Tay-Sachs disease (Hexosaminidase A deficiency)

introduction
tay-sachs is a neurodegenerative disorder inherited in an autosomal recessive pattern, usually manifested in human victims at first between 3-6 months of age and causing death before age 4. the molecular basis of tay-sachs is a mutation in the gene HEXA on chromasome 15, which codes for the alpha subunit of beta-hexosaminidase A (Hex A), an alpha-beta heterodimeric, lysosomal enzyme that along with with GM2 activator protein, catalyzes the breakdown of the glycosphingolipid GM2. an analogous disorder, sandhoff disease, occurs when HEXB is mutated, thus causing the production of deficient beta-hexosaminidase B (Hex B), the beta-beta homodimeric isoenzyme of Hex A. in addition, GM2 activator disease occurs as the result of the production of deficient GM2 activator protein.

when the mutated HEXA gene yields defective Hex A, GM2 accumulates in the patient's neurons causing neurodegeneration, blindness, seizures and eventually total incapacitation and death. although the most common form of tay-sachs, acute infantile hexosaminidase A deficiency, is fatal early in life, adult onset forms exsist that manifest more variable symptoms.

for more summary, visit NIH's GeneTests

genetic screening for tay-sachs
tests exsist for the more than 90 disease-causing mutations of Hexa, although the most commonly performed ones test for six specific alleles that usually account for Hex A deficiency. of these six alleles, three nullify Hex A's activity and account for classic TSD (+TATC1278, +1IVC12, and +1IVS9), one causes adult-onset TSD (G269S) and two are considered pseudodeficient, meaning their protein products act upon GM2 but are inactive against the synthetic substrate used to test individuals' Hex A activity levels in their blood serum (R247W and R249W) - GM2 is too unstable a reagant to be used in laboratory testing. the null alleles of HEXA are far more prevelant in persons of Ashkenazi Jewish heritage and the adult-onset and pseudodeficient alleles in persons of non-Jewish heritage. before widespread population-based carrier screening was in place, 1 in 3600 Ashkenazi Jewish births resulted in TSD, indicating 1 in 30 Jewish Americans of Ashkenazi heritage as a carrier (compare to 1 in 250 Sephardic Jews and 1 in 300 non-Jews). since the implementation of widespread education, population-based carrier screening and genetic counseling, though, TSD incidence among North American Jews of Ashkenazi lineage has been reduced by over 90%.

Citation: GeneTests

An interesting article adressing the social and ethical dilemmas presented by the rise of techniques such as preimplantion diagnosis (PID), antenatal screening (ANS) and antenatal diagnosis (AND)...briefly mentions the practice of terminating TDS-positive fetuses identified via AND: Antenatal screening and its possible meaning from unborn baby's perspective

knockout gene experimentation and its implications

mice embryos were engineered by knockout gene therapy to express each of the three gangliosidoses. although usually a powerful tool in elucidating complex physiological processes in humans, knocking out mouse genes Hexa and Hexb (inducing tay-sachs and sandhoff, respectively) yielded a vast difference in phenotypes when compared to the human versions of the diseases. Hexa -/- mice exhibited some neuropathological symptoms of TDS, namely limited accumulation of GM2 in the nervous system, but remained asymptomatic. Hexb -/- mice experienced severe GM2 accumulation causing fatal neurodegeneration. Finally, Gm2a -/- mice displayed limited GM2 build-up and defects in balance and motor coordination.

view the full text at The Proceedings of the National Academy of Sciences


symptoms/treatment

the symptoms of tay-sachs are quite horrific. by 6-10 mo. of age, infant stops aqcuiring new motor skills, decreases in visual attentiveness, exhibits irregular eye movement. by 10-12 mo., voluntary movements and attentiveness diminish, vision deteriorates and seizures increase in frequency. between 18-24 mo., progressive enlargement of the head, decerebrate posturing, difficulty swallowing, increasingly severe seizures and eventually a vegetative state. death usually occurs before 4 yrs. of age.

adequate nutrition/hydration, protection of the airway and management of infectious disease are the only measures able to be taken on part of the patient. seizure control drugs exsist but with limited effectiveness.

Citation: GeneTests

Cytogenetic location of HEXA gene on chromasome 15 (scroll to bottom)


The Hexa mRNA transcript is 3163 bp long Entrez Nucleotide


the FASTA format of the 529 aa protein

Structure of the compound GM2: PubChem