Information on the following diseases can be found in the Related Disorders section of this report:

• Tay-Sachs Disease
• Gaucher Disease
• Niemann-Pick Disease
• Fabry's Disease
• Leigh's Disease
• Batten Disease
• Kufs Disease

The first symptoms of the infantile form of Sandhoff disease typically begin between the ages of 3 to 6 months. These may include feeding problems, general weakness (lethargy), and an exaggerated startle reflex in response to sudden loud noises. A physician's examination with a special instrument typically reveals round, red spots (cherry macules) in the eyes. Motor delays and mental deterioration are progressive and are characterized by motor weakness, spasticity, heart murmurs, seizures (myoclonic and generalized), blindness, and/or abnormally enlarged spleen (splenomegaly). Firm stroking of the sole of the foot produces a typical reflex response (Babinski sign), and the outer toes spread after the side of the sole of the foot has been stroked.

Juvenile and adult forms of Sandhoff disease have been described that are more variable in the age of onset and severity of symptoms.

Sandhoff disease is an autosomal recessive genetic disorder caused by an abnormal gene for the beta subunit of the hexosaminidase B (HEXB) enzyme. This gene abnormality results in a deficiency of enzymes called hexosaminidase A and B that are responsible for breaking down GM2 gangliosides made by the nerve cells. The accumulation of GM2 gangliosides in the lysosomes of nerve cells damages the nerve cells and leads to a progressive loss of neurological function.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Sandhoff disease is a very rare disorder that affects males and females in equal numbers. This disorder occurs in people of many different ethnic backgrounds. Sandhoff disease may be more common in the Creole population of northern Argentina, the Metis Indians in Saskatchewan, Canada and individuals of Lebanese ancestry.

Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. This disorder is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or "digest" nutrients, including certain complex carbohydrates and fats. (For more information on this disorder, choose "Tay-Sachs" as your search term in the Rare Disease Database.)

Gaucher disease is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen and liver. The symptoms and physical findings associated with Gaucher disease vary greatly from case to case. Some individuals will develop few or no symptoms (asymptomatic); others may have serious complications. Common symptoms associated with Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia), and skeletal abnormalities. Three separate forms of Gaucher disease have been identified and are distinguished by the absence of, or the presence and extent of, neurological complications. All three forms of Gaucher disease are inherited as autosomal recessive traits. (For more information on this disorder, choose "Gaucher" as your search term in the Rare Disease Database.)

Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells. (For more information on this disorder, choose "Niemann-Pick" as your search term in the Rare Disease Database.)

Batten disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Batten disease is sometimes considered the juvenile form of the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. . (For more information on this disorder, choose "Batten" as your search term in the Rare Disease Database.)

Leigh's disease is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh's disease usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh's disease progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. (For more information on this disorder, choose "Leigh" as your search term in the Rare Disease Database.)

Kufs Disease is characterized by neurologic symptoms that may mimic mental illness, movement malfunction, and problems with sight. Kufs Disease is linked to excess accumulations of pigments (lipofuscins) dissolved in fat tissues that are found throughout the central nervous system. Kufs Disease, Batten Disease, Bielchowsky Disease, and Santavuori-Haltia Disease are different forms of the same family of disorders (neuronal ceroid lipofuscinoses [NCL]) that are differentiated by the age of onset. The various forms of this disorder are often extremely difficult to differentiate from other progressive degenerative diseases of the central nervous system. . (For more information on this disorder, choose "Kuf" as your search term in the Rare Disease Database.)

Diagnosis
Sandhoff disease can be diagnosed by performing an enzyme assay to determine activity of the hexosaminidase A and B enzymes. Affected individuals have absent or reduced activity of both enzymes. Molecular genetic (DNA) testing is available to determine the specific gene mutation that is present in the beta subunit of the Hexosaminidase B gene and confirm the diagnosis.

Treatment
Treatment of Sandhoff disease is symptomatic and supportive and includes nutritional and respiratory therapy. Anticonvulsants may be prescribed to temporarily control seizures. Death from respiratory infection usually occurs by age three for the infantile form of the disease.

Genetic counseling is recommended for affected individuals and their families.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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