Autosomal Recessive Flashcards Preview

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Flashcards in Autosomal Recessive Deck (55)
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1

Recurrence risk

1/4

2

Chance of unaffected sibling being carrier?

2/3

3

Location of majority of mutant allele?

Hidden in carriers

4

For an affected child of an AR disorder, the more rare the disease, the higher the chance of?

Parental consanguinity

5

Phenylketonuria (PKU)
Phenotype

High phenylalanine in blood
High phenylalanine metabolites in urine
Hyperactivity and epilepsy
Mental retardation and microcephaly

6

PKU biochemical defects?

98% Defect in PAH (phenylalanine hydroxylase)
1-2% defect in BH4 synthesis/recycle (PAH cofactor also involved in serotonin and dopamine biosynthesis)

7

PKU and mutant alleles?

High allelic heterogeneity
Compound heterozygosity
Varied phenotype severity

8

PKU: Newborn screening

Mass spectrometry to look at absolute phenylalanine level as well as phenylalanine/tyrosine ratio

9

PKU: Newborn screening timing?

Wait a moment because brand new bambino can retain mama enzyme

10

PKU Maternal Effect
Problem

PKU women who are off low-phenylalanine diet in pregnancy have markedly increased risk of miscarriage or congenital malformation and mental retardation of babies

11

PKU Maternal Effect Prevention

Maintain low Phe diet throughout child bearing years

12

PKU Treatment

Low Phe diet
BH4 supplementation

Other
Neutral a.a. supplement (BBB)
Enzyme replacement
Gene therapy

13

ATD (Alpha1 antitrypsin deficiency)

Deficiency in alpha1-antitrypsin (SERPINA1, AAT) a protease inhibitor - (of elastase)

14

ATD - more common in?

North Europe

15

ATD occurence?

1/2500
carrier frequency - 4%

16

ATD diagnostic issue?

Underdiagnosed

17

ATD
Increased risk of ?

Emphysema
Liver cirrhosis -> cancer

18

ATD and ecogenetics?

Earlier and more severe in smoker

19

The phenomenon where genes and lifestyle influence phenotype, such as early and more severe ATD symptoms in smokers is known as?

Ecogenetics

20

ATD biochemical defects

Deficiency in Alpha-1 antitrypsin

21

What is alpha1-antitrypsin?

a protease (elastase) inhibitor

22

What is elastase?

An enzyme released by activated neurtrophils at the airway, destroying elastin in connective tissues

23

ATD patients have imbalance of?

Elastase and SERPINA1

24

ATD is caused by?

Mutation in alpha1-AT (SERPINA1) gene

25

Where is alpha1-AT produced?

liver

26

Where is alpha1-AT transported?

to the lungs via blood from the liver

27

How many common alleles encode functional alpha1AT

Three common M alleles

28

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

Z allele (Glu342Lys) - most common mutant allele

S allele (Glu264Val)

29

Allelic heterogeneity in PKU and ATD

ATD has relatively little alleleic heterogeneity, with two common, Z and S, mutant alleles causing phenotype - unlike PKU which can have many mutant alleles

30

ATD
Z allele

(Glu342Lys) most common
Z/Z 15% normal SERPINA1 level

The z allele makes a protein that is not folded properly and tends to accumulate in the ER of liver cells, leading to liver damage