Week 4

Question 1

Down (T21, 1/1000)

Answer 1

1. Can be detected via FISH

2. MR, short stature, flat face, yellow spots on eyeball, one crease on hand, tongue protrusion

Question 2

Patau (T13, 1/10000)

Answer 2

1. Risk increases with older pregnant women

2. Small eyes + colobama, cleft palate opening, weak muscle tones (die at infancy)

Question 3

Edwards (T18, 1/3000)

Answer 3

1. 10% make it over a year, few last until 30s
2. Heart/kidney defects, no esophageal-stomach connection (part of intestine outside stomach), clenched fist, small pelvis

Question 4

Achondroplasia (Short Limb Dwarfism, 1/20000)

Answer 4

1. Risk increases with older men; De Novo
2. Faulty cartilage-to-bone formation, AD with complete penetrance
   > FGFR3 mutated: G1138A and C –> G380R (paternal)

Question 5

Women age and chromosomal aberrations

Answer 5

Immature eggs at birth –> ovaries with 1-2 million immature germ cells –> decrease with age (follicular degeneration) –> almost none at 50

Question 6

Turner (XO in F, 1/5000)

Answer 6

1. Short Stature, learning impaired, high CHF risk, kidney defect, infertility
2. X and Y pair up at PAR in meiosis with possible CO
   > Result: haploinsufficiency in some X genes
   > SHOX gene is normally expressed in both M and F on PAR, but is mutated in idiopathic short stature because TF it encodes is broken –> poor osteoblast/chondryocyte development
3. Treatment: growth hormone; estrogen placement (decrease osteoporosis and increase 2’ sex character)

Question 7

Male Chromosome

Answer 7

1. PAR pairs with X

2. SRY: near PAR; bad CO can translocate this to X; encodes TDF

Question 8

XX Male (1/20000)

Answer 8

1. SRY onto X

2. Short stature, spontaneous puberty, low testosterone (no sperm/sterile), gynecomastia

Question 9

XY Female (1/20000)

Answer 9

1. SRY deletion

2. Oocytes degenerate by birth (sterile), taller, no estrogen –> no puberty

Question 10

XXY (Klinefelter, 1/1000)

Answer 10

1. 15-20% SHOX genes escape inactivation –> height
2. Low IQ, immaturity/shyness, poor peer relationship, long limbs/tall; hypogonadism + hypogenitalism (small testes, partial 2’ sex character, gynecomastia); high SLE
3. Treatment: testosterone replacement

Question 11

XYY (1/1000, #47)

Answer 11

1. Normal sex characteristics, tall/low weight, skeletal abnormality; aggression and large facial features

Question 12

XXX Female (1/1000)

Answer 12

1. Can discard extra X via selective disjunction

2. Quiet infants, delayed motor/low IQ, social issues, tall

Question 13

Severe Lupus Erythematosus (SLE, 9x in FEMALES)

Answer 13

1. non-PAR TLR7 Gene escapes X-Inactivation in Immune cells –> B cells more active to TLR3 ligands

Question 14

Non-disjunction + UPD

Answer 14

1. Trisomy rescue
2. UPD:
   > a. Silenced gene –> no gene function
   > b. Both UPD with active silenced gene (only one parent origin silenced) –> overproduction impairs normal development

Question 15

Mitotic failure –> fertilization –> Mosaicism (Down)

Answer 15

Abnormal chromosomal segregation in rapidly dividing cells (colon) –> tumor

Question 16

Muscle Characteristics

Answer 16

1. Function: locomotion, valve opening, upright posture, support internal organs, heat, move blood
2. 650 types: elasticity; needs lots of energy, nerve impulse –> contraction; highly organized
3. Normal functioning: 1) enzyme breakdown FA/glycogen for E; 2) Structural integrity proteins; 3) mechanical cell property

Question 17

Skeletal (40%)

