation. Carriers usually do not have symptoms related to the gene mutation. Carrier testing is typically offered to individuals who have family members with a genetic condition, family members of an identified carrier, and individuals in ethnic or racial groups known to have a higher carrier rate for a particular condition.^[3]

There two types of carrier screening tests: DNA and biochemical. Sandhoff carrier screening is available through DNA or biochemical testing. DNA carrier screening detects specific known mutations that are ‘looked’ for in the test. A negative DNA carrier result does not eliminate an individual's chances of being a carrier because of the possibility of carrying an unknown mutation or one not ‘looked’ for in the test. Biochemical testing, also called an enzyme assay, detects the level of the enzyme(s) in question in the blood. Enzyme assays can be done using serum or leukocytes (white blood cells). Serum is typically the standard test, but leukocyte testing is recommended when the person being tested is pregnant, on birth control pills or taking any medications that affect hormones because all of these situations can potentially interfere with the accuracy of the serum test. DNA carrier screening may be recommended if the results of the biochemical test are uncertain.^[4]

Sandhoff disease is associated with deficiencies of both hexosaminidase A (hex A) and hexosaminidase B (hex B) enzyme activity. Carriers of Sandhoff disease have reduced (but adequate) amounts of both hex A and hex B. While most hex A assays are performed to identify Tay-Sachs carriers, the test also can also identify individuals that are carriers of Sandhoff disease. Looking at the total hexosaminidase activity in combination with the percent of hex A activity present can aid in determining whether an individual is a carrier of Sandhoff disease. Typically, a decreased amount of total hexosaminidase activity along with an increase in the proportion of hex A activity in leukocytes is suggestive of a Sandhoff carrier.^[5] In contrast, Tay-Sachs carriers have a decrease in the amount of hex A activity. When the hex A enzyme result indicates that an individual is a possible Sandhoff carrier, the next step is typically to offer carrier testing to the individual's partner. If the partner is negative, the risk for the couple to have a child affected with the disorder is very significantly decreased. If the partner is also a possible carrier, more comprehensive testing may be offered.

We are unable to make recommendations about genetic screening and/or testing, but we do recommend genetic counseling for questions about carrier and prenatal genetic screening. Genetic counselors are non-directive healthcare professionals that help individuals understand their options. Genetic counselors are very knowledgable about testing guidelines and procedures. They can help a person to understand the tests and what the results mean for individuals, partners, children and extended family members.^[6]

There is no specific treatment or cure for Sandhoff disease. Management is symptomatic and supportive. Supportive treatment includes proper nutrition and hydration and keeping the airway open. Anticonvulsants may be used to control seizures.^[2] There are current research efforts underway, including experimental gene therapy, substrate reduction therapy, bone marrow transplants, and stem cell therapy.^[7][8] Additional information about these investigational treatments for Sandhoff disease can be accessed through the National Tay-Sachs & Allied Diseases Association website.

The prognosis for individuals with Sandhoff disease is poor. Death usually occurs by age 3 or 4 and is often caused by respiratory infections.^[2][9]