Term
A child presents with multiple bone fractures and Blue sclerae, as well as hearing loss and dental imperfections.
What should you do? |
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Definition
Get a family history, because this sounds like Osteogenesis Imperfecta (collagen 1), an autosomal dominant condition often confused with child abuse (1:10,000)
Collagen 1 defect messes up Bones (in middle ear and elsewhere), Dentin (teeth) and Cornea |
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Term
Patient presents with hyperextensible skin, multiple bruises and hypermobile joints. They complain that they commonly bleed from minor abrasions.
What is going on? |
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Definition
Hyperextensible skin + hypermobile joints + easy bruising/bleeding = Ehlers-Danlos syndrome (collagen type III- reticulin).
There are 6 types with varying inheritance patterns. |
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Term
A patient presents with progressive nephritis and deafness, as well as visual issues.
There is a likely family history of what X-linked recessive condition? |
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Definition
| Alport syndrome (collagen type IV- basement membrane in kidney, ears and eyes) |
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Term
| What is the significance of an alpha-1 anti-trypsin deficiency? |
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Definition
This enzyme normally inhibits elastase, which breaks down tropoelastin/fibrillin scaffolding.
You can break down of elastin and loss of elasticity in lungs, vocal cords, and arteries (can lead to Emphysema or Cirrosis) |
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Term
| Where is elastin found and how is it associated with Marfan's syndrome? |
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Definition
1) Found in lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connecting vertebrae).
2) Fibrillin defect, which normally forms scaffold with Tropoelastin, often causing aortic stenosis of patients with Marfan's |
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Term
Provide a biological example of each of the following genetic principles.
1. Co-dominance
2. Variable expression
3. Incomplete penetrance
4. Pleiotropy
5. Imprinting
6. Anticipation
7. Loss of heterozygosity
8. Dominant negative mutation
9. Linkage disequilibrium
10. Mosaicism |
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Definition
1. Blood groups (neither of 2 alleles is dominant)
2. Neurofibromatsis type 1 severity
3. Not all individuals with mutation get disease
4. PKU causes many seemingly unrelated symptoms (retardation/hair/skin)
5. Prader-Willi and Angelman's (maternal vs. paternal allele)
6. Huntington's (disease severity/onset time worsens with succeeding generations)
7. Retinoblastoma (if mutation develops, complementary allele must be deleted/mutated before cancer develops)
8 . Mutation of Tx factor in its allosteric site (heterozygote produces nonfunctional altered protein that prevents normal gene product from functioning)
9. Population measure of tendency of alleles at 2 linked loci to occur together more than expected
10. Lyonization- random X inactivation in females |
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Term
| How might a mutation in a Tx factor in its allosteric site be a "Dominant negative mutation"? |
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Definition
1. Exerts dominant effect.
Heterozygote produces nonfunctional altered protein that prevents normal gene product from functioning. In this case, mutant Tx factor still binds DNA, and prevents WT Tx factor from binding. |
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Term
Which of the following is not an example of Mosaicism?
a. Lyonization
b. Chimeric individual derived from 2 zygotes that subsequently fuse
c. Mutation in embryonic precursor of bone marrow stem cell
d. Varying disease severity in Neurofibromatosis 1 |
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Definition
D. This is just variable expression. To be mosaic, cells in the body have to differ in genetic makeup due to post-fertilizaiton loss of genetic information during mitosis, NOT just to different expression levels.
a. Lyonization is when random X inactivation occurs in females
b. This is, by definition, mosaicism (chimeric individual from fusion of two zygotes)
c. Hematologic mosaicism |
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Term
| Why does PKU cause many seemingly unrelated symptoms ranging from mental retardation to hair/skin changes? |
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Definition
| Pleiotropy- 1 gene has >1 effect on phenotype! |
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Term
| What do Marfan's syndrome, MEN 2B and homocystinuria, as well as Albinism have in common? |
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Definition
All 4 conditions are associated with Locus Heterogeneity.
