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Tay Sach's Presentation



History

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-1881 Warren Tay, British eye doctor

*Cherry red spot on one year old patient's retina.

*Associated with the child's physical and mental retardation

-1886 Bernard Sachs, American Neurologist

*Calls the disease amaurotic familial idiocy

*Noted distended and misshapen neurons in people with the disease.

-Bloated neurons

*Noted how it strikes mostly people of Jewish descent and sometimes French Canadians

*He didn't know how the disease worked, or what chemicals caused it

-Limitations on technology

-1930's Ernst Klenk

*Disease now called Tay Sach's Disease

*He discovered Gangliosides

-Noted buildup of these in neurons

-Led to destruction of neurological system and death to patient

Symptoms of the Disease

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-Child normal during the first few weeks

*Can't tell difference between normal child and TSD child at this point

-5-6 months later, symptoms set in.

*Infant stops thriving

*Retardation, both mental and physical, sets in

*Child reacts violently to loud noises

*Child begins to lose peripheral vision

-Spot Tay noted on retina

-Deterioration continues during the ages of three and four

*Children unable to crawl

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*Children have decreased motor functions

*Seizures will set in. The severity of these depends on the stage the disease has reached

-If child makes it to age five, he or she will be blind and paralyzed.

-Most die before the age of six.

*Neurons continue to bloat until they explode, and child dies because of loss of neural function

How-The Genetic Basis

-Caused by a lack of metabolism of Gangliosides due to a mutation in the gene coding for the enzyme Hexosaminidase A (or HEX A)

-Passed on genetically through autosomal recessive genes

-Mutation of HEX A occurs at chromosome 15

Put up fifth transparency-Point out where on the gene there this is believed to occur

-Mutation of this gene causes a subunit of the HEX A molecule to be unable to take on its proper

confirmation

*HEX A is the first step in an enzyme cascade used to break down gangliosides

On Transparency-Point out where the HEX A makes the initial cut

*Without this enzyme, cascade doesn't occur, and gangliosides build up

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-Recessive autosomal gene causes TSD

-1/4 chance when two carriers procreate that they'll have a child with the disease

-Hits mostly the Ashkenazic Jewish community

*Descended from Central and Eastern European Jews

-Within community, frequency of carriers is one out of every thirty

Explain the figures on Transparency four

-Why does this lethal allele remain in this Jewish community?

*Separation and isolation of Jewish Communities over time has produced diversity between, but not within the various Jewish communities.

*Two theories as to how it became prevalent in the Ashkenazic Jewish community:

1)Inbreeding caused the founder effect (where a small amount of people give rise

to a bigger population) and genetic drift (where genetic frequencies fluctuate in small populations.

2)Natural Selection theory. Heterozygotes are less vulnerable to tuberculosis, which was prevalent in the Jewish ghetto's of East Europe

-Exact mutation

*Most common cause of Child TSD is +TATC on exon eleven of chromosome fifteen

-Codes for the alpha subunit

-Deficency in this subunit causes no HEX A to be produced

*Depending on type of added genetic info, you can have less severe versions of Tay Sach's

-Juvenile TSD, has slower progression, children live to fifteen

-Late onset TDS, less severe, happens to adults, symptoms such as headaches

-Now that we know how it is caused in the first place, we must look at effects in the cell

Effects in the Cell

-Mutation of HEX A causes buildup of, in specific, GM2 Gangliosides

*Gangliosides are believed to be important in cell cell interaction, as well as receptors

for hormones, toxins, and bacteria-especially in neurons

*Reside on outer membrane of cells via hydrophillic lipid part

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-HEX A is a hetero-oligomer composed of an alpha and beta subunit. There subunits are manufactured separately of one another in the ER, then transported to the Golgi

*The golgi receive these prepro subunits and changes them into pro subunits. (Removal

of signal sequences, etc.)

*In golgi, the mannose residues are phoshpylorated.

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-These mannose residues are the signals the cell uses to sort the proteins as being

lysosomal

-Signal patch allows the subunit to be recognized by Anacetylglucosamine, and

a phosphate is then donated.

-Controversy exists as to when the subunits join together

*Sandhoff feels that it occurs in the golgi, but he is still shaky about that conclusion

*Definitely not in the ER though

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-In lysosome, HEX A comes togehter with the GM2-Activator Complex

*Activator is a helper enzyme that allows the alpha and beta subunits to react with the

GM2 gangliosides, since there is steric hindrance for the HEX A to react at the membrane surface.

*Hydrolysis of GM2 occurs, and the ganglioside, now called GM3, is returned to the

membrane, where it will react with other enzymes

-In Tay Sach's

*No signal patch produced, because of change in confirmation

*Mannose residues not phosphorylated

*Thus, rather than traveling to the lysosome, they are excreted from the cell via the default pathway

-Since HEX A can't be produced, as the alpha subunits are secreted, more HEX B

a composite of two beta subunits, is produced. This has not been shown to

decrease the severity of Tay Sach's

Treatment and Prevention

-As of now, no know cure or treatment exists

*Recent reductions in disease are result of preventive measures

-Preventive measures

*Carrier Screening

-Serum and Leukocyte HEX A profiling takes place for people suspected of

being carriers (heterozygotes)

-Low counts mean that they are carriers

-Two means to do this

(1)Heat and pH test- the alpha subunits are heat liable, and pH liable. Examie

activity rates before and after heat and/or acid is added

(2)Chemical Tests

*Yoav Ben-Yoseph tests concerning N-Acetyl-B-galactosamines

-When alpha subunits react with these chemicals, they cause them

to either appear different, or even to glow

-In this case, you can study the effect directly by noting how much

color or flourescence is produced

-Carrier screening initially took place through Synagogues

*Baltimore MD synagogues

*Lab quality and quality of tests increased over time. Issue during the early 80's

-Initial tests showed 50% of female population was heterozygote

-Later, noted that oral contraceptives could produce misleading results

*Five courses of action recommended to carriers

(1)Don't have children once married

(2)Adopt once married

(3)Conceive through donor ovum or artificial insemination

(4)Risk having the child, but test after conceived to see if it has the disease

*There is a 1/4 chance that the child will have the disease

(5)As suggested by conservative NY hasidic rabbis, find a different partner

-If the child is at risk?

*Testing through amniocentesis or chrionic villus sampling

*Testing done in same way as carrier screening

*Most children found having the disease in this way are terminated (aborted)

-No therapy known

*Enzyme replacement theory:

-Injected pure HEX A into blood. It was taken up by liver and made into globosides.

-Modification of blood brain barrier in animals also failed

-Later, attempted to inject pure HEX A into brain and spine. Similarly showed

no effect.

-Human Genome Project

*Best chance for treatment is gene replacement

*Still many, many years away