Tay-Sachs disease is inherited in the autosomal recessive pattern, depicted above.
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Tay-Sachs disease

Tay-Sachs disease (abbreviated TSD, also known as "GM2 gangliosidosis") is a fatal genetic disorder, inherited in an autosomal recessive pattern, in which harmful quantities of a fatty substance called ganglioside GM2 accumulate in the nerve cells in the brain. more...

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The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye in 1881, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish population of 1887.

Symptoms

Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cells become distended with fatty material, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in.

A much rarer form of the disorder which occurs in patients in their twenties and early thirties is characterized by unsteadiness of gait and progressive neurological deterioration. Patients with Tay-Sachs have a "cherry-red" spot in the back of their eyes (the retina).

Pathogenesis

The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of acidic fatty materials known as gangliosides. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity. Both parents must be carriers in order to have an affected child. Prenatal monitoring of pregnancies is available if desired.

To expand on the genetic basis, Tay-Sachs is an autosomal recessive genetic condition: if both parents are carriers, there is a 25% risk with each pregnancy for an affected child.

The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. This enzyme is necessary for breaking down N-galactosamine from GM2 gangliosides in brain and nerve cells. More than ninety mutations have been identified in the HEXA gene. These consist of base pair insertions, base pair deletions, splice site mutations, and point mutations. All of these mutations alter the protein product. For example, a four base pair insertion in exon 11 results in an altered reading frame for the HEXA gene while a three base pair deletion eliminates the amino acid phenylalanine from the protein product at position 304. A G to C point mutation at amino acid 180 changes the codon UAC to UAG causing termination of the polypeptide. A G to A point mutation at amino acid 170 changes the codon CGA to CAA and CGG to CAG which produces glutamine instead of arginine. A G to C mutation in the splice site of intron 12 has also been identified. This mutation creates a recognition site for the restriction enzyme Ddel resulting in abnormal splicing and the production of aberrant mRNA species.

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Mutation revealed for adult Tay-Sachs
From Science News, 3/18/89 by Ingrid Wickelgren

Mutation revealed for adult Tay-Sachs

Scientists have discovered the genetic mutation responsible for the adult form of Tay-Sachs disease, a rare, degenerative brain disorder most commonly seen in its childhood form. The finding, along with the recent discovery of two mutations that can cause the childhood disorder, may allow screening of people who carry a Tay-Sachs gene to tell them which form of the disease they carry, says study coauthor Richard L. Proia, a biochemist at the National Institutes of Health.

People with late-onset Tay-Sachs suffer progressive mental and motor deterioration, with symptoms that vary from stuttering and falling to depression, schizophrenia and premature death. "But [adult Tay-Sachs] is nothing like infantile Tay-Sachs," which leads to death in early childhood, says biochemist Elizabeth F. Neufeld of the University of California, Los Angeles.

To contract either form of Tay-Sachs, a person must inherit a defective gene from both parents. The most common Tay-Sachs carriers, Ashkenazi Jews, frequently choose to take an enzyme test screening for this incurable disease and, if positive, usually opt for prenatal diagnosis or, in rare cases, not to conceive children. Genetic testing would be most useful in prenatal diagnosis, because the enzyme test may yield ambiguous results in fetuses predisposed to develop the adult form of the disease, says biochemist Eugene E. Grebner of Thomas Jefferson University in Philadelphia.

Both adult and infantile forms of the disease are caused by defects in an enzyme called beta-hexosaminidase. In the infantile disorder, brain cells do not produce this enzyme, and in the adult case, they produce a poorly functioning enzyme. In both, brain cells degenerate because they accumulate a membrane lipid normally metabolized by beta-hexosaminidase.

To find the adult mutation, Proia and geneticist Ruth Navon examined DNA from an adult Tay-Sachs patient who also carries the gene for infantile Tay-Sacs. The small amount of beta-hexosaminidase RNA his cells made from the late-onset mutant gene allowed the scientists to isolate the mutant. Sequencing the gene revealed the oddity: one changed base pair, a mutation for which eight additional adult Tay-Sachs patients proved positve and 20 asymptomatic individuals tested negative, the scientists report in the March 17 SCIENCE.

In separate work, Neufeld and Michael M. Kaback of the University of California, San Diego, found the same mutation. Their findings will appear next month in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

COPYRIGHT 1989 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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