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Foundations Exam 1 > Clinical Correlations > Flashcards

Clinical Correlations Flashcards

1
Q

MELAS

A

Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes

mitochondrial inheritance

red-ragged fibers, hemiparesis, seizures

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2
Q

what illnesses do the following nucleoside analogs treat?
a. acyclovir
b. AZT
c. ddC
d. gemcitabine
e. remdesivir

A

a. acyclovir - HSV (deoxyguanosine)
b. AZT - HIV (thymidine)
c. ddC - HIV (deoxycytidine)
d. gemcitabine - cancer (deoxycytidine)
e. remdesivir - covid (adenosine)

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3
Q

function of quinolone drugs

A

block activity of DNA gyrase (prokaryotic Top II)

inhibit bacterial DNA synthesis

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4
Q

function of chemotherapeutic drugs Camptothecin and Adriamycin/Etoposide

A

Camptothecin targets Topo I

Adriamycin and Etoposide target Topo II

convert topoisomerases into DNA breaking agents by inhibiting ability of top to REJOIN DNA

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5
Q

what do inhibitors of HSV helicase-primase do?

A

stabilize interaction of helicase-primase with its viral DNA substrate

inhibiting progression of HSV DNA replication

(effective in HSV strains resistant to nucleoside-based therapies)

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6
Q

Dyskeratosis congenita

A

reduced telomerase activity —> affects stem and germ cells in tissues dividing rapidly/often

bone marrow failure due to loss of hematopoietic renewal

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7
Q

Lynch syndrome

A

HNPCC

mismatch repair (MMR) defect (shows MSI)

mutation in MSH2 or MLH1

colorectal cancer

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8
Q

mutation in DNA glycosylase MYH

A

high risk of colon cancer

defect in base excision repair (BER)

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9
Q

Werner’s syndrome

A

autosomal RECESSIVE

RecQ family WRN helicase mutation —> defect in BER

premature aging (20-30y), cataracts, atherosclerosis, cancer, telomere shortening

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10
Q

xeroderma pigmentosum (XP)

A

defect in GG-NER

XP protein mutations affecting recognition or helicase activity

solar sensitivity, skin cancer

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11
Q

cockayne syndrome

A

defective TC-NER

mutation in CSA or CSB recognition proteins

growth delays, intellectual disability, sun sensitive (but NOT cancer risk)
premature aging, from birth

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12
Q

Cisplatin

A

chemotherapeutic drug, forms bulky intra-strand adducts in DNA

treats tumors deficient in NER

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13
Q

ataxia oculomotor apraxia (AOA1)

A

autosomal RECESSIVE

mutation in aprataxin (APTX) - DNA “end processor” with hydrolase and transferase activity —> ssB repair defect

ataxia, oculomotor apraxia, hypercholesterolemia, hypoalbuminemia

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14
Q

ataxia telangiectasia (AT)

A

autosomal RECESSIVE

mutation in ATM (signal to cell cycle checkpoint, active in B/T development) —> dsB NHEJ defect

immune deficiency, chromosomal abnormalities (B, T cells), lymphoid cancer, hypersensitive to ionizing radiation

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15
Q

alpha-amanitin

A

mushroom toxin, inhibits RNA pol II

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16
Q

molnupiravir

A

covid drug (prodrug)

substrate for viral RNA-dependent RNA polymerase

causes viral mutagenesis, inhibiting viral replication

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17
Q

rifampicin

A

antibiotic specific for bacterial RNA pol

part of combination therapy for M. tuberculosis

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18
Q

Rett syndrome

A

X-linked DOMINANT** (heterogenous females only)

mutation in MECP2 (loss of methylation—> inappropriate gene expression)

begins young - seizures, lung infections, autism, failure to gain speech/walk

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19
Q

mis-regulation of transcription by HIV-1

A

programmed ribosomal frame shifting: generate >1 protein from single mRNA

pseudoknots stall ribosome

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20
Q

how does polio virus mess with translation

A

contains internal ribosome entry site (IERS) that allows cap-independent translation

cleaves eIF4G, diverts machinery, IRES binds eIF4G, direct recruitment of 40S

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21
Q

how does Corynebacterium diptheriae mess with translation

A

toxin (diphtheria) inactivates eEF-2 (transfers ADP-ribose from NAD), inhibiting translocation

