Clinical Correlations Flashcards
MELAS
Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes
mitochondrial inheritance
red-ragged fibers, hemiparesis, seizures
what illnesses do the following nucleoside analogs treat?
a. acyclovir
b. AZT
c. ddC
d. gemcitabine
e. remdesivir
a. acyclovir - HSV (deoxyguanosine)
b. AZT - HIV (thymidine)
c. ddC - HIV (deoxycytidine)
d. gemcitabine - cancer (deoxycytidine)
e. remdesivir - covid (adenosine)
function of quinolone drugs
block activity of DNA gyrase (prokaryotic Top II)
inhibit bacterial DNA synthesis
function of chemotherapeutic drugs Camptothecin and Adriamycin/Etoposide
Camptothecin targets Topo I
Adriamycin and Etoposide target Topo II
convert topoisomerases into DNA breaking agents by inhibiting ability of top to REJOIN DNA
what do inhibitors of HSV helicase-primase do?
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)
Dyskeratosis congenita
reduced telomerase activity —> affects stem and germ cells in tissues dividing rapidly/often
bone marrow failure due to loss of hematopoietic renewal
Lynch syndrome
HNPCC
mismatch repair (MMR) defect (shows MSI)
mutation in MSH2 or MLH1
colorectal cancer
mutation in DNA glycosylase MYH
high risk of colon cancer
defect in base excision repair (BER)
Werner’s syndrome
autosomal RECESSIVE
RecQ family WRN helicase mutation —> defect in BER
premature aging (20-30y), cataracts, atherosclerosis, cancer, telomere shortening
xeroderma pigmentosum (XP)
defect in GG-NER
XP protein mutations affecting recognition or helicase activity
solar sensitivity, skin cancer
cockayne syndrome
defective TC-NER
mutation in CSA or CSB recognition proteins
growth delays, intellectual disability, sun sensitive (but NOT cancer risk)
premature aging, from birth
Cisplatin
chemotherapeutic drug, forms bulky intra-strand adducts in DNA
treats tumors deficient in NER
ataxia oculomotor apraxia (AOA1)
autosomal RECESSIVE
mutation in aprataxin (APTX) - DNA “end processor” with hydrolase and transferase activity —> ssB repair defect
ataxia, oculomotor apraxia, hypercholesterolemia, hypoalbuminemia
ataxia telangiectasia (AT)
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
alpha-amanitin
mushroom toxin, inhibits RNA pol II
molnupiravir
covid drug (prodrug)
substrate for viral RNA-dependent RNA polymerase
causes viral mutagenesis, inhibiting viral replication
rifampicin
antibiotic specific for bacterial RNA pol
part of combination therapy for M. tuberculosis
Rett syndrome
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
mis-regulation of transcription by HIV-1
programmed ribosomal frame shifting: generate >1 protein from single mRNA
pseudoknots stall ribosome
how does polio virus mess with translation
contains internal ribosome entry site (IERS) that allows cap-independent translation
cleaves eIF4G, diverts machinery, IRES binds eIF4G, direct recruitment of 40S
how does Corynebacterium diptheriae mess with translation
toxin (diphtheria) inactivates eEF-2 (transfers ADP-ribose from NAD), inhibiting translocation
presents with soar throat, grey/white pseudomembranes
hemochromatosis
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
male-limited precocious puberty
autosomal DOMINANT**
sex-limited, only expressed in males - early onset puberty
mutation in LH receptor (constitutively active)
females can carry but no phenotype
why does neurofibromatosis make creating a pedigree difficult
autosomal DOMINANT
but variable expressivity - all individuals affected, but severity varies
Hemophilia A
X LINKED RECESSIVE
mutation in Factor VIII (clotting)
males have severe phenotype
heterozygous females may have mild disease (skewed X inactivation)
when osteogenesis imperfecta (autosomal dominant) or Duchenne muscular dystrophy (X-linked recessive) appear in a population, the most likely cause is…
new mutation
genetically lethal diseases, no inheritance pattern
Huntington disease
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
Fragile X syndrome
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
Friedreich ataxia
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
myotonic dystrophy, type 1 (DM1)
*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
Down Syndrome: Trisomy 21
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)
Trisomy 18
EDWARD syndrome
meiotic nondisjunction
prominent occiput, small for gestational age, clenched hands, rocker-bottom feet, dolichocephaly (long), severe cognitive disability
Trisomy 13
PATAU syndrome
meiotic nondisjunction
anophthalmia (missing eye), cleft lip/plate, holoprosencephaly, severe cognitive disability, polydactyly
Turner syndrome
MONOSOMY X: 45, X
short, cardiovascular defect, ovarian failure (primary amenorrhea), lymphedema
47, XXY
KLEINFELTER syndrome
paternal nondisjunction
tall, androgen insufficiency
Prader-Willi syndrome
chromosome 15 PATERNAL deletion of maternally imprinted gene (Prader = Paternal)
most common form of syndromic obesity, genital hypoplasia, neonatal hypotonia, reach milestones late
Angelman syndrome
chromosome 15 MATERNAL deletion in paternally imprinted gene (angelMan = Maternal)
loss of E3 ubiquitin ligase
nonverbal, seizures, happy demeanor, microcephaly, cognitive impairment
what goes wrong in cystic fibrosis and what is its inheritance pattern
autosomal recessive
LOF mutation in CFTR Cl- channel (normal ligand is ATP)
impaired channel function —> abnormal salt transport —> mucus buildup inside respiratory epithelial cells
what does tetrodotoxin (TTX) do?
