Tay-Sachs Disease (TSD)
So important because:
Severe (especially for deaths in childhood, 4-5 years of life).
Simple biochem structure.
Easy for genetic screening.
Higher freq. In Ashkenazi Jews
Why? Cause mutation is 80x higher and Jews seek more physician care.
Some extent in other groups such as:
◦ French-Canadian Quebec.
◦ Cajun families in SouthWest Louisiana.
◦ Pennsylvania Dutch.
Factors for ethnic variation in rates:
◦ Bias affects rates.
◦ Environmental factors.
◦ Cultural factors.
◦ Genetic factors.
▪ Random genetic drift.
Founder effect and Bottle neck effect.
Inborn Error of Metabolism
1. Gaucher's Disease
▪ Sphenomegaly (enlarge of spleen).
▪ Hepatosplenomeghaly (enlarge of spleen and liver).
▪ Bone and joint pain.
▪ Variable age of onset.
Non-lethal (not deadly).
▪ nj=very rare.
▪ Gaucher (1882) saw a 32 yo woman dead with enlarged
liver and spleen. And he studied the cells of the spleen.
▪ 80 genetic changes that cause Gaucher's disease have
Four mutations account for 50% of the patients. Only three of the genetic variants are Gaucher's type
2. Niemann pick disease
1. Abdominal enlargement
2. Physical and mental retardation by 6 months.
3. Death at 3 years of age
4. prevalence j=1/100,000 and nj=500,000
3. Tay sachs disease
▪ First described by: Warren Tay 1881
▪ Symptoms at 6 months and fatal after.
▪ 1887 Bernard Sachs provided the first clinical and pathologic
▪ Megalencephaly: Head is large in relative size to the body, and frog
▪ Porous brain tissue.
▪ Simple autosomal recessive.
▪ Complete penetrance.
▪ Carriers appear normal and only distinguished by a reduced amount
of beta-hexomidase A.
▪ Mental and physical retardation at 4-6 months.
▪ Death by 4 years.
▪ Prevalence j=1/3000 nj=very rare
▪ heterozygous freq. of 3-4%.
▪ Biological fitness of homozygous is 0.
▪ Some clinical heterozygous: cripple activity of Hex A
▪ Hex A is to break down complex lipid molecule
Located on long arm Chromosome 15q23-q24.
◦ 65 single base substitutions.
◦ 1 large & 10 small deletions.
◦ 2 small insertions.
◦ One insertion, consisting of 4 bases within exon 11 is found in
80% of the carriers of TSD.
◦ Exon the coding regions to form mRNA.
▪ Freq. of TSD:
1/600 Ashkenazie births.
◦ 80% of the 13-14million jews.
◦ Hebrew term for German.
◦ Migrated to Rhineland in the 9 century. ◦ Moved to present day Poland, Lithuania, Belarus, Ukraine,
◦ Variation: A=highest prop. From S. Lithuania and N.E Poland,
B=lower in Ukrainian region, C=very few from the western
▪ 5 fold differentials.
1/500.000 non-jewish births.
<1/500,000 oriental or sephardic jews.
◦ M yriantopoulous and Aronson have demonstrated that a
selective advantage of about 1.25% for the heterozygote over
the homozygote would be sufficient to maintain the TSD gene
◦ M&A studied the grandparents of TSD patients (1970s)
◦ 1,244 siblings within 388 siblingships.
◦ Control group of 2,848 siblings within 812 siblingships.
◦ TSD grandparental fertility was higher but not significant
◦ Consanguineous Marriages higher among Jews because:
▪ Jewish community is small and isolated.
▪ Laws prohibiting Jews from marrying non-jews.
▪ Strong ties: marry within families.
▪ Consanguinity were sanctioned and blessed.
▪ Jewish marriage according to biblical, talmudic, and
▪ Marriage commonly arranged by parents and Shadchen.
▪ Meritorious: uncle and niece.
◦ Fraikor's explanation:
▪ The carrier freq. For TSD was probably significant in Russia
in the 19 century because of polygamy, inbreeding, small