"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.
SOCIAL AND MOLECULAR ASPECT
GIA DUONG
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

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
st
Encycolpedia -1 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.
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
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.
GENETICS
- Of the more than 100 HEXA mutation identified to date,
the vast majority (>90) are associated with the acute infantile
Tay-Sachs disease
-Mutations in HEXA and GM2A genes causing GM2
gangliosidosishave been characterized in detail, and include pa
gene deletion, splicing mutations, nonsenseand missense mut
-These mutations cause defects in
transcription, translation, monomer folding and/or
Dimerization.
Chromosome 15
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
Molecular View
HEXA
Structure Overview
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
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 aspartate residue stabilizes the positively charged
oxazolinium intermediate that develops during the substrate-assisted catalytic mechanis
carried outby human Hex
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
(misfolded hexosaminidase A), NGT acts as a
molecular chaperone by binding in the active
site of hexosaminidase A which helps create a
properly folded hexosaminidase A
Alpha subunit active site
Beta sub unit active site
Mutation Severity

Each missense mutation has been colored
according to
the severity of the GM2 gangliosidosis
phenotype, 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.
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 lysosomal sialidase in
neurons, a new form of therapy, essentially
curing the disease, could be on the
horizontreatment with the drug OGT 918
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