Autosomal Recessive & Autosomal Dominant Disorders Flashcards
Do AR or AD disease ten towards “vertical pedigree”?
Autosomal Dominant
tend to appear in each generation
Autosomal dominant disorders frequently involved what sort of defects?
Structural protein defects
What factors may complicate the assessment of an autosomal dominant pedigree?
- Wider range of clinical presentations than AR
- Penetrance is more of an issue
- Expressivity is more of an issue
What mutation is seen with achondroplasia?
Mutation in FGF-R3 protiein
=> inhibition of chondrocyte synthesis
What mutation is seen in Marfan syndrome?
Mutation in fibrillin gene on Chr15
=> connective tissue disorder
What mutation is seen with Neurofibromatosis Type 1?
Mutation in the NF-1 gene on Chr17
What sort of mutation is seen in Huntington’s Disease?
Expansion of CAG-repeat in HD gene on Chr4
What is the paternal age effect?
The increased frequency of inheriting disease gene when father is over 39 years old.
If a carrier couple births an unexpected, affected child, what is the recurrence risk for each unborn child of the same couple?
25% recurrence risk
What is allelic heterogeneity?
The existence of multiple alleles of a single gene
What is a compound heterozygote?
One who carries different mutant alleles at the same genetic locus.
What sort of defect is seen in phenylketonuria?
Defects in the PAH gene encoding phenylalanine hydroxylase
= a liver enzyme that converts Phe to Tyr (using O and co-factor BII4 [tetrahydrobiopterin])
What is the danger of untreated PKU?
High levels of phenylalanine in PKU damages the developing central nervous system in early childhood and interferes with function of a mature brain.
What is the Guthrie test for PKU?
Thienylalanine inhibits the growth of the bacterium Bacillus Subtilis and that inhibition can be overcome by high levels of Phe in a blood sample
=> inhibition of bacterial growth = PKU baby
When should a newborn baby be screened for PKU?
Newborns are tested after birth and then again a few days later at their first pediatrician visit.
Testing within 1-2 days of birth only is not effective enough since PAH levels may be normal from residual maternal supply.
Why are ATD (alpha1-antitrypsin deficiency) patients at greater risk for developing emphysema, liver cirrhosis, and liver carcinoma?
When too many neutrophils are recruited to the lungs, more elastase is released, which destroys connective tissue proteins and causes alveolar wall damage and emphysema.
Accumulation of misfolded alpha1-AT mutant protein in the liver leads to cirrhosis and carcinoma.
What are the two most common mutant alleles that cause ATD?
The Z-allele = Glu342Lys –> expresses a misfolded protein that aggregates in liver cells
The S-allele = Glu264Val –> expresses an unstable protein
What are the corresponding percentages of normal alpha1-AT activities with the following genotypes for ATD?
(1) Z/Z, (2) S/S, & (3) Z/S
(1) Z/Z = 10-15% (most cases)
(2) S/S = 50-60% (don’t usually express disease)
(3) Z/S = 30-35% (may develop emphysema)
What sort of disease is Tay-Sachs Disease?
T-S is a lysosomal storage disease as a result of the inability to degrade GM2 ganglioside
=> 300-fold accumulation of this sphingolipid in neuronal lysosomes of CNS
A defective HexB gene is indicative of what disease?
Sandhoff disease Type II
A defective HexA gene is indicative of Tay-Sachs disease Type I, on which chromosome is this gene found?
Chromosome 15
Which gene is defective with the AB-variant of Tay-Sachs disease, and on which chromosome is it found?
GM2AP on Chr 5
What is the risk for developing Tay-Sachs in the Ashkenazi Jewish population?
1/3600
Aside from the Ashkenazi Jewish, what other populations are at higher risk for developing Tay-Sachs?
French-Candadian communities of Quebec
Old Order Amish community in Pennsylvania
Cajun population of Louisiana