Answer 17

1. (Out to in) Epi/peri (White branches)/endomysium (blood vessels) –> fascicles –> muscle fibers with microfibrils (myoblasts and many nyclei)
2. Nerve impulse –> Ca2+ influx –> tropomyosin away from actin by troponin complex –> myosin + actin w/ ATP –> actin pulled and contraction

Question 18

Enzyme-related Muscle Disorders

Answer 18

1. McArdle: phosphorylase
2. Pompe: acid maltase
3. Tarui: phosphofructokinase
4. Forbes/Cori: debrancher enzyme

Question 19

Duchenne Muscular Dystrophy (DMD, 1/3300 males)
X-linked Recessive: Progressive Muscle Wasting
2.4 bp at xp21.2 (0.08% human genome)

Answer 19

1. ONE OF MOST COMMON GENETIC DISEASE
2. Hip weakness, large calves/pseudohypertrophy, heart failure, Gowers manuever
3. Cross-section: uneven muscle fiber sizes, increase in immune cells/many nuclei; adipose fills connective
4. xP21.2: 2/3 Familial (Mother Carrier), 1/3 Sporadic
   > Heterozygous Female: X-Autosome Translocation
   > Male: xP21.2 deletion (gene is 8x10^6 bp away from known marker)

Question 20

Random Inactivation X, X/A, A/X, A

Answer 20

1. Lethal case:
   > 1 DMD, 2 distal Xp, partial autosome inactive
2. Carrier Female:
   > no DMD, 1 distal Xp, 2 autosomes

Question 21

Dystrophin

Answer 21

1. cDNA: F-actin (cytoskeletal microfilaments and thin muscle filaments) – Central Rod Domain (24 repeating units of 88-126 AA; 100-125 mm long with 3000 AA) – Cystein-Rich (280AA)+B-dystroglycan – C-terminal (420 AA with syntrophin and a-dystrobrenin binding sites)

Question 22

Dystrophin and DMD

Answer 22

1. DMD: 100% no dystrophin or missing C-terminal
   > sarcolemma needs dystrophin for dystrophin-glycoprotein complex (DGC)
   > no DGC –> no bridge between internal contraction and EC matrix –> membrane rupture –> degeneration

Question 23

Becker Muscular Dystrophy (BMD; 1/3000 Males)

X-linked recessive; sporadic

Answer 23

1. Apparent muscle-wasting later in life; longer life
2. West-blot: becker 1 (smallest), becker 2 (smaller), Dystrophin (DNE)
3. High mutation frequency: unequal CO between chromosomes with tandem repeats
   > Normal –> staggered –> recombo causes added/deleted (SPORADIC)
   > Results: ORF kept –> BMD; frameshift –> DMD

Question 24

Limb-Girdle Muscular Dystrophy

Answer 24

1. Hips and Shoulder muscle
2. Normal dystrophin, but LGMD1 (D) and LGMD (R)
3. 18 different LGMD all on autosome
   > communication issue between ICM and ECM

Question 25

Dilated Cardiomyopathy (DCM)-- MALES

Answer 25

1. 60% CM, 4% population 2. FATAL AND SUDDEN DEATH 3. Large LV (ineffective pumping, wall-thinning, poor contractility); requires heart transplant 4. Fatigue, SOB, poor exercise, palpitation, comorbidity 5. 25-35% familial: viral infection, atherosclerosis, malnutrition, myocardial toxins (tobacco)

Question 26

Muscle Disorders Treatment:

Answer 26

1. Glucocorticoids: increase muscle strength: > Decrease inflammation and stabilize membranes > Side effect: short, late puberty (bone fragility, HTN) 2. Gene Therapy: intravascular-- recombinant adeno-associated viral vectors (rAAVs) + microdystrophin gene 3. Exon Skipping: injection of antisense oligonucleotides (stop codon/defects skipped) 4. Ataluren (PTC124): oral--ribosomal readthrough of nonsense mutations --> bypass during translation