Autosomal Recessive & Autosomal Dominant Disorders

Question 1

Do AR or AD disease ten towards “vertical pedigree”?

Answer 1

Autosomal Dominant

tend to appear in each generation

Question 2

Autosomal dominant disorders frequently involved what sort of defects?

Answer 2

Structural protein defects

Question 3

What factors may complicate the assessment of an autosomal dominant pedigree?

Answer 3

• Wider range of clinical presentations than AR
• Penetrance is more of an issue
• Expressivity is more of an issue

Question 4

What mutation is seen with achondroplasia?

Answer 4

Mutation in FGF-R3 protiein

=> inhibition of chondrocyte synthesis

Question 5

What mutation is seen in Marfan syndrome?

Answer 5

Mutation in fibrillin gene on Chr15

=> connective tissue disorder

Question 6

What mutation is seen with Neurofibromatosis Type 1?

Answer 6

Mutation in the NF-1 gene on Chr17

Question 7

What sort of mutation is seen in Huntington’s Disease?

Answer 7

Expansion of CAG-repeat in HD gene on Chr4

Question 8

What is the paternal age effect?

Answer 8

The increased frequency of inheriting disease gene when father is over 39 years old.

Question 9

If a carrier couple births an unexpected, affected child, what is the recurrence risk for each unborn child of the same couple?

Answer 9

25% recurrence risk

Question 10

What is allelic heterogeneity?

Answer 10

The existence of multiple alleles of a single gene

Question 11

What is a compound heterozygote?

Answer 11

One who carries different mutant alleles at the same genetic locus.

Question 12

What sort of defect is seen in phenylketonuria?

Answer 12

Defects in the PAH gene encoding phenylalanine hydroxylase

= a liver enzyme that converts Phe to Tyr (using O and co-factor BII4 [tetrahydrobiopterin])

Question 13

What is the danger of untreated PKU?

Answer 13

High levels of phenylalanine in PKU damages the developing central nervous system in early childhood and interferes with function of a mature brain.

Question 14

What is the Guthrie test for PKU?

Answer 14

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

Question 15

When should a newborn baby be screened for PKU?

Answer 15

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.

Question 16

Why are ATD (alpha1-antitrypsin deficiency) patients at greater risk for developing emphysema, liver cirrhosis, and liver carcinoma?

Answer 16

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.

Question 17

What are the two most common mutant alleles that cause ATD?

Answer 17

The Z-allele = Glu342Lys –> expresses a misfolded protein that aggregates in liver cells

The S-allele = Glu264Val –> expresses an unstable protein

Question 18

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

Answer 18

(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)

Question 19

What sort of disease is Tay-Sachs Disease?

Answer 19

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

Question 20

A defective HexB gene is indicative of what disease?

Answer 20

Sandhoff disease Type II

Question 21

A defective HexA gene is indicative of Tay-Sachs disease Type I, on which chromosome is this gene found?

Answer 21

Chromosome 15

Question 22

Which gene is defective with the AB-variant of Tay-Sachs disease, and on which chromosome is it found?

Answer 22

GM2AP on Chr 5

Question 23

What is the risk for developing Tay-Sachs in the Ashkenazi Jewish population?

Answer 23

1/3600

Question 24

Aside from the Ashkenazi Jewish, what other populations are at higher risk for developing Tay-Sachs?

Answer 24

French-Candadian communities of Quebec
Old Order Amish community in Pennsylvania
Cajun population of Louisiana