Day 1-2 through autosomal recessive disorders Flashcards
lS
risk of disease in siblins of affected/risk of disease in gen. pop. Risk of disease in relatives
heritability
Proportion of variance in trait that is due to genetic variation
Heterogeneity
The “same” disease can be caused by different alleles at one location or by alleles at different locations in the genome. (Locus vs. allelic)
Phenocopy
environmentally caused phenotype that mimics the genetic version of the trait (Ex. Thalidomide vs. genetics)
Odds Ratio (OR)
Risk of disease if carrying a given gene variant/Risk of disease if not carrying a given gene variant
haplotype
a set of DNA variations (polymorphisms) that tend to be inherited together. A set of SNPs found on the same chromosome
linkage disequilibrium
the non random association of alleles at different loci
What is the karyotype of a Pt wth Turners Syndrome?
XO
What abnormalities of the CVS are present in a Pt with TS?
Bicuspid Aortic Valve; Coarctation of the aorta; Systemic Hypertension; Prolonged QTc Syndrome; Partial anomalous pulmonary venous connection; Persistent left SVC; systemic hypertension
Abnormalities of the eye with TS?
Inner canthal folds; ptosis; blue sclera
Abnormalities of the skeleton system with TS?
Cubitus Valgus; Short 4th metacarpal/metatarsal; Short stature; madelung deformtiy; scoliosis
Abnormalities of the neck with TS?
Web Neck; Lower Hairline; cystic hygroma
Learning abnormalities associated with TS?
Difficulty in math; visual spatial skills; low nonverbal scores
Describe ear; nose; mouth of Pt with TS
Prominent Auricles; lowset; high narrow mouth palate; small mandible
Describe chest of Pt with TS?
Broad widely spaced Nipples; pectus excavatum
Abnormalities with endocrine system in Pts with TS
Hypothyroidism; gonadal dysgenesis
Abnormalities of reproductive system in TS
Non functioning ovaries; infertility
Allelic heterogeneity
the existence of multiple mutant alleles of a single gene
Compound heterozygote
one who carries two different mutant alleles of the same gene
Phenylketonuria (PKU) phenotype
Microcephaly; profound mental retardation if untreated. Neurobehavioral symptoms (hyperactivity; seizure; tremor; and gait disorders). High phenylalanine/low tyrosine levels in the plasma (conversion from Phe to Tyr is impaired). High phenylalanine metabolites in urine and sweat > characteristic �mousy� odor.
What leads to PKU?
Defects in PAH gene(phenylalanine hydroxylase) ~98%. Defects in PAH cofactor BH4 (tetrahydrobiopterin) ~1 to 2%
If a Pt has PKU b/c of defect in BH4; what other effects will they have?
Issues making dopamine (BH4 also a cofactor tyr hydroxylase); issues making seratonin (BH4 is also a cofactor for trp hydroxylase)
Where is PAH gene?
12q22 to 24.
How many alleles have been identified at the PAH gene? How does this relate to most PKU Pts?
Over 400 (high allelic heterogeneity). Most PKU patients are compound heterozygotes
What are two methods of newborn screening for PKU? (old and current)
Guthrie test (old) and Mass Spectrometry (current)
How did a guthrie test work?
Based on the findings that thienylalanine inhibits growth of B. subtilis and that such inhibition can be overcome by high level of phenylalanine in blood sample of a PKU baby
How does Mass Spectrometry work?
Sorts many molecules in a blood specimen by mass and measures the quantity of each molecule
Why is the timing of test important for PKU diagnosis?
A newborn level of phenylalanine is typicallly normal bc mom had normal PAH. Must test after baby begins eating/metabolizing on its own; but before irreversible damage is done.
What are treatments for PKU?
Low phenylalaine diet; BH4 supplements if they are BH4 deficient and also supplements to balance neurotransmitters. Gene therapy? Enzyme therapy?
Why must a woman stay on a low-phenylalanine diet throughout child bearing years?
No matter the genotype of the child; if the mother has elevated phenylalanine levvels during fetal development there is a very high risk of miscarriage and congential malformations; mental retardation; growth impairment
What is the phenotype of alpha1 Antitrypsin Deficieny (ATD) Pts?
20x increased risk of emphysema (worse with smokers). Late onset; but 80 to 90% will develop symptoms. Also; liver cirrhosis/liver carcinoma
What is frequency of alpha1 ATD?
Occurrence ~ 1/2500; carrier frequency ~ 1/25. Most common among Northern European Caucasians
What does alpha1 antitrypsin normally do?
