Autosomal Recessive Flashcards
Recurrence risk
1/4
Chance of unaffected sibling being carrier?
2/3
Location of majority of mutant allele?
Hidden in carriers
For an affected child of an AR disorder, the more rare the disease, the higher the chance of?
Parental consanguinity
Phenylketonuria (PKU)
Phenotype
High phenylalanine in blood
High phenylalanine metabolites in urine
Hyperactivity and epilepsy
Mental retardation and microcephaly
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)
PKU and mutant alleles?
High allelic heterogeneity
Compound heterozygosity
Varied phenotype severity
PKU: Newborn screening
Mass spectrometry to look at absolute phenylalanine level as well as phenylalanine/tyrosine ratio
PKU: Newborn screening timing?
Wait a moment because brand new bambino can retain mama enzyme
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
PKU Maternal Effect Prevention
Maintain low Phe diet throughout child bearing years
PKU Treatment
Low Phe diet
BH4 supplementation
Other
Neutral a.a. supplement (BBB)
Enzyme replacement
Gene therapy
ATD (Alpha1 antitrypsin deficiency)
Deficiency in alpha1-antitrypsin (SERPINA1, AAT) a protease inhibitor - (of elastase)
ATD - more common in?
North Europe
ATD occurence?
1/2500
carrier frequency - 4%
ATD diagnostic issue?
Underdiagnosed
ATD
Increased risk of ?
Emphysema
Liver cirrhosis -> cancer
ATD and ecogenetics?
Earlier and more severe in smoker
The phenomenon where genes and lifestyle influence phenotype, such as early and more severe ATD symptoms in smokers is known as?
Ecogenetics
ATD biochemical defects
Deficiency in Alpha-1 antitrypsin
What is alpha1-antitrypsin?
a protease (elastase) inhibitor
What is elastase?
An enzyme released by activated neurtrophils at the airway, destroying elastin in connective tissues
ATD patients have imbalance of?
Elastase and SERPINA1
ATD is caused by?
Mutation in alpha1-AT (SERPINA1) gene
Where is alpha1-AT produced?
liver
Where is alpha1-AT transported?
to the lungs via blood from the liver
How many common alleles encode functional alpha1AT
Three common M alleles
What are the two most common mutant alleles that cause ATD?
Z allele (Glu342Lys) - most common mutant allele
S allele (Glu264Val)
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
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
ATD
S allele
(Glu264Val)
Makes unstable SERPINA1 protein
S/S –> 50-60% SERPINA1 level
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
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
What is Tay-Sachs Disease?
A fatal genetic disorder in children that causes progressive destruction of teh CNS
When do T-S babies start to develop neurological signs?
3-6 mos, die by 2-4
What are the first signs of T-S
Muscle weakness and startle response
Advanced symptoms of T-S
Loss of voluntary movement
Seizure
Mental retardation
Vegetative state
What causes T-S?
T-S is a lysosomal storage disorder with >300x accumulation of Gm2 ganglioside in the lysosome
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
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
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
Which gene do T-S patients usually have a mutation in?
HEX-A
Which codes for the alpha subunit of hexoaminidase A
What disease is caused by HEX-B mutation?
Sandhoff disease (Gm2 gangliosidosis II) - a similar lysosomal storage disorder
Sandhoff disease effects?
HEXB gene
Thus effects both Hexoaminidase A and Hexoaminidase B (a B/B homodimer)
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
High-risk group for T-S
Ashkenazi Jewish population
100 fold higher risk (1/3600)
T-S Disease: Screening - carrier
enzymatic activity assay - 97% accuracy for Ashkenzi Jew population because carriers have lower HexA enzyme levels in blood
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
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
Chromosome HEXA
15q23-24
Chromosome HEXB
5q13
PKU Guthrie Test
High levels of PKU enables bacterial growth in presence of inhibitor theinylalanine
Chromosome PAH (pku)
12q22-24
Chormosome ATD
14q32
Screening for ATD
Sequence specific oligonucleotide probes can be used to distinguish M,Z, and S alleles
