Sandhoff disease

Overview
Sandhoff disease is a rare inherited lipid storage disorder that causes progressive destruction of nerve cells in the brain and spinal cord.

History
Sandhoff disease was first illustrated in Life Science in 1968 by a German chemist named Konrad Sandhoff. Konrad Sandhoff investigates biochemical and enzymatic aspects of the gangliosidoses and other storage diseases.

Types
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. As the disease progresses, infants 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 infants with Sandhoff disease may also have enlarged organs (organomegaly) or bone abnormalities. Children with the severe form of this disorder 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.

Symptoms
Symptoms of Sandhoff disease can appear in childhood, adolescence and in adulthood. The symptoms are motor weakness, startle reaction to sound, early blindness, progressive mental and motor deterioration, frequent respiratory infections, macrocephaly (an enlarged head), doll-like facial appearance, seizures, cherry red spots in the eyes, myoclonus (muscle contractions), and enlarged liver and spleen. These symptoms are similar to those of Tay-Sachs disease. The diseases are both inherited, and both involve the central nervous system.

Causes


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. These enzymes, beta-hexosaminidase A and beta-hexosaminidase B, function in nerve cells to break down fatty substances, complex sugars, and molecules that are linked to sugars. In particular, beta-hexosaminidase A breaks down a fatty compound called GM2 ganglioside. Mutations in the HEXB gene disrupt the activity of these enzymes, preventing the breakdown of GM2 ganglioside and other molecules.

As a result, these compounds can accumulate to toxic levels within cells. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of nerve cells, causing the signs and symptoms of Sandhoff disease. The condition is inherited in an autosomal recessive pattern.

Incidence
Sandhoff disease is a rare disorder; its frequency varies among populations. The condition appears to be more common in the Creole population of northern Argentina, the Metis Indians in Saskatchewan, Canada, and people from Lebanon. It is also found in Eastern European, Ashkenazi Jews, but it can affect any ethnic group.

Diagnosis
Sandhoff disease can be detected through the following procedures (before it is apparent through physical examination): a biopsy removing a sample of tissue from the liver, genetic testing, molecular analysis of cells and tissues (to determine the presence of a genetic metabolic disorder), enzyme assay, and occasionally a urinalysis to determine if the above-noted compounds are abnormally stored within the body. For a child to suffer from this disease, both parents must be carriers, and both must transmit the mutation to the child. Thus, even in the case where both parents have the mutation, there is only a 25 percent chance their child will inherit the condition. Frequently, parents are given the opportunity to have a DNA screening if they are at high risk, to determine their carrier status before they have children. However, it is also highly recommended to undergo testing even for those parents who do not have a family history of Sandhoff disease. Over 95% of the families that have children with Sandhoff disease had no known prior family history of the condition, as the mutation in the HEXB gene is "silent," or recessive, and often passed undetected from one generation to the next. Naturally, if an individual carries the mutation, he or she has a risk of transmitting it to the unborn child. Genetic counseling is recommended for those who have the mutation.

Treatment
Sandhoff disease does not have any standard specific treatment or cure. However, a person suffering from the disease needs proper nutrition, hydration, and maintenance of clear airways. To reduce some symptoms that may occur with Sandhoff disease, the patient may take anticonvulsants to manage seizures or medications to treat respiratory infections, and consume a precise diet consisting of puree foods due to difficulties swallowing. Infants with the disease usually die by the age of 3 due to respiratory infections.

Recent work done at Burham Institute for Medical Research and scheduled to be published in Nature, indicates that human embryonic stem cells may provide a potential therapy for the disease.

Stem cell transplants, if done at a young enough age, have been shown in some cases to arrest progression of the disease and allow children to have a normal lifespan. Dr. Joanne Kurtzburg at Duke University has successfully performed these transplants on Sandhoff children as well as Tay-Sachs children.