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
tamoxifen
estrogen receptor antagonist selective for breast tissue
gets chaperoned into nucleus, then represses estrogen response element (DNA sequence)
Addison’s diseases, Cushing’s syndrome, and Kallman syndrome all have this in common
steroid-hormone related diseases
Addison’s: autoimmune adrenal insufficiency
Cushing’s: hyperaldosteronism (secondary) —> high ACTH
Kallman: delayed puberty, developmental disorder
how does ras mutation play a role in cancer
ras: small G-protein in ras-MAPK pathway
oncogenic mutation in ras makes it resistant to GAP —> constitutively active
(common mutation in tumors)
cell signaling cause of neurofibromatosis type 1
mutation in GAP genes results in overactive Ras
[mutation is in NF1, which encodes neurofibromin-1 GAP]
cell signaling mutation that causes Noonan syndrome
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
hereditary spherocytosis
mutations in spectrins —> spherical RBC susceptible to destruction in spleen
spectrins associate with membrane proteins to stabilize biconcave shape of erythrocyte
tetrodotoxin and lidocaine both exhibit this cellular effect:
sodium channel blockers
tetrodotoxin: puffer fish toxin puffs up sodium channel to irreversibly block it
lidocaine: anesthetic to treat tachycardia
effect of curare
blocks Na/K ion channel
competitively antagonizes nicotinic Ach receptor at neuromuscular junction —> paralysis
chloroquine is frequently used to develop malaria, but resistance commonly occurs. how?
increased expression of ABC pump
how do these toxins target actin cytoskeleton: phalloidin, cytochalasin, latrunculin
bind and stabilize actin or block polymerization from + barbed end
how do Listeria and Rickettsia (rocky mountain fever) bacteria both target actin?
hijack actin polymerization machinery to make themselves an actin tail to shuttle them around
spread without detection from cell to cell
how do each of these toxins target microtubules: paclitaxel, colchicine, vincristine
stabilize microtubules or block polymerization from + end
what cytoskeletal component is associated with congenital heart disease and cardiomyopathy?
actin - heavily expressed in the heart muscles for contraction
Griscelli syndrome Type 1 presentation and cause
silver hair, light skin, severe neurological defects
defective myosin transportation of melanosome to cell periphery
Kartagener Syndrome
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)
match the disease with the defective cell structure:
Zellweger syndrome, I-cell disease, hypercholesterolemia
lysosomes, endosomes, peroxisomes
Zellweger syndrome: defective peroxisomes - enzymes not transported into peroxisome
I-cell disease: defective lysosomes
hypercholesterolemia: defective endocytosis
Zellweger syndrome
defect in recognition signal of peroxisomal enzyme proteins - do not get delivered to peroxisome ! Zo [for Zellweger] no !!
peroxisome is defective
botulinum and tetanus toxins affect vesicular transport by cleaving ____
v-SNARES, preventing vesicular fusion and NT release
Inclusion (I-cell) disease
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
what happens to cell function during Legionairre’s disease?
bacteria engulfed in phagosome hijack it! and block delivery to lysosome
bacteria isn’t degraded so replicates instead
how does a mutation in LDL receptor tail prevent cholesterol clearance and cause hypercholesterolemia?
interferes with receptor binding to adaptin
so even if cargo is bound to receptor it cannot be incorporated into vesicle for exit [clearance]
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?
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)
what causes EMT
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)
pemphigus vs pemphigoid
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
what do osteogenesis imperfecta, chondrodysplasia, and Ehler-Danlos syndrome have in common?
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)
a patient comes in with scurvy. how will this affect their collagen?
scurvy: due to vitamin C deficiency
vitamin C required for hydroxylation of alpha chain of collagen —> they would have reduced collagen formation
epiphyseal dysplasia is due to mutation in what kind of collagen (2 types)?
- fibril-forming collagen Type II
- fibril-associated collagen Type IX
important for joints together, mutation leads to arthritis
how do mutations in collagens Type XVII (17) and VII (7) cause blistering diseases?
Type XVII is transmembrane collagen —> blistering between epithelium and basement membrane
Type VII is network forming —> blistering between basement membrane and stroma (connective tissue)
Marfan syndrome
long appendages, chest deformity, aorta prone to rupture (AD inheritance)
Fibrillin 1 (glycoprotein) mutation causes defect in elastin
cause and presentation of Epidermolysis bulbosa
Type VII (7) network-forming collagen defect
epithelium and basement membrane peel away
Glanzmann’s disease
clotting disorder caused by mutation in integrin beta 3
inability of platelets to bind fibrinogen
how is Bcl-2 implicated in cancer?
high levels of Bcl-2 (anti-apoptotic) cause decreased propensity to undergo apoptosis —> increased cancer growth
linked to poor disease outcomes
3 ways p53 helps prevent cancer formation
- initiates apoptosis by blocking Bcl-2 and Bcl-XL while promoting Bak/Bax
- activates DNA repair proteins
- arrests growth by holding cell cycle at G1/S checkpoint
polyhydramnios vs oligohydramnios
polyhydramnios: excess amniotic fluid (might be due to fetus’ inability to swallow or esophageal-duodenal atresia)
oligohydramnios: insufficient amniotic fluid
congenital human disorders of hedgehog signaling primarily affect what bodily regions?
CNS and limb
Hh is localized to organizing centers in posterior limb bud and ventral midline of CNS during embryogenesis
major biological causes of human holoprosencephaly (HPE) (2)?
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
mechanism and effect of cyclopamine (plant alkaloid)
inhibits Shh signaling by blocking Smo (which Shh disinhibits by binding Ptc1) —> Gli phosphorylation into GliR occurs constitutively, target genes constantly repressed
Smith-Lemli-Opitz Syndrome
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
what mutation in the Hh pathway causes medulloblastoma?
medulloblastoma: tumor in cerebellum during development
LOF Ptc1 mutation —> constant disinhibition of Smo, even in absence of Hh —> target genes constitutively activated