Mutations ast different loci can produce the same phenotype. |
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Term
| Why might there be variable expression of Leber's Hereditary Optic Neurophaty (LHON) in different individuals? |
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Definition
| Heteroplasmy- presence of both normal and mutated mtDNA are associated with variable penetrance of mitochondrial inherited diseases. |
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Term
Which of the following is not a requirement of Hardy-Weinberg Equilibrium?
a. No selection for genotypes at given locus
b. No anticipation
c. No migration
d. Random mating
e. No mutation at given locus |
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Definition
b. Anticipation- or the progressive worsening of a genetic condition (severity or earlier onset) in successive generations (Huntington's)
HWE
p2 + 2pq + q2 and p + q=1 (p and q are different alleles) |
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Term
| What is the population frequency of Duchenne muscular dystrophy in males and females according to harvey weinberg equilibrium if p= 0.9 and q= 0.1 |
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Definition
DMD is an X-linked recessive condition, which according to HWE will present as q in males and q^2 in females.
q= frequency of allele and q^2 is frequency of homozygotes
males= 0.1 and females= 0.01 (must be homozygous to be affected) |
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Term
| Which two syndromes arise from inactivation or deletion of genes on chromosome 15 and how do they differ? |
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Definition
Can also occur due to uniparental disomy
1) Prader-Willi syndrome- Innactivated maternal allele and Paternal allele is deleted
- Mental retardation, hyperphagia, obesity, hypogonadism and hypotonia
2) AngelMan's syndrome- normally imprinted paternal allele and Maternal allele deleted
- Mental retardation, seizures, ataxia, inappropriate laughter ("happy puppet") |
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Term
True or False:
Autosomal dominant conditions normally involve enzyme deficiencies. |
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Definition
False- Autosomal recessive conditions occur because of enzyme deficiencies (25% of offspring from 2 carrier parents). They often are severe and present in childhood.
Autosomal dominant conditions involve structural proteins (Huntington's, Marfan's) |
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Term
Which of the following is NOT a mitochondrial myopathy?
a. Leber's hereditary optic neuropathy
b. Duchenne muscular dystrophy
c. Myocolonic epilepsy
d. Mitochondrial encephalopathy |
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Definition
B- This is an X-linked recessive condition
Mitochondrial diseases tend to exhibit variable expression due to heteroplasmy and involve failures in oxidative phosphorylation. |
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Term
| What kind of disease transmission occurs in Hypophosphatemic rickets? |
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Definition
X-linked dominant- ALL females of affected father will have it, and both males and females of affected mother will have it.
Formerly known as vitamin D-resistant rickets, it results from increased phosphate wasting at proximal tubules (not enough phosphate is reaabsorbed and it cannot be treated with UV light like nutritional rickets) and presents like normal rickets (softening/weakening of bones) |
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Term
Achondroplasia
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
- Dwarfism (head and trunk normal size)
- AD
- Increased paternal age
- FGFR3 |
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Term
Autosomal-dominant polycystic kidney disease (ADPKD)
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Flank pain, hematuria, HTN, progressive renal failure
- BILATERAL enlargement of kidneys due to multiple large cysts
I- AD (recessive in infantile form)
R- Polycystic liver disease, Berry Aneurisms, mitral valvue prolapse
M- Mutation in PKD1 (chromosome 16) |
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Term
Familial adenomatous polyposis
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Adenomatous polyps cover colon after puberty
I- AD
R- Colon cancer may result
M- Chromosome 5 (APC gene); 5 letters in "polyp"
APC is a tumor suppressor gene involved in regulating beta-catenin signalling and cellular growth |
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Term
Familial hypercholesterolemia (hyperlipidemia type IIA)
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Severe Atherosclerotic disease early in life, with tendon xanthomas (Achilles tendon)
Elevated LDL and cholesterol= 300 mg/dL (hetero) and 700 mg/dL (homo- RARE)
I- AD
R- May develop MI early in life
M- LDL receptor defect |
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Term
Hereditary hemorrhagic telangiectasia (Osler-eber-Rendu syndrome)
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Telangiectasia, recurrent epistaxis (nose bleed), skin discoloration, AVMs
I- AD
R- Hemorrhaging
M- unknown- involves aberrant TGF-b signalling |
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Term
Hereditary spherocytosis
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Spheroid erythrocytes with hemolytic anemia and increased MCHC (mean Hb concentration)- TREAT WITH SPLENECTOMY
I- AD
R- Sometimes gallstones occur
M- Spectrin or Ankryn defect |
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Term
Huntington's
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
Hunting 4 food
P- Depression, progressive dementia, chorea, caudate atrophy, less GABA and ACh
I- AD
R- Suicide, Psychosis, Anger
M- CAG repeat disorder at chromosome 4 (Hunting 4 food) |
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Term
Marfan's Syndrome
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Tall with long extremeties, pectus excavatum, hyperextensive joints, arachnodactyly and subluxated lenses
I- AD
R- Cystic medial necrosis of aorta...aortic incompetence and dissection of aneurysms and floppy mitral valve.