presents with soar throat, grey/white pseudomembranes

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22
Q

hemochromatosis

A

autosomal RECESSIVE

defective iron storage (excess in body) - HFE mutation

phenotype varies by sex: women have mechanism to get rid of excess iron

most common single-gene inherited disease in US

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23
Q

male-limited precocious puberty

A

autosomal DOMINANT**

sex-limited, only expressed in males - early onset puberty

mutation in LH receptor (constitutively active)

females can carry but no phenotype

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24
Q

why does neurofibromatosis make creating a pedigree difficult

A

autosomal DOMINANT

but variable expressivity - all individuals affected, but severity varies

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25
Q

Hemophilia A

A

X LINKED RECESSIVE

mutation in Factor VIII (clotting)

males have severe phenotype

heterozygous females may have mild disease (skewed X inactivation)

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26
Q

when osteogenesis imperfecta (autosomal dominant) or Duchenne muscular dystrophy (X-linked recessive) appear in a population, the most likely cause is…

A

new mutation

genetically lethal diseases, no inheritance pattern

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27
Q

Huntington disease

A

autosomal DOMINANT**

TNR (CAG, glutamine) in EXON of chromosome 4 —> protein misfolding, aggregation

disease with 40+ repeats

paternal transmission - expansion through spermatogenesis

abnormal saccadic eye movements, chorea, neuronal loss in striatum, mood, behavior

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28
Q

Fragile X syndrome

A

X-LINKED DOMINANT*

TNR (CGG) in 5’-UTR

maternal transmission - expansion in oogenesis

pre-mutation —> primary ovarian insufficiency, ataxia syndrome

most common cause of inherited cognitive disability, autism

male full mutation: long face, prominent jaw, mitral valve prolapse

female full mutation: mild cognitive disability

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29
Q

Friedreich ataxia

A

autosomal RECESSIVE

TNR (GAA) in INTRON of chromosome 9 —> mRNA transcript lost

most common cause of hereditary ataxia

develops young - ataxia, sensory loss, mitochondrial dysfunction, CHF, diabetes mellitus, progressive weakness

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30
Q

myotonic dystrophy, type 1 (DM1)

A

*autosomal DOMINANT**

TNR (CTG) in 3’-UTR of DMPK —> RNA toxicity

maternal transmission (expansion)

most common cause of adult-onset muscular dystrophy

mild (cataracts), classic (muscle wasting, myotonia, arrhythmias), severe/congenital

pronounced genetic anticipation

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31
Q

Down Syndrome: Trisomy 21

A

meiotic nondisjunction

most common chromosomal abnormality, most frequent genetic cause of cognitive disability

slanted eyes, flat face, macroglossia, nuchal folds, brachycephaly (wide), early-onset Alzheimer’s, hypotonia, cardiac septal defects, duodenal atresia, neoplasia (leukemia)

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32
Q

Trisomy 18

A

EDWARD syndrome

meiotic nondisjunction

prominent occiput, small for gestational age, clenched hands, rocker-bottom feet, dolichocephaly (long), severe cognitive disability

33
Q

Trisomy 13

A

PATAU syndrome

meiotic nondisjunction

anophthalmia (missing eye), cleft lip/plate, holoprosencephaly, severe cognitive disability, polydactyly

34
Q

Turner syndrome

A

MONOSOMY X: 45, X

short, cardiovascular defect, ovarian failure (primary amenorrhea), lymphedema

35
Q

47, XXY

A

KLEINFELTER syndrome

paternal nondisjunction

tall, androgen insufficiency

36
Q

Prader-Willi syndrome

A

chromosome 15 PATERNAL deletion of maternally imprinted gene (Prader = Paternal)

most common form of syndromic obesity, genital hypoplasia, neonatal hypotonia, reach milestones late

37
Q

Angelman syndrome

A

chromosome 15 MATERNAL deletion in paternally imprinted gene (angelMan = Maternal)

loss of E3 ubiquitin ligase

nonverbal, seizures, happy demeanor, microcephaly, cognitive impairment

38
Q

what goes wrong in cystic fibrosis and what is its inheritance pattern

A

autosomal recessive

LOF mutation in CFTR Cl- channel (normal ligand is ATP)

impaired channel function —> abnormal salt transport —> mucus buildup inside respiratory epithelial cells

39
Q

what does tetrodotoxin (TTX) do?

