Autosomal Recessive Flashcards Preview

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Flashcards in Autosomal Recessive Deck (55):
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

31

ATD
S allele

(Glu264Val)
Makes unstable SERPINA1 protein
S/S --> 50-60% SERPINA1 level

32

Sometime individuals with ATD have liver failure, what is the reason for this?

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

33

ATD treatment

Inhaled brochodilators and steroids
Vaccinations against flu and pneumonia
Pulmonary rehab, O2
Lung transplant

In develpment
- ERT
- Gene Therapy
- Release of misfolded AAT protein from the liver to the blood

34

What is Tay-Sachs Disease?

A fatal genetic disorder in children that causes progressive destruction of teh CNS

35

When do T-S babies start to develop neurological signs?

3-6 mos, die by 2-4

36

What are the first signs of T-S

Muscle weakness and startle response

37

Advanced symptoms of T-S

Loss of voluntary movement
Seizure
Mental retardation
Vegetative state

38

What causes T-S?

T-S is a lysosomal storage disorder with >300x accumulation of Gm2 ganglioside in the lysosome

39

Why does T-S target the brain?

Gm2 ganglioside is primarily synthesized in the neurons of the brain and a component of the neuron cell membrane

40

What is defective in T-S and what is the consequence?

Hexosaminidase A

T-S patients are unable to degrade Gm2 ganglioside because a defective hexoaminidase A

41

What is the structure of hexoaminidase A?

Hexoaminidase A consists of two subunits - alpha and beta - which are encoded by the HEXA and HEXB genes, respectively

42

Which gene do T-S patients usually have a mutation in?

HEX-A
Which codes for the alpha subunit of hexoaminidase A

43

What disease is caused by HEX-B mutation?

Sandhoff disease (Gm2 gangliosidosis II) - a similar lysosomal storage disorder

44

Sandhoff disease effects?

HEXB gene
Thus effects both Hexoaminidase A and Hexoaminidase B (a B/B homodimer)

45

AB variant of T-S

HexA and HexB are normal, Gm2 accumulates because of a defect in activator protein (GM2-AP) which facilitates interaction between lipid substrate and HexA alpha subunit within cell

46

High-risk group for T-S

Ashkenazi Jewish population
100 fold higher risk (1/3600)

47

T-S Disease: Screening - carrier

enzymatic activity assay - 97% accuracy for Ashkenzi Jew population because carriers have lower HexA enzyme levels in blood

48

T-S prenatal screening

enzyme test can be performed on cultured amniotic fluid cells to detect T-S fetus when both parents are known carriers - this screening has reduced teh number of T-S cases by about 95% over passed 30 years

49

T-S screening DNA test

Three mutant alleles account for >95% of total mutations in Ashkenazi Jew
Current DNA can detect 95% of carriers in this group
60% non-Jewish

So some carriers will be missed by DNA test alone

50

Chromosome HEXA

15q23-24

51

Chromosome HEXB

5q13

52

PKU Guthrie Test

High levels of PKU enables bacterial growth in presence of inhibitor theinylalanine

53

Chromosome PAH (pku)

12q22-24

54

Chormosome ATD

14q32

55

Screening for ATD

Sequence specific oligonucleotide probes can be used to distinguish M,Z, and S alleles