M- Fibrillin mutation- connective tissue of skeleton, heart, and eyes. |
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Term
Multiple Endocrine Neoplasias (MEN)
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Distinct syndromes (1, 2A, 2B) with familial tumors of endocrine glands (pancreas, pituitary, thyroid, parathyroid and adrenal medulla)
I- AD
R- Death from cancer is issue, or compromised endocrine function
M- MEN2A and MEN2B with ret gene |
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Term
NF1 (von Recklinghausen's disease)
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Cafe-au-lait spots, neural tumors, Lisch nodules (pigmented iris). Optic gliomas and Skeletal disease.
I- AD
R- Vision loss and brain damage
M- Long-arm (q) of chromosome 17
NF-1 is a negative regulator of the Ras oncogene signal transduction pathway |
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Term
NF2
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Bilateral acoustic schwannomas, juvenile cataracts
I- AD
R- Hearing loss and vision loss in kids
M- Chromosome 22 (type 2= 22) |
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Term
Which autosomal dominant disease is associated with each of the following chromosomes?
a. 3
b. 4
c. 5
d. 17
e. 22 |
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Definition
a. chromosome 3= Von Hippel Lindau (3 words)
b. chromosome 4= Huntington's (hunt 4 food)
c. chromosome 5= Familial Andenomatous polyposis (5 letters in "polyp")
d. chromosome 17= NF1 (17 letters in "von Recklinghausen")
e. chromosome 22= NF2 (NF2= 22) |
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Term
Tuberous Sclerosis
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Facial lesions (adenoma sebaceum), hypopigmented "ash leaf spots" on skin, cortical and retinal hemartomas, seizures, retardation, renal cysts and renal angiomyolipoma
I- AD (incomplete penetration and variable presentation)
R- Cardiac Rhabomyoma and incidence of astrocytoma
M- ?? Mutations in TSC1 (hamartin) or TSC2 (tuberin) |
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Term
von Hippel-Lindau
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Hemangioblastoma of retina/cerebellum/medulla with 50% of patients getting multiple bilateral renal cell carcinomas and other tumors
I- AD
R- Bilateral renal cell carcinoma and other tumors (Pheochromocytoma)
M- Deletion of VHL gene (tumor suppressor) on chromosome 3p resulting in constitutive expression of HIF and activation of angiogenic growth factors |
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Term
| What is the molecular basis of von Hippel-Lindau disease? |
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Definition
| You get hemangioblastomas in CNS (from blood vessels) because of deletion of VHL tumor suppressor, which leads to HIF expression and angiogenic growth factor expression. |
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Term
Cystic Fibrosis
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
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Definition
P- Recurrent pulmonary infections (Pseudomonas and S. aureus), chronic bronchitis, bronchiectasis, pancreatic insufficiency (steatorrhea), nasal polyps, meconium ileus in newborns
I- Autosomal recessive
R-
- Fat soluble vitamin deficiency (ADEK)
- Failure to thrive in infants.
- Infertility in males due to absent vas deferens.
