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M2M2 > Autosomal Recessive > Flashcards

Autosomal Recessive Flashcards

1
Q

Recurrence risk

A

1/4

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2
Q

Chance of unaffected sibling being carrier?

A

2/3

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3
Q

Location of majority of mutant allele?

A

Hidden in carriers

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4
Q

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

A

Parental consanguinity

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5
Q

Phenylketonuria (PKU)

Phenotype

A

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

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6
Q

PKU biochemical defects?

A

98% Defect in PAH (phenylalanine hydroxylase)

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

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7
Q

PKU and mutant alleles?

A

High allelic heterogeneity
Compound heterozygosity
Varied phenotype severity

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8
Q

PKU: Newborn screening

A

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

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9
Q

PKU: Newborn screening timing?

A

Wait a moment because brand new bambino can retain mama enzyme

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10
Q

PKU Maternal Effect

Problem

A

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

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11
Q

PKU Maternal Effect Prevention

A

Maintain low Phe diet throughout child bearing years

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12
Q

PKU Treatment

A

Low Phe diet
BH4 supplementation

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

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13
Q

ATD (Alpha1 antitrypsin deficiency)

A

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

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14
Q

ATD - more common in?

A

North Europe

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15
Q

ATD occurence?

A

1/2500

carrier frequency - 4%

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16
Q

ATD diagnostic issue?

A

Underdiagnosed

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17
Q

ATD

Increased risk of ?

A

Emphysema

Liver cirrhosis -> cancer

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18
Q

ATD and ecogenetics?

A

Earlier and more severe in smoker

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19
Q

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

A

Ecogenetics

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20
Q

ATD biochemical defects

A

Deficiency in Alpha-1 antitrypsin

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21
Q

What is alpha1-antitrypsin?

A

a protease (elastase) inhibitor

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22
Q

What is elastase?

A

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

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23
Q

ATD patients have imbalance of?

A

Elastase and SERPINA1

24
Q

ATD is caused by?

A

Mutation in alpha1-AT (SERPINA1) gene

25
Q

Where is alpha1-AT produced?

A

liver

26
Q

Where is alpha1-AT transported?

A

to the lungs via blood from the liver

27
Q

How many common alleles encode functional alpha1AT

A

Three common M alleles

28
Q

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

A

Z allele (Glu342Lys) - most common mutant allele

S allele (Glu264Val)

29
Q

Allelic heterogeneity in PKU and ATD

A

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
Q

ATD

Z allele

A

(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
Q

ATD

S allele

A

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

32
Q

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

A

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
Q

ATD treatment

A

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
Q

What is Tay-Sachs Disease?

A

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

35
Q

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

A

3-6 mos, die by 2-4

36
Q

What are the first signs of T-S

A

Muscle weakness and startle response

37
Q

Advanced symptoms of T-S

A

Loss of voluntary movement
Seizure
Mental retardation
Vegetative state

38
Q

What causes T-S?

A

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

39
Q

Why does T-S target the brain?

A

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

40
Q

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

A

Hexosaminidase A

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

41
Q

What is the structure of hexoaminidase A?

A

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

42
Q

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

A

HEX-A

Which codes for the alpha subunit of hexoaminidase A

43
Q

What disease is caused by HEX-B mutation?

A

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

44
Q

Sandhoff disease effects?

A

HEXB gene

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

45
Q

AB variant of T-S

A

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
Q

High-risk group for T-S

A

Ashkenazi Jewish population

100 fold higher risk (1/3600)

47
Q

T-S Disease: Screening - carrier

A

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

48
Q

T-S prenatal screening

A

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
Q

T-S screening DNA test

A

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
Q

Chromosome HEXA

A

15q23-24

51
Q

Chromosome HEXB

A

5q13

52
Q

PKU Guthrie Test

A

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

53
Q

Chromosome PAH (pku)

A

12q22-24

54
Q

Chormosome ATD

A

14q32

55
Q

Screening for ATD

A

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

M2M2 (27 decks)

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