Taysac disease.docx

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University of Toronto Scarborough
Larry Sawchuk

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:  Artifactual: ◦ Bias affects rates.  Real reasons: ◦ Environmental factors. ▪ Selection ◦ Cultural factors. ▪ Selection ◦ 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). ▪ J=1/3000 ▪ 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 been described.  Four mutations account for 50% of the patients. Only three of the genetic variants are Gaucher's type 2. Niemann pick disease Type A 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 description. ▪ Megalencephaly: Head is large in relative size to the body, and frog position. ▪ 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.  78 mutations: ◦ 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, Russia. ◦ Variation: A=highest prop. From S. Lithuania and N.E Poland, B=lower in Ukrainian region, C=very few from the western Balkans. ▪ 5 fold differentials.  1/500.000 non-jewish births.  <1/500,000 oriental or sephardic jews.  Heterozygout Advantage ◦ 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 at equilibrium. ◦ 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 rabbinical. ▪ Marriage commonly arranged by parents and Shadchen. ▪ Meritorious: uncle and niece. ◦ Fraikor's explanation: ▪ The carrier freq. For TSD was probably significant in Russia th in the 19 century because of polygamy, inbreeding, small
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