Autosomal Recessive

Question 1

PKU - Associated Gene

Answer 1

PAH

or

BH4 cofactor -
involved in neurotransmitter synthesis - dopamine & serotonin

Question 2

PKU - Mechanism

Answer 2

High allelic heterogeneity –> compound heterozygosity

impaired conversion of Phe into Try
Increased phenylalanine in blood

Question 3

PKU - Clinical presentation

Answer 3

toxic to CNS - epilepsy, intellectual disability, hyperactivity

Question 4

PKU - Newborn Screen

Answer 4

Tandem Mass Spectrometry
simultaneously sorts molecules in blood by weight (mass), size, quantity to give phe/tyr ratio

Timing is important - PAH is normal at birth due to maternal PAH

Question 5

PKU - Treatment

Answer 5

PAH defect - Keep low phenylalanine diet (especially pregnant moms to avoid miscarriage and congenital malformations)

BH4 defect - low phenylalanine diet, drugs to supplement low neurotransmitter production

Question 6

ATD - Associated Gene

Answer 6

alpha1-antitrypsin (SERPINA1, AAT) - serine protease inhibitor

made in liver, major target is elastase (released by neutrophils in lung)

Question 7

ATD - Most affected population

Answer 7

North European

Question 8

ATD - Mechanism

Answer 8

unchecked elastase destroys connective tissue in lungs, leading to alveolar wall damage

Question 9

ATD - most common mutant alleles

Answer 9

Z & S

Z - most common
misfolded protein aggregates in liver ER, leads to live and lung damage

S - unstable protein that’s less effective

S/S - 50% normal activity, rarely symptoms
Z/S - develop emphysema

Question 10

ATD - Clinical presentation

Answer 10

increased risk of emphysema, liver cirrhosis, liver cancer
Earlier and more severe symptoms in smokers (ecogenetics)
smoke damages lung, increased neutrophils to fight damage, increased elastase

Question 11

5-alpha reductase deficiency - Associated gene

Answer 11

5-alpha reductase gene

Question 12

5-alpha reductase deficiency - Mechanism

Answer 12

decreased ability to convert testosterone into dihydrotestosterone (DHT)

Question 13

5-alpha reductase deficiency - Clinical presentation

Answer 13

46 XY - males with ambiguous external genitalia

undervirilized male (possibly female-ish) - increased virilization at end of puberty

Question 14

Tay Sachs disease - Most affected population

Answer 14

Ashkenazi Jews

Question 15

Tay Sachs disease - Associated gene

Answer 15

alpha subunit of HexA (heterodimer alpha-beta)

degrades Gm2 ganglioside

Question 16

Tay Sachs disease - Mechanism

Answer 16

ganglioside Gm2 buildup in CNS neuron lysosomes

Question 17

Tay Sachs disease - Clinical presentation

Answer 17

fatal genetic disorder
progressive neurodegeneration of CNS
1st signs - muscle weakness, startle response
advanced signs - loss of voluntary movement, seizure, intellectual disability, vegetative

Question 18

Tay Sachs disease - Screening

Answer 18

Ashkenazi-
3 mutant alleles for 95%
DNA test detects 95% of carriers

Prenatal screening when both parents are carriers via amniotic fluid

Enzymatic activity test -
HexA & B, A is heat inactivated

Question 19

Sandhoff - Associated gene

Answer 19

HexA (alpha-beta)

HexB (beta-beta)

Question 20

Sandhoff - Mechanism

Answer 20

Gm2 ganglioside II build up

Question 21

AB Tay Sachs - Associated gene

Answer 21

Gm2 activator - facilitates interaction between substrate and HexA

Question 22

AB Tay Sachs - Mechanism

Answer 22

Gm2 buildup

Question 23

Gaucher - Most affected population

Answer 23

Ashkenazi Jews

Question 24

Gaucher - Associated gene

Answer 24

Codes for glucocerebrosidase enzyme - breaks down glucocerebroside

Question 25

Gaucher - Mechanism

Answer 25

Lysosomal storage disease
can’t break down glucocerebroside in cell membranes
function

Question 26

Gaucher - Clinical presentation

Answer 26

Hepatosplenomegaly
thrombocytopenia
anemia

Question 27

Guacher - Treatment

Answer 27

enzyme replacement therapy