A

pufferfish toxin - binds sodium ion channels irreversibly
(with a large “puffed up” molecule similar to hydrated sodium)

disrupts action potential propagation —> diaphragm paralysis and death

40
Q

tamoxifen

A

estrogen receptor antagonist selective for breast tissue

gets chaperoned into nucleus, then represses estrogen response element (DNA sequence)

41
Q

Addison’s diseases, Cushing’s syndrome, and Kallman syndrome all have this in common

A

steroid-hormone related diseases

Addison’s: autoimmune adrenal insufficiency
Cushing’s: hyperaldosteronism (secondary) —> high ACTH
Kallman: delayed puberty, developmental disorder

42
Q

how does ras mutation play a role in cancer

A

ras: small G-protein in ras-MAPK pathway

oncogenic mutation in ras makes it resistant to GAP —> constitutively active

(common mutation in tumors)

43
Q

cell signaling cause of neurofibromatosis type 1

A

mutation in GAP genes results in overactive Ras

[mutation is in NF1, which encodes neurofibromin-1 GAP]

44
Q

cell signaling mutation that causes Noonan syndrome

A

hyperactive Ras due to GOF mutation resulting in defective GAP activity

[mutation is in PTPN11 gene which encodes protein tyrosine phosphatase SHP2]

Noonan syndrome: abnormal development in various parts of body

45
Q

hereditary spherocytosis

A

mutations in spectrins —> spherical RBC susceptible to destruction in spleen

spectrins associate with membrane proteins to stabilize biconcave shape of erythrocyte

46
Q

tetrodotoxin and lidocaine both exhibit this cellular effect:

A

sodium channel blockers

tetrodotoxin: puffer fish toxin puffs up sodium channel to irreversibly block it
lidocaine: anesthetic to treat tachycardia

47
Q

effect of curare

A

blocks Na/K ion channel

competitively antagonizes nicotinic Ach receptor at neuromuscular junction —> paralysis

48
Q

chloroquine is frequently used to develop malaria, but resistance commonly occurs. how?

A

increased expression of ABC pump

49
Q

how do these toxins target actin cytoskeleton: phalloidin, cytochalasin, latrunculin

A

bind and stabilize actin or block polymerization from + barbed end

50
Q

how do Listeria and Rickettsia (rocky mountain fever) bacteria both target actin?

A

hijack actin polymerization machinery to make themselves an actin tail to shuttle them around

spread without detection from cell to cell

51
Q

how do each of these toxins target microtubules: paclitaxel, colchicine, vincristine

A

stabilize microtubules or block polymerization from + end

52
Q

what cytoskeletal component is associated with congenital heart disease and cardiomyopathy?

A

actin - heavily expressed in the heart muscles for contraction

53
Q

Griscelli syndrome Type 1 presentation and cause

A

silver hair, light skin, severe neurological defects

defective myosin transportation of melanosome to cell periphery

54
Q

Kartagener Syndrome

A

aka Primary Ciliary Dsykinesia

mutations in dynein heavy chain —> immobile cilia/flagella

chronic infections of respiratory tract (can’t clear it), sterile males (immobile sperm)

55
Q

match the disease with the defective cell structure:
Zellweger syndrome, I-cell disease, hypercholesterolemia

lysosomes, endosomes, peroxisomes

A

Zellweger syndrome: defective peroxisomes - enzymes not transported into peroxisome

I-cell disease: defective lysosomes

hypercholesterolemia: defective endocytosis

56
Q

Zellweger syndrome

A

defect in recognition signal of peroxisomal enzyme proteins - do not get delivered to peroxisome ! Zo [for Zellweger] no !!

peroxisome is defective

57
Q

botulinum and tetanus toxins affect vesicular transport by cleaving ____

A

v-SNARES, preventing vesicular fusion and NT release

58
Q

Inclusion (I-cell) disease

A

mannose-6 residue is not phosphorylated on lysosomal proteins due to phosphotransferase mutation

all lysosomal enzymes [very inclusive !] are secreted because they cannot be recognized by M-6-P receptor in trans-Golgi, so are not directed towards lysosome

59
Q

what happens to cell function during Legionairre’s disease?

A

bacteria engulfed in phagosome hijack it! and block delivery to lysosome

bacteria isn’t degraded so replicates instead

60
Q

how does a mutation in LDL receptor tail prevent cholesterol clearance and cause hypercholesterolemia?

