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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
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

M2M2 (27 decks)

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