TAY-SACHS DISEASE

1. "Payton was a beautiful baby girl — but she would not sit up. Four months passed, and similar milestones seemed to slip away. She wouldn't roll over. She wouldn't play with her toys. She still wouldn't sit up. Payton's symptoms progressively worsened. Loud noises inexplicably startled her. An inability to coordinate muscle movement between her mouth and tongue caused her to choke on food and produce excessive saliva." Because neither of Peyton's parents were Jewish, Her doctors did not suspect Tay-Sachs disease until she was 10 months old, when her ophthalmologist noticed the cherry red spots in her eyes. Payton died in 2006 at the age of 3½.

2. SOCIAL AND MOLECULAR ASPECT TAY-SACHS DISEASE GIA DUONG

3. Overview • Autosomal recessive genetic disorder caused by the mutation of the HEXA (HexosaminidaseA) gene on chromosome 15 • Deterioration of mental and physical abilities due to excess deposit of gangliosides (GM2) in the brain • Common among Ashkenazi Jews, French Canadian, and Cajuns of Southern Louisiana

4. History and Social • First known as “auroticfamilial idiocy” in 1900-a term used by Bernard Sachs based on his observation on many cases from the same single Jewish family • It is a curious fact that amaurotic family idiocy, a rare and fatal disease of children, occurs mostly among Jews. The largest number of cases have been observed in the United States—over thirty in number.The chief characteristics of the disease are progressive mental and physical enfeeblement; weakness and paralysis of all the extremities. On investigation of the reported cases it has been found that neither consanguinity nor syphilitic, alcoholic, or nervous antecedents in the family history are factors in the etiology of the disease. No preventive measures have as yet been discovered, and no treatment has been of any benefit, all the cases having terminated fatally 1091- 1906. Jewish Encycolpedia -1st edition • Disease was named after Warren Tay, a British ophthalmologist and Bernard Sachs, an American neurologist in 1930s after the molecular and genetic basis of the disease was understood.

5. Classification &Symtom • Infantile TSD • Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cell become distended with gangliosides, 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. Death usually occurs before the age of 4 • Juvenile TSA • Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech difficulties, and swallowing difficulties. Patients with Juvenile TSD usually die between 5–15 years • Late Onset Tay-Sach (LOTS) • Occurs in patients in their 20s and early 30s. LOTS is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness

6. CAUSE • TSD is caused by insufficient activity of hexosamindase A that catalyzes the hydrolysis of gangliosides, a fatty acid derivative • Hexosaminidase A is a enzyme found in the lysosomes in the neural cells that breaks down lipids. • When Hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. • Hydrolysis of GM2-ganglioside requires three proteins. • Alpha and beta subunits of hexosaminidase A • GM2 activator protein (GM2A): cofactor for the enzyme. ***Deficiency in any one of these proteins leads to storage of the ganglioside. Mutation from the gene cause incorrect folding.

7. GENETICS • - Of the more than 100 HEXA mutation identified to date, • the vast majority (>90) are associated with the acute infantileTay-Sachs disease • Mutations in HEXA and GM2A genes causing GM2gangliosidosishave been characterized in detail, and include partialgene deletion, splicing mutations, nonsenseand missense mutations. • These mutations cause defects in • transcription, translation, monomer folding and/or • Dimerization. Chromosome 15

8. GENETICS (Cont) • Ashkenazi Jews. • A four base pair insertion in exon 11 (1278insTATC). • Most prevalent mutation in the Ashkenazi Jewish population, •  Infantile form of Tay-Sachs disease • Cajun in Southern Louisiana • Same mutation found among Ashkenazi Jews • Originate from a single founder non-Jewish couple, that lived in France in the 18th century • French Canadians. • Unrelated to the predominant Ashkenazi mutation • Long sequence deletion • HEXA • Alpha-subunit  encoded by HEXA • Beta-subunit  encoded by HEXB • The primary sequences of these subunits are approximately 60% identical. • GM2 activator protein (GM2AP) encoded by GM2A

9. Molecular ViewHEXA Structure Overview

10. Reaction GM2 is presented to Hex A by the GM2 activator protein (GM2AP). Hex A removes the terminal b-linked GalNAc from the GM2 ganglioside to produce the GM3 ganglioside

11. Mechanism In both active sites of beta and alpha subunits, a glutamate residue acts as a general acid-base that assists in cleaving the terminal b-linked GalNAc or GlcNAc residues from substrates; whereas an adjacent aspartateresidue stabilizes the positively charged oxazolinium intermediate that develops during the substrate-assisted catalytic mechanism carried outbyhuman Hex

12. Active sites • Two active sites are present in the Hex A dimer. • Residues of the a-subunit • Residues of the b-subunit • Located at the opening of the TIM barrels • NGT (NAG-thiazoline)  Use to examine the active site binding • Function: In patients with Tay-Sachs disease (misfoldedhexosaminidase A), NGT acts as a molecular chaperone by binding in the active site of hexosaminidase A which helps create a properly folded hexosaminidase A

13. Alpha subunit active site

14. Beta sub unit active site

15. Mutation Severity • Each missensemutation has been colored according to the severity of the GM2 gangliosidosisphenotype, red for acute to subacute, green for chronic and blue for asymptomatic (mutations that lower Hex A activity, but not below the critical threshold needed to prevent storage). The majority of residues involved in acute and chronic TSD are located throughout domain II of the a-subunit, distributed amongst the b-strands and helices comprising the TIM barrel. Notably, only a few mutations are found among residues of the active site.

17. Pharmaceutical • Substrate reduction therapy: • One experiment has demonstrated that, by using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides can be metabolized so that they become almost inconsequential. If a safe pharmacological treatment can be developed, one that causes the increased expression of lysosomalsialidase in neurons, a new form of therapy, essentially curing the disease, could be on the horizontreatmentwith the drug OGT 918

18. Prevention • Screening • Detect Carriers • Prenatal testing • Screening success with Ashkenazi Jews • TSD in the Jewish population had declined by more than 90% since the advent of genetic screening