Normally inhibits elastase; a serine protease. AKA SERPINA1 (SERPIN = SErineProteaseINhibitor)
What type of cells release elastase? What does elastase do?
Activated neutrophils at the airway release it. It destroys elastin in connective tissues
Why is it bad to have ATD?
Without antitrypsin; elastase runs wild and destroys all the elastin. This is bad for the avleoli
Where is alpha1 antitrypsin made and secreted?
Made in the liver; secreted into plasma
Where is SERPINA1 gene located?
On chromosome 14 (14q32.13)
Which alleles encode functional AT proteins?
3 common M alleles
Which allele is the most common mutant allele? What does it change?
Z allele. Glu342Lys
What is so bad about the Z allele?
Make a protein that is not folded properly; tends to accumulate in the ER of liver cells > cell damage. Z/Z genotypes have ~15% of normal SERPINA1 level
What is another common mutant allele in ATD? What does it change?
S allele. Glu264Val
How does the S allele lead to ATD?
Make an unstable/less effective SERPINA1 protein. S/S genotypes have 50 to 60% of normal SERPINA1 level
Describe the ecognetics of ATD
Smoking accelerates onset of emphysema in ATD Pts. Damage to lungs from smoking >> body sends more neutrophils to lung -> more neutrophils release more elastase -> more severe damage
Describe phenotype of Tay Sachs Disease (aka Gm2 gangliosidosis type I)?
Progressive destruction of CNS. Starts at 3-6 mo. And is fatal by 2 to 4 years. Begins with muscle weakness and increased starle response. Advanced symptoms include seizures; loss of voluntary movement; mental retardation; vegetative state. “Cerry-red spot” in eyes.
What are the biochemical defects in T S disease?
A lysosomal storage disorder with (>300x) accumulation of GM2 ganglioside in the lysosome. Pts are unable to degrade GM2 ganglioside b/c of a defective hexosaminidase A. Pts usually have mutations in the HEXA gene
What are the two subunits of the enzyme hexosaminidase A (HexA)? What genes encode for the two subunits?
Alpha and beta subunits. Encoded by HEXA and HEXB genes; respectively.
What do mutations in HEXA gene lead to?
Tay Sachs
What do mutations in HEXB gene lead to?
Sandhoff disease (GM2 gangliosidosis II)
Where is the Gm2 ganglioside primarily sythesized? What system is primarily affected by T S?
Primarily synthesized in the neurons of the brain and a component of neuron cell membrane. Impact is mostly in the brain.
Which subunit is defective in T S? Which gene encodes for that? Which enzyme is affected?
The alpha subunit is defective. Encoded for the HEXA gene. The HexA (hexosaminidase A) enzyme is affected because it has both alpha and beta subunits
What are the two subunit of the enzyme hexosaminidase B (Hex B)?
HexB is a homodimer of beta-beta
Which subunit is defective in Sandhoff disease? Which gene encodes for that? Which enzyme(s) is affected?
andhoff disease is caused by a defective ? subunit. Encoded for by HEXB gene. Both HexA and HexB activities are affected.
On which chromosome is the HEXA gene? (Encodes for alpha subunit)
Chromosome 15 (Chr 15q23-24)
On which chromosome is the HEXB gene? (Encodes for beta subunit)
Chromosome 5 (Chr5q13)
What is defective in the AB-variant of Tay-Sachs?
GM2-AP (GM2 activator protein). **Note the HExA and HexB enzyme are totally fine; but GM2 still accumulates**
What does the GM2-AP do?
Facilitates interaction between the lipid substrate and the HexA enzyme (alpha subunit) within the cell. Brings the lipid from the cell to the alpha subunit
On which chromosome is the GM2AP gene?
Chr 5q32-33
What is the most common HEXA mutant allele? What does it do on a molecular basis?
A 4bp insertion in exon 11 of HEXA. Causes a frameshift and a premature stop codon (it’s a null allele).
What are the 4 types of screening that can be done for Tay-Sachs?
Enzymatic activity assay; Carrier Screening; Prenatal screening; DNA testing
Describe enzymatic activity assay for Tay-Sachs
Both HexA and HexB enzymes are present in the serum. Their activities can be distinguished in such assays because only HexA is inactivated by heat
Describe carrier screening for Tay-Sachs
Has 97% accuracy because carriers have lower HexA enzyme levels in the blood. Primarily done among Ashkenazi Jewish population
