Autosomal Recessive

Question 1

Phenylketonuria (PKU) phenotypes

Answer 1

High phenylalanine level in the blood
High phenylalanine metabolites in the urine
Hyperactivity and epilepsy
Mental retardation
Microcephaly

Question 2

Phenylketonuria(PKU) Biochemical Defects

Answer 2

• Defects in PAH gene—>
  no phenylalanine to tyrosine
  (defective phenylalanine hydroxylase)
• Defects in PAH cofactor BH4 (tetrahydrobiopterin) (1~2%)

Question 3

PAH cofactor BH4 interaction

Answer 3

phe hydroxylase
tyr hydroxylase (E)
trp hydroxylase (serotonin)

Question 4

PKU molecular defects

Answer 4

Defect in PAH gene

400 alleles
high allelic heterogeneity
(7 major in Europe, 6 major in Asia)

compound heterozygosity–> varies in serverity by mixing different mutant alleles.

Question 5

PKU screen

Answer 5

Tandem Mass Spectrometry

• fast, measure weight, size, quantitiy
• measures multiple molecules simultaneously

Question 6

PKU window

Answer 6

1-2 days after birth
and (F/Y ratio check)
2 weeks check up day
- you do not want to miss the window
- early days shows normal, Maternal phenylalanine hydroxylase active.

Question 7

alpha 1- antitrypsin deficiency (ATD) phenotypes

Answer 7

• Common in Nortern Europeans
• 1/2500, carrier freq=4%
• risk of emphysema
• risk of liver cirrhosis and cancer
• early and severe symptom for smokers
  (ecogenetics)

Question 8

alpha 1-antitrypsin deficiency (ATD) biochemical defect

Answer 8

• deficiency in alpha-1-antitrypsin
• SERPINA 1, AAT
• no SERPINA1—>no inhabiting elastase
• elastase destroys elastin—>emphysema, lung damage
• cycles repeat by neutrphil action releasing elastase

Question 9

alpha 1 antitrypsin deficiency (ATD)

molecular basis

Answer 9

Mutation in alpha1-antitrypsin gene (SERPINA1)

• z allele—> Most common, disturb folding, 15% normal lvl
• s allele—> unstable SERPINA 1 protein, 50-60% normal level

Question 10

ATD treatment

Answer 10

COPD(lung disease treatment)

• inhaled steroids
• vaccinations
• pulmonary rehabiltation
• lung transplant
• enzyme replacement therapy
• gene therapy
• releasing misfolded AAT protein from liver to blood

Question 11

Tay-Sachs Disease phenotype

Answer 11

Destruction of central nervous system
onset 3-6 months
die 2-4 yrs
1/3600 in Ashkenasi Jewish population

-muscle weakness, startle response to sudden sound

• loss of voluntary movement
• seizures
• mental retardation
• vegetative state

Question 12

Tay- Sachs Disease biochemical defect

Answer 12

• Lysosomal storage disorder
• defective hexosaminidaseA (alpha beta subunits)
• mutation in HEXA gene
• no Gm2 ganglioside degradation

Question 13

Sandhoff disease cause

Answer 13

Mutation in HEXB gene

similar lysosomal storage disorder to Tay Sachs disease.

Question 14

AB variant

Answer 14

GM2AP deficiency

no GM2 ganglioside degradation

Question 15

Tay Sachs disease screening

Answer 15

-Carrier screening in high risk population
(Ashkenazic Jewish, Queback, Amish, Cajun)

• Prenatal diagnosis when carrier parents
• Enzymatic activity test

-DNA test
(3 mutant alleles, 95% detection in AS Jewish)
(60% in non Jewish)