Autosomal Recessive Disorders (Huang L1) Flashcards
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.)
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
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
300-fold
sphingolipid
lysosomes
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.
heterodimer
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?
- Enzymatic activity assay
- Carrier screening
- Prenatal screening
- 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?
1/2500
carrier freq 4%
more common in those with Northern European ancestry
is an underdiagnosed disease