Tay Sachs Disease
From Science Online
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Introduction
Tay Sachs Disease is an inherited, fatal lipid disorder. Large quantities of a fatty substance, known ganglioside Gm2, builds up in tissue and nerve cells around the brain. Tay Sachs attacks and severely damages the nervous system. The condition is caused by poor activity of the enzyme beta- hexosaminidase A, which catalyzes biodegradation of the fatty, acidic substance known as gangliosides.
Causes/ Etiology of Beta-Hexosaminidase A
"Hexa" provides instructions for making the enzyme beta- hexosaminidase A, which plays a very critical role in the body's central nervous system. This particular enzyme is located in cell structures called lysosomes, which are considered the cells "recycling center". Inside each lysosome, this beta- hexosaminidase A aids in the breakdown of a fatty substance, GM2 ganglioside. Ganglioside GM2 activator protei is a lipid transfer protein that stimulates the enzymatic processing of gangliosides. Gangliosides are located in the cell plasma membrane and regulate cell signal transduction. Mutations within this Hexa gene leads to the disruption of beta- hexosaminidase A's normal activity, preventing its proper breakdown. This will then accumulate to very toxic levels in the brain and spinal cord, which leads to the destruction of nerve cells, which eventually cause sign and symptoms of Tay Sachs disease. Tay Sachs disease impairs proper lysosome enzyme function and involves tremendous build up of GM2 ganglioside, this disease is also referred as lysosome storage disorder or GM2- gangliosidosis.(Univ. of Maryland Med. Center)
Diagnosis/ Treatment
At this time, there is NO CURE for Tay Sachs disease. In the case that both parents are carriers a prenatal test, such as aminocentesis, is almost necessary. If the results from the prenatal test come back positive, an abortion seems to be only solution. The most common forms and symptoms of Tay Sachs Disease occur during infancy. The child may appear to be normal for the first 3-7 months of infancy, then symptoms occur. These include: - slowing of development - weakening muscles - loss of motor skills (MedTV)
Genetics
The Tay Sachs mutation occurs on chromosome 15, also known as the hexosaminidase A gene (alpha polypeptide). More than 95 mutations on this HEXA gene cause the disease. Preventing the normal breakdown of GM2 ganglioside in the nervous system, these mutations reduce and eliminate the activity of the enzyme beta- hexosamindase A. The HEXA gene is located on the long arm of chromosome 15 between sites 23 and 24. The HEXA gene is located from base pair 70,422,832 to base pair 70,455,392 on chromosome 15.
Tay Sachs disease is an inherited autosomal recessive disorder, which means the child must inherit one recessive gene from each parent. Mostly known as a Jewish genetic disease affecting 1 in every 2500 Ashkenazi Jews. Also, it is estimated that 1 in 25 Ashkenazi Jews are carriers of this disease. Currently more than 100 mutations in the alpha subunit gene of N- acteyl-B- hexosaminidase have been characterized in Tay Sachs Disease. In a recent study of the hexosaminidase- A mutation in a Jewish, Turkish population came up with the following results:
"At least six mutations were identified in Turkish Tay-Sachs (TS) patients to date: A donor splice site mutation (G412→A) and a stop codon mutation R137X in exon 3, a donor splice site mutation in intron 5 (INS-5 G→A), an in-frame 12 bp deletion in exon 10 (∆ 1096-1107 or 1098-1109), which seems the most frequent mutation in the Turkish population, a stop codon mutation R393X in exon 11 and a single G1362→A transition in exon 123,4,5,6. This report describes the identification of a frameshift mutation in exon 13 (∆C1510) of HEXA as the seventh mutation of TSpatients in the Turkish population, and this mutation was present in both alleles of our patient." All the tests preformed in this experiment of mutations were done through PCR.
This is only six common mutations, yet there are over a hundred that can lead either to Tay Sachs disease or other common signs and symptoms of the malfunction of the Beta- Hexosaminidase A enzyme.
Structure
Above is the crystallographic structure of human beta-Hexosaminidase A, a very complex molecule that plays a major role in the fatal Tay- Sachs disease. This structure contains 137 different Alpha helices, mostly noticeable on the ends of the molecule. Also, this structure contains 164 Beta Sheets that are mostly concentrated in the middle of the molecule.
References
Primary:
Identification of 7th hexosaminidase A mutation of Tay-Sachs disease [1]
Production of recombinant beta-hexosaminidase A, a potential enzyme for replacement therapy for Tay-Sachs and Sandhoff diseases [2]
Biochemical characterization of the GM2 gangliosidosis B1 variant [3]
Other:
National Institute of Neurological Disorders and Stroke [4]
University of Maryland Medical Center [5]
Med TV [6]
