Autosomal Recessive Disorders (Huang L1) Flashcards Preview

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Flashcards in Autosomal Recessive Disorders (Huang L1) Deck (52)
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Describe the phenotype of Tay-Sachs disease.

CNS neurons progressively destroyed

Most Common:
early onset (infancy), fatal
normal till 3-6mo. old ---> fatal by age 3-4yrs
muscle weakness, decreased attentiveness, increased startle response

neurodegeneration: seizures, vision & hearing loss, diminished mental function, paralysis

Characteristic: "Cherry-Red Spot" on the eye


The ___________ population is at a ________ higher risk of T-S than the general population.

Ashkenazi Jewish

100-fold higher risk (1 in 3600 vs. 1 in 360,000 in gen.pop.)


Some other high risk groups for T-S?

French Canadian (Quebec)
Old Order Amish (Pennsylvania)
Cajun (Louisiana)


What is the biological category of TS disease?

Lysosomal Storage disease


Patients with T-S disease are unable to degrade _________ leading to a ______-fold buildup of this ___________ in swolen ________.

G_M2 Ganglioside


In particular, the lysosomes in what kind of cell become swollen with sphingolipids?

Neurons in the brain and spinal cord


What protein is deficient in T-S disease and what does it normally metabolize?

Hexosaminidase A (HexA)
metabolizes G_M2


HexA is a ________ of alpha/beta subunits which are encoded for by ______ and ______ repsectively.

HEX A & HEX B genes


What is another name for Tay-Sachs disease?

G_M2 gangliosidosis Type I


What is G_M2 gangliosidosis type II?
What are the symptoms of this disease?

Sandhoff disease.
Another lysosomal storage disorder

Symptoms the same as T-S disease. Neurological


What is the key biochemical difference between T-S disease and Sandhoff disease?

In TS the HEXA gene is unable to make the alpha monomer needed for the alpha/beta heterodimer that degrades G_M2

In Sandhoff disease, the HEXB gene is unable to make the beta monomer needed for BOTH the alpha/beta heterodimer and the beta/beta homodimer (which degrades globosides)


Which chromosomes are the HEX A and HEX B genes found on?

15 and 5 respectively


What is the AB-variant of T-S disease?

The AB variant is an activator deficiency.
GM2AP gene (chr 5) synthesizes the activator protein for the alpha/beta heterodimer that degrades G_M2 ganglioside.

The HEXA and HEXB genes are both normal, but their heterodimer product cannot be turned on.


How many different HEXA mutations are known (T-S disease) and what is the most common ?

over 100 mutations are known

the most common one (80% of cases) is a 4bp insertion (frameshift) in exon 11 of HEXA (chr. 15)
--> premature stop codon (null allele)


How does one screen for T-S disease?

1. Enzymatic activity assay
2. Carrier screening
3. Prenatal screening
4. DNA testing


In prenatal T-S screening, what sort of sample is tested and what sort of disease reduction has this accomplished?

Test cultured amniotic fluid cells (if both parents are carriers, otherwise don't bother right?)

Thsi test has reduced T-S incidence by 95% over the past 3 decades.


How accurate is the DNA test for carriers of T-S disease mutations?

95% accurate in Ashkenazi Jewish pop.
60% accurate in General Population


Is T-S _always_ fatal?

There are juvenille and adult-onset forms of the disease. These pts. have reduced HexA activity.


Describe the phenotype of alpha1-Antitrypsin Deficiency (ATD)

Late onset (esp. non-smokers)
80-90% penetrance

Emphysema (esp. smokers),
liver cirrhosis
increased risk of liver carcinoma
(accumulation of misfolded alpha1-AT protein in the liver)


What is the prevalance of alpha1-ATD and what is a high-risk group for this disease?

carrier freq 4%
more common in those with Northern European ancestry

is an underdiagnosed disease


What are the alleles associated with alpha1-ATD?

Wild-type M
Mutant (2) Z and S

Z = bad
S = less bad


What are the function levels of the various genotypes of alpha1-ATC?

Z/Z 10-15% of normal alpha1-AT activity
S/S 50-60%
Z/S 30-35%


Alpha1-antitrypsin (ATT or SERPINA1) is made in the liver and secreted into plasma. What does it do?

SERPINA1 (serine proteas inhibitor - serpins) is a suicide substrate

It binds to and inhibits specific serine proteases. In particular, SERPINA1 likes elastase, which is released by neutrophils in the lung.

If there is not enough SERPINA1, then too much elastase accumulates and this will destroy connective tissue (elastin) in the lung --> alveolar damage & emhysema


How many different mutant alleles are there that cause alpha1-ATD and which are the most common ones? Which chromosome does the SERPINA1 gene live on?

about 20 possible mutant alleles. S & Z are most common.
SERPINA1 lives on long arm of chr. 14


What are the particulars of the worst allele? (the Z allele)

Z allele codes for a Glu342Lys resulting in a misfolded protein.
This protein then gets stuck in the ER of liver cells. Thus the liver is damaged (cirrhosis in addition to the lung damage). Since the protein aggregates in the liver, it never makes it to the lungs to do its job.


What are the particulars of the S allele? Why is it "less bad" than the Z allele?

S allele codes for Glu264Val which results in an unstable protein. This protein is functional but less effective --> milder symptoms


How might one go about screening for alpha1-antitrypsin deficiency?

Sequence Specific oligonucleotide probes can distinguish btwn M, S & Z alleles.

Provides accurate prenatal diagnosis.


What are the Ecogenetic factors associated with alpha1-antitrypsin deficiency?

Smoking = bad (duh)

In particular, in response to the damage caused by smoking, the body sends more neutrophils to the lung
neutrophils release elastase
---> more severe lung damage than just the normal amount of unchecked elastase.


What treatments are being developed for alpha1-antitrypsin deficiency?

Delivery of human SERPINA1 to the lungs by either intravenous infusion or aerosol inhalation


What do we call the existence of multiple mutant alleles of a single gene?

Allelic heterogeneity