Autosomal Recessive Disorders

Question 1

Horizontal Pedigree

Answer 1

Autosomal recessive.

Question 2

Other things about AR pedigree?

Answer 2

Men and women equally affected.
Recurrence risk is 25% for each unborn child of the same couple.
Probability of an unaffected sibling being a carrier is 2/3.

Question 3

PKU phenotype

Answer 3

Microcephaly, profound mental retardation. High Phe and low tyrosine because conversion from phe to tyr is impaired.

Question 4

PKU mutation

Answer 4

Typically a mutation in the PAH gene excoding the enzyme, but some have mutation in BH4 (cofactor of PAH). BH4 is also cofactor for 2 other enzymes, tyrosinehydroxylase and tryptophan hydroxylase… which synthesize neurotransmitters.

Question 5

PAH gene is a good example of….

Answer 5

Allelic heterogeneity.
Often partial or complete loss-of-function alleles. Over 400 alleles have been id’ed.
Most are compound heterozygotes (more than one mutant allele).

Question 6

Guthrie Test or Mass Spectrometry

Answer 6

Guthrie for PKU… high level of phenylalanine can inhibit bacterial growth.
Mass spec: Current method of choice for many newborn screenings.

Question 7

Timing of PKU screening

Answer 7

Often phenylalanine level is normal at birth because of normal PAH in maternal supply (increases progressively with protein feedings).
So need to test early, not too early.

Question 8

Why is maternal PKU treated in pregnancy?

Answer 8

Because you need low-phenylalanine diet. Even if fetus is genotypically normal, you can get elevated Phe in maternal circulation that causes developmental issues.

Question 9

Alpha-1 Antitrypsin Deficiency (ATD)

Answer 9

AR. 20 fold increased risk of emphysema. Liver cirrhosis (accumulation of misfolded protein).
Associated with Z and S alleles. Z/Z is most severe (only 10-15% of enzyme activity).
Also has alleleic heterogeneity.

Question 10

Tell me about the ATD biochemistry…

Answer 10

Alpha-1-antitrypsin (also called SERPINA1) is made in the liver and secreted into plasma.
SERPINA1 is a member of serpins (serine protease inhibitor) that are suicide substrates, they bind and inhibit specific serine proteases. Main target is elastase. Released by neutrophils in the lung.
If left unchecked, elastase can destroy the lung. Emphysema.

Question 11

Tay Sachs Disease

Answer 11

Inherited, progressively destroys neurons in brain and spinal cord.
Neurodegeneration, seizures, vision and hearing loss, diminishing mental fx. Cherry red spot (eye abnormality).

Ashkenazi jews are 100 fold higher risk. Also french-canadian communities of quebec, old order amish community in Penn, Cajun population of Louisiana.

Question 12

Tay Saches biochemistry?

Answer 12

Lysosomal storage disease.
Inability to degrade GM2 gangliosides, get sphingolipid accumulation in lysosomes of neurons.

Defective HexA needed to metabolize Gm2 is responsible (HexA is heterodimer of alpha-beta)… encoded by hexA and HexB genes.

T-S is caused by defective alpha-subunit. Only HEXA affected.
T-S is considered a B variant because there is more B and it’s normal.

Question 13

Sandhoff disease

Answer 13

Hex A and HexB are mutated. HexB is a homodimer of beta-beta.
Same neurological symptoms of T-S.
Caused by defective BETA subunit (HexA and HexB affected).

Question 14

AB Variant of Tay-Sachs

Answer 14

Both HexA and HexB are normal but Gm2 accumulates due to defect in Gm2 activator protein (GM2-AP), which facilitates interaction between lipid substrate and HexA enzyme (alpha subunit).

Question 15

Screening for Tay-Sachs

Answer 15

both HexA and HexB enzymes are present in serum, their activities can be distinguished in such assay because ONLY HEXA is inactivated by heat.
Can do prenatal screening.