Sandhoff disease

Definition

Sandhoff disease is a relatively rare, genetically inherited disease that results in the progressive deterioration of the central nervous system . In Sandhoff disease, abnormal lipid (fat) accumulation due to a storage defect causes damage to the brain as well as other organs of the body.

Description

Sandhoff disease is an autosomal recessive disorder, meaning that having an affected offspring requires both unaffected parents to be carriers. Parents who carry the disorder will have a 25% risk of having an affected offspring in subsequent pregnancies. This disease is similar to a related disorder known as Tay-Sachs disease, although Sandhoff disease is more severe.

Demographics

As Sandhoff disease is a recessive disorder, males and females are affected with equal frequency. This disorder is more common in people with non-Jewish descent, unlike Tay-Sachs disease, which is prevalent mainly in individuals with Jewish ancestry.

Causes and symptoms

Sandhoff disease is caused by mutations in two different genes that encode subunits that make up a protein called hexosaminidase. Hexosaminidase is an enzyme that breaks down certain fats in the brain. This enzyme is either composed of an alpha and a beta subunit (HexA) or two beta subunits (HexB). Sandhoff disease is caused by a mutation in a gene that is distinct from the gene that causes Tay-Sachs disease. In Tay-Sachs disease, a mutation that affects the alpha subunit of the enzyme causes a deficiency in HexA. Sandhoff disease is caused by mutations that affect the beta subunit, rendering both the HexA and HexB enzymes deficient. A deficiency of this enzyme leads to the accumulation of GM2 ganglioside, a fatty material found in the brain.

The beta subunit is encoded by a gene localized to chromosome 5, while the alpha subunit is encoded by a gene on chromosome 13. There is also another gene on chromosome 5 that encodes an activator that is required for either enzyme to be functional. Similar symptoms are observed in diseases arising from mutations that affect any of these three genes. Only biochemical genetic analysis of enzyme activity can pinpoint the cause and specify the disorder. However, Sandhoff disease can be distinguished from Tay-Sachs disease clinically by virtue of skeletal system or abdominal organ involvement (if present) in the later disease.

At birth, infants tend to be without symptoms and usually do not develop them until approximately six months of age. The symptoms begin with motor deficits (lack of normal movement) and a characteristic startle reaction to various sounds. Babies with Sandhoff disease progressively deteriorate in terms of motor function, and they often have seizures and myoclonus . Myoclonus is abnormal, exaggerated muscle contractions. Blindness can also be part of the symptoms. The loss of motor function includes the ability to swallow, and the affected infant has an increased risk for inhaling feedings into the lungs, frequently leading to pneumonia.

A typical physical feature of Sandhoff disease is the presence of cherry-red spots in the back of the eyes. Additionally, affected children have an abnormally enlarged head and appear to have a doll-like appearance.

Diagnosis

Because Sandhoff disease and Tay-Sachs disease have similar clinical symptoms, distinguishing them requires biochemical analysis. This involves a test to measure enzyme activity of the two hexosaminidase enzymes. If the enzyme activity results indicate that there is no hexosaminidase activity, it means that the patient has Sandhoff disease. If, however, there is still B subunit activity, then this indicates that the patient might have Tay-Sachs disease.

Treatment

There is no cure for Sandhoff disease, and treatment is based on lessening the symptoms once they begin. Medication is usually given to reduce seizures, for example, and a feeding tube may be inserted to prevent aspiration of feedings into the lungs.

Recovery and rehabilitation

Emphasis is placed on comfort rather than recovery, due to the progressive nature of Sandhoff disease. Because of the nature of the disorder, rehabilitation is not usually applicable to help with improving the motor deficits that develop. Physical therapy may be helpful to maintain muscle tone and skeletal alignment for as long as possible, while positional strategies and devices provided by an occupational therapist may increase comfort as symptoms progress.

Clinical trials

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is sponsoring, as of February 2004, a study to evaluate children with glycosphingolipid (GSL) storage disorders (such as Sandhoff disease) to investigate changes that occur in the brain that are responsible for nervous system degeneration. In this study, patients will receive medical treatment for their disorder. Contact the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), located at 9000 Rockville Pike, Bethesda, Maryland, 20892, Recruiting: Patient Recruitment and Public Liaison Office, (800) 411-1222 or [email protected].

Prognosis

The prognosis for Sandhoff disease is poor. Affected babies usually do not survive past the age of three and typically, death occurs due to complications associated with respiratory infections.

Special concerns

Children who are affected with Sandhoff disease will require full time supervision and caretaking responsibilities. Psychological counseling for family members is often helpful. Genetic counseling for reproductive risks is recommended. There are also several support groups operated and comprised of other families nationwide with Sandhoff disease.

Resources

BOOKS

Icon Health Publications. The Official Parent's Sourcebook on Sandhoff Disease: A Revised and Updated Directory for the Internet Age. New York: Icon Group International, 2002.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Genetics in Medicine. Philadelphia : Saunders, 2001.

PERIODICALS

Gilbert, F., R. S. Kucherlapati, R. P. Creagan, M. J. Murnane, G. J. Darlington, and F. H. Ruddle. "Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes." Proc. Nat. Acad. Sci. 72 (1975): 263–267, 1975.

Neufeld, E. F. "Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase." J. Biol. Chem. 264 (1989): 10927–10930.

OTHER

"What every family should know: Sandhoff disease." The National Tay-Sachs & Allied Diseases Association. (February1, 2004). <http://www.ntsad.org/pages/sandhoff.htm>.

"NINDS Sandhoff Disease Information Page." National Institute of Neurological Disorders and Stroke. (February 1, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/sandhoff.htm>.

ORGANIZATIONS

National Tay-Sachs and Allied Diseases Association. 2001 Beacon Street Suite 204, Brighton, MA 02135. (617) 277-4463. (617) 277-0134. (800) 90-NTSAD (906-8723). [email protected]. <http://www.ntsad.org>.

National Organization for Rare Disorders (NORD). P.O. Box 1968 (55 Kenosia Avenue), Danbury, CT 06813-1968. (203) 744-0100. (203) 798-2291. (800) 999-NORD (6673). [email protected]. <http://www.rarediseases.org>.

Bryan Richard Cobb, PhD