M- Mutations in CFTR chloride channel (chromosome 7, Phe508), leading to secretion of abnormally thick mucus that plugs lungs, pancreas and liver |
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Term
Which of the following are NOT associated with Cystic Fibrosis?
a. Mutation in chloride channel causing abnormal protein folding
b. Recurrent pulmonary infections
c. Fat-soluble (ADEK) vitamin deficiency
d. Treat with N-acetylcysteine
e. Defect in methylation of FMR1 |
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Definition
E- This is an X-linked defect seen in Fragile X syndrome (2nd highest cause of genetic mental retardation (after DS). You would see macro-orchidism (enlarged testes), long face with large jaw, large everted ears, autism and mitral valve prolapse.
A) CF involved a mutation in the CFTR chloride channel that prevents proper folding and transport to the cell membrane. This leads to the production of thick mucous that plugs the lungs and predisposes individuals to chronic bronchitis and B) recurrent infections (Pseudomonas and S. aureus)
C) Fat soluble vitamin deficiency is caused by pancreatic insufficiency due to chloride defect.
D) Treating with N-acetylcystein cleaves disulfide bridges in mucous and breaks up plugs. |
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Term
Which of the following is NOT an autosomal recessive disease?
a. Cystic Fibrosis
b. Hereditary spherocytosis
c. Hemochromatosis
d. ARPKD
e. PKU |
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Definition
| B- is autosomal dominant condition with spheroid erythrocytes leading to hemolytic anemia |
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Term
What are the major X-linked recessive disorders?
(hint.. Be Wise, Fools GOLD Heeds Silly Hope) |
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Definition
** females rarely affected because of X chromosome inactivation in each cell**
1) Bruton's agammaglobulinemia
2) Wiskott-Aldrich syndrome
3) Fabry's disease (glycogen storage)
4) G6PD deficiency
5) Ocular albinism
6) Lesch-Nyhan syndrome
7) Duchenne's (and Becker's ) MD
8) Hunter's Syndrome
9) Hemophilia A and B |
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Term
Duchenne's Muscular Dystrophy
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
|
Definition
** Diagnose with increase CPK and muscle biopsy**
** Onset <5 years old**
P- Weakness in pelvic girdle muscles progressing superiorly.
- Use of Gower's maneuver (assistance of upper extremities to stand)
- Pseudohypertrophy of calf muscles
I- X-linked recessive
R- Cardiac myopathy.
M- Frame-shift deletion of dystrophin gene leading to deletion and accelerated muscle breakdown (dystrophin anchors muscle fibers in skeletal and cardiac muscle) |
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Term
Becker's Muscular Dystrophy
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
|
Definition
Less severe than Duchenne's and onset in adolescence/early adulthood
P- Myopathy (Cardiac and Skeletal)
I- X-linked recessive
R- Cardiac problems, mobility issues
M- Mutated dystrophin |
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Term
| How do Duchenne's and Becker's Muscular Dystrophies differ? |
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Definition
Both are X-linked recessive mutations in the dystrophin gene, an important molecular in anchoring cardiac and skeletal muscle fibers
1) Duchenne's is a frameshift mutation leading to the deletion of Dystrophin. It is MORE SEVERE and has earlier onset (<5)
2) Becker's involves mutated Dystrophin, but without frameshift. Onset is adolescence/early adulthood. |
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Term
Fragile X syndrome
PIRM
- Presentation
- Inheritance
- Risk
- Molecular defect |
|
Definition
P- Macro-orchidism (huge testes), Mental retardation, Long face with large jaw, large everted ears, autism
I- X-linked defect
R- Mitral valve prolapse (cardiac issues)
M- Methylation of FMR1
- Trinucleotide repeat (CGG) |
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Term
| What are the 4 major trinucleotide repeat disorders? |
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Definition
**May show genetic anticipation**
X-Girlfriends's First Aid Helped Ace My Test
1) Fragile X (CGGn)
2) Friedreich's ataxia (GAAn)
3) Huntington's (CAGn)
4) Myotonic dystrophy (CTGn)
Try (trinucleotide) Hunting for my friend eggs (x) |
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Term
| What are the 3 major autosomal trisomies, the replicated chromosome and the population incidence of each? |
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Definition
1) Down syndrome (21- 1:700)- flat face, epicantial folds and symian crease
2) Edward's syndrome (18- 1:8000)
- Severe mental retardation
- Micrognathia (small jaw)
- Low-set ears
- Clenched hands
3) Patau's syndrome (13- 1:15,000)
- Severe mental retardation
- Cleft liP/Palate
- holoprosencephaly
- polydactaly |
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Term
After screening a pregnant mother for autosomal trisomies, you notice decreases alpha fetoprotein levels, decreased beta-hCG, decreased estriol and normal inhibin A.