A

interferes with receptor binding to adaptin

so even if cargo is bound to receptor it cannot be incorporated into vesicle for exit [clearance]

61
Q

a patient has a mutation in Claudin 19, an important protein expressed in renal tubule tight junctions. What would you expect the effect to be?

A

claudins regulate paracellular permeability and reabsorption of calcium and magnesium in renal tubules

would see LOW serum Mg2+ and HIGH urinary Ca2+ (neither is being reabsorbed as well)

62
Q

what causes EMT

A

EMT: epitelial to mesenchymal transition, important part of cancer progression

due to loss of E-cadherin (main protein for holding epithelial cells together in sheet)

63
Q

pemphigus vs pemphigoid

A

pemphigus: blistering between epidermis, due to autoantibodies against spot desmosomes (intermediate filaments)

pemphigoid: blistering between epidermis and dermis (between cell and basal lamina), due to autoantibodies against hemidesmosomes

64
Q

what do osteogenesis imperfecta, chondrodysplasia, and Ehler-Danlos syndrome have in common?

A

tissue-specific diseases associated with mutations in fibril-forming collagens

osteogenesis imperfecta: brittle bone, Type I defect (found everywhere)
chondrodysplasia: Type II (cartilage)
Ehler-Danlos: aneurism, Type III (aorta, blood vessels)

65
Q

a patient comes in with scurvy. how will this affect their collagen?

A

scurvy: due to vitamin C deficiency

vitamin C required for hydroxylation of alpha chain of collagen —> they would have reduced collagen formation

66
Q

epiphyseal dysplasia is due to mutation in what kind of collagen (2 types)?

A
  1. fibril-forming collagen Type II
  2. fibril-associated collagen Type IX

important for joints together, mutation leads to arthritis

67
Q

how do mutations in collagens Type XVII (17) and VII (7) cause blistering diseases?

A

Type XVII is transmembrane collagen —> blistering between epithelium and basement membrane

Type VII is network forming —> blistering between basement membrane and stroma (connective tissue)

68
Q

Marfan syndrome

A

long appendages, chest deformity, aorta prone to rupture (AD inheritance)

Fibrillin 1 (glycoprotein) mutation causes defect in elastin

69
Q

cause and presentation of Epidermolysis bulbosa

A

Type VII (7) network-forming collagen defect

epithelium and basement membrane peel away

70
Q

Glanzmann’s disease

A

clotting disorder caused by mutation in integrin beta 3

inability of platelets to bind fibrinogen

71
Q

how is Bcl-2 implicated in cancer?

A

high levels of Bcl-2 (anti-apoptotic) cause decreased propensity to undergo apoptosis —> increased cancer growth

linked to poor disease outcomes

72
Q

3 ways p53 helps prevent cancer formation

A
  1. initiates apoptosis by blocking Bcl-2 and Bcl-XL while promoting Bak/Bax
  2. activates DNA repair proteins
  3. arrests growth by holding cell cycle at G1/S checkpoint
73
Q

polyhydramnios vs oligohydramnios

A

polyhydramnios: excess amniotic fluid (might be due to fetus’ inability to swallow or esophageal-duodenal atresia)

oligohydramnios: insufficient amniotic fluid

74
Q

congenital human disorders of hedgehog signaling primarily affect what bodily regions?

A

CNS and limb

Hh is localized to organizing centers in posterior limb bud and ventral midline of CNS during embryogenesis

75
Q

major biological causes of human holoprosencephaly (HPE) (2)?

A

HPE: failure of embryonic prosencephalic vesicles to divide into 2 hemispheres

major causes:
1. Shh protein haplo-insufficiency (single copy of gene is not sufficient)
2. Gli2 mutation

76
Q

mechanism and effect of cyclopamine (plant alkaloid)

A

inhibits Shh signaling by blocking Smo (which Shh disinhibits by binding Ptc1) —> Gli phosphorylation into GliR occurs constitutively, target genes constantly repressed

77
Q

Smith-Lemli-Opitz Syndrome

A

mutation in cholesterol synthesis [sterol delta-7-reductase]

cholesterol depletion during gestation —> depleted processing of Shh (needed for auto-cleavage)

limb and CNS effects, similar to Shh knockdown

78
Q

what mutation in the Hh pathway causes medulloblastoma?

A

medulloblastoma: tumor in cerebellum during development

LOF Ptc1 mutation —> constant disinhibition of Smo, even in absence of Hh —> target genes constitutively activated

Foundations Exam 1 (33 decks)

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