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Sandhoff disease is a rare inherited disorder that causes progressive destruction of nerve cells in the brain and spinal cord (the central nervous system).
The most common and severe form of Sandhoff disease begins in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Sandhoff disease develop seizures, vision and hearing loss, mental retardation, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Some affected children may also have enlarged organs (organomegaly) or bone abnormalities. Children with the severe infantile form of Sandhoff disease usually live only into early childhood.
Other forms of Sandhoff disease are very rare. Signs and symptoms can begin in childhood, adolescence, or adulthood and are usually milder than those seen with the infantile form of Sandhoff disease. As in the infantile form, mental abilities and coordination are affected. 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.
Sandhoff disease is a rare disorder; its frequency varies among populations. This condition appears to be more common in the Creole population of northern Argentina; the Metis Indians in Saskatchewan, Canada; and people from Lebanon.
Mutations in the HEXB gene cause Sandhoff disease.
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 cellular structures called lysosomes, which act as the cell's 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.
Mutations in the HEXB gene disrupt the activity of beta-hexosaminidase A and beta-hexosaminidase B, preventing the breakdown of GM2 ganglioside and other molecules. As a result, these compounds can accumulate to toxic levels within cells. A buildup of GM2 ganglioside in the central nervous system leads to the progressive destruction of nerve cells, which causes many of the signs and symptoms of Sandhoff disease.
Because Sandhoff disease impairs the function of lysosomal enzymes and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.