Which trisomy is this? |
|
Definition
Election age (18): Edward's syndrome (chromosome 18- 1:8,000)
1) All 4 are normal in Patau's (13- 1:15,000)
2) You would also see deceased alpha fetoprotein and decreased estriol in Down's Syndrome, but with INCREASED B-hCG and Inhibin A. Also, you would see nuchal translucency on ultrasound |
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Term
Which condition is associated with meiotic nondisjunction in 95% of cases?
a. Down syndrome
b. Edward's syndrome
c. Fragile X syndrome
d. Patau's syndrome |
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Definition
A- With increased events with maternal age (1:25 after age 45!)
A, B and D are all autosomal trisomies
C is an X-linked defect in methylation of FMR1 (2nd most common cause of genetic mental retardation) |
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Term
| What is a robertsonian translocation? |
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Definition
Nonreciprical translocation of chromosome pairs 13,14,15,21,22 where 2 long arms of acrocentric chromosomes fuse at centromere and short arms are lost.
- If balanced, no issue
- If imbalanced, miscarriage, stillbirth and chromosomal imbalance (Down's and Patau's) |
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Term
A child is born with microcephaly, moderate mental retardation, high-pitched crying that sounds like a cat, and cardiac abnormalities (VSD)
What is the molecular basis of this condition? |
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Definition
Cri du chat- cry of the cat
Microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-) |
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Term
A child is born with a distinct "elfin" face, mental retardation and hypercalcemia (increased sensitivity to vitamin D). They seem to have cardiac issues as well.
However, they are extremely friendly and have well developed verbal skills.
What is the molecular basis of this condition?
What is the molecular basis of this condition? |
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Definition
| William's syndrome- Micro-deletion of long chromosome 7 (vs. microdeletion of short arm of chromosome 5 in Cri-du-chat) |
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Term
| What is the relationship between DiGeorge and Velocardiofacial syndrome? |
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Definition
CATCH-22 due to aberrant development of 3d and 4th branchial pouches
Cleft palate, Abnormal faces, Thymic aplasia-T-cell deficiency, Cardiac defects, Hypocalcemia secondary to parathyroid aplasia- all due to microdeletion at 22q11
1) DiGeorge- Thymic, parathyroid and cardiac defects
2) Velocardiofacial- palate, facial and cardiac defects |
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Term
| Why do you see dissecting aortic anneurysms and mitral valve prolapse in patients with Autosomal dominant defects in fibrillin-1? |
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Definition
This is Marfan's, and fibrillin is critical for tropoelastic scaffolding.
You have cystic medial necrosis of aortic and mitral valve tissue, leading to weakening and out-pouching of walls. |
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Term
| Which organ systems are hit in Cystic fibrosis? |
|
Definition
AR mutations in CFTR on chromosome 7 (commonly Phe508)
1) Bilateral absense of vas deferens
2) Pancreatic insufficiency (fat soluble vitamins)
3) Thick mucus in respiratory tract (Staph and Pseudomonas) |
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Term
| What are the expected pregnancy quad results for each of the trisomies? |
|
Definition
1) Down's (21)
- Low AFP and estriol
- High beta-hCG and inhibin A
2) Edwards (18)
- Decreased AFP, beta-hCG and estriol
- normal inhibin A
3) Patau's (13)
- All normal |
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Term
What are the chromosomal abnormalities in Williams and Cri-du-chat syndromes, respectively?
What about DiGeorge and Velocardiofacial? |
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Definition
1) Cri-du-chat is deletion of 5p
2) Williams is 7q
3) DiGeorge and Velocardiofacial are 22q11 |
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