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...
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.
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).
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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