BMS Exam 1 Diseases Flashcards
Sideroblastic Anemia
Etiology
- Hereditary: ALAS-2 mutation
- Acquired: Isoniazid, EtoH, Lead, Pyridoxine deficiency
- RBCs microcytic and hypochromic
- Ring sideroblasts in BM
Lead Poisoning
Sources Pb
- Cosmetics, jewelery, toys
- Paint
- Pottery/cermics, soil
- Water pipes, valves
- Occupational: battery, ceramics, construction, furniture
Enzymes inhibited: ALAD, Ferrochelatase
Clinical Presentation:
- Lethargy, anorexia, abd cramps, arthralgia
- Anemia, HA, abd cramps, gingival and long bone lead line, PN
- Covulsions, Coma, encephalopathy, renal failure
Dx:
- ALA in urine, Zn PP in blood, Basophilic stippling in smear
Tx:
- desferrioxamine, sodium calcium edetate, penicillamine
Acute Intermittent Porphyria (AIP)
Etiology: PBGD deficiency, 4Ms
- 4Ms –> CYP synthesis –> dec heme –> reduced inhibition of ALAS
- Autosomal dominant
Sx:
- NO SKIN LESIONS
- PN, abd colic, paralyses, pysch
- Accumulation of ALA (and/or PBG) neurotoxic to ANS and PNS
Dx:
- dark brown/red wine urine color (ALA/PBG accumulation)
Tx:
- Avoid 4M
- Glucose loading
- Heme/Hematin
Porphyria Cutanea Tarda (PCT)
Etiology: UROD deficiency
- EToH, hepatic fe overload, sunlight, HBV/HCV, HIV
- genetic/nongenetic factors
Sx:
- Skin- bullae, hypertrichosis, heliotrope
- Urine- dark pink fluorescing
Tx:
- Remove environmental exposures
- Sunscreen
- Desferrioxamine
- phlebotomy
Erythropoetic Protoporphyria (EPP)
Etiology: Ferrochelatase mutations; autosomal dom
Sx:
- Photosensitivity
- Early childhood presentation
- Chronic liver dz later in life
Dx: Feces accumulates porphyrin
Tx: Avoid sun
Autosomal Dominant Porphyrias
AIP, EPP
Congenital erythropoetic porphyria (autosomal recessive)
Rett Syndrome
Autism spectrum disorder with monogenic origin
- progressive neuro dev disorder
- see signs in first 6-8 months
- X lined dominant (higher incidence F)
- Deficiency in methyl CpG binding protein MECP2
- MECP2 normally abundant in brain, so loss of fx causes overexpression of genes with potentially damaging effects
Prader-Willi Syndrome
Disorder of genomic imprinting
- Mental retardation
- Hyperphagia (–> obesity)
- Deletion of the paternal gene on ch 15
Angelman Syndrome
Disorder of genomic imprinting
- Excessive laughter (always smiling)
- Seizures (mental retardation)
- Deletion of maternal gene on ch 15
Ataxia Oculomotor Apraxia
Molecular Defect: APTX (aprataxin) Pathway: SSB Repair Clinical Features: - Ataxia - Autosomal recessive - Neurologic impairment (cerebellar atrophy, limited eye movement, involuntary movements) - HLD, hypoalbumin - No immunological deficiency - No cancer - Mildly sensitive to x-rays - Onset 1-16 yrs
Ataxia Telangiectasia
Molecular Defect: ATM (DSB Sensor protein kinase)
Pathway: DSB Repair
Clinical Features:
- Ataxia, and telangiectasias
- Autosomal recessive
- Progressive neuro impairment (cerebellar ataxia)
- Immunodeficiency (abnormalities T/B cells)
—> propensity for lymphoid tumors
- Xray hypersx
- Inc Cancer (lymphoid tumors)
- Onset early childhood
Cockayne Syndrome
Molecular Defect: CSA/CSB (Affects recognition of stalled RNAPII)
Pathway: TC-NER
Clinical Features:
- Autosomal recessive
- Growth retard (short), photosx, progeria
- Neuro and cognitive impairment (cerebellar atrophy–> enlarged ventricles)
- No cancer
Werners Syndrome
Molecular Defect: WRN Helicase Pathway: BER, DSB Clinical Features - Autosomal recessive - Premature aging (progeria) - Stocky appearange (fat deposit and short, flat feet, high pitched voice due to offset puberty) - Hypogonadism, DM, cataracts, CVD - Cancers: sarcomas - Onset 20s/30s, early death
Xeroderma Pigmentosum
Molecular Defect: XPE/CPC (GG-NER) and/or XPA/XPD (common pathway)
Pathway: NER
Clinical Features:
- Autosomal recessive (heterozygotes asx)
- Potential neuro sx (depending on pathway)
- Extreme photosx (burns, freckling)
- Melanomas
- Ocular abnormalities
- Onset age 1-2 yo
Lynch Syndrome (HNPCC)
Molecular Defect: MSH2, MLH1
(MSH2/MLH1 –> MSI-H and MSH 6 –> MSI-L)
Pathway: MMR
-Caused by MSI
Clinical Features:
- Early onset cancers (6 months) CRC
- Survival rate higher than random variant
- Intestinal villi distorted in Lynch
- Autosomal dominant
(HETAL: POLE, POLD1 genes; Turcot (brain); Muir Torre (skin features);
A-Thalassemia (Silent Carrier State)
1 alpha gene deleted
- Normocytic cells
A-Thalassemia Trait
2 alpha genes deleted
- AA (usually one from each chrom)
- Asians (usually both from one chrom)
- Slightly microcytic, slight anemia
HbH Disease
3 alpha genes deleted
- Typical in asians bc you need at least 1 chrom with no alpha
- B-Chain excess and formation of B4 tetramers that are insoluble (less toxic than alpha aggregates seen in b-thal). Damages RBC membrane –> chronic hemolytic anemia
- less Hb formed; microcytic
A-Thalassemia (Hb Bart’s)
4 alpha genes deleted
- Most common in asians
- Alpha produced early in embryonic production
- Gamma also produced, but since beta isn’t produced till later in preg, you form G4-tetramers (Bart’s). Very poor O2 release –> Fetal hydrops –> death in womb or shortly after birth
- No more allostery so no BPG or Bohr’s effect
B-Thalassemia trait (minor)
1 beta gene mutation
- Mild excess alpha chains that aggregate, but cell can handle it
- Deficiency in B-globin
- Dec HbA, Dec Hb content
- Microcytic, mild anemia
- Gamma/delta unaffected so relative increase in HbF (gamma) and HbA2 (delta)
- due to intron mutation that moves the intron 3’ splice side upstream
B-Thalassemia Major
2 beta gene mutation
- More aggregate that will precipitate and become toxic and cause apoptosis
- Ineffective erythropoiesis –> severe dec in production –> severe anemia
- Low or no HbA, microcytosis
- Increase in HbA2, but not enough for life –> require transfusion to live
- Relative increase in HbF
- Manifestations shortly after birth
- Can use allele-specific dot blotting to detect
HbA
a2,b2
HbA2
a2,d2
HbF
a2,y2
HbS
a2,bs2
HbH
b4
Hb Barts
y4
Sickle Cell Anemia - Molecular basis
HbS mutation resulting from B6 Glu –> Val
- Sickling occurs at high concentrations of doexy HbS forming rod shaped polymers/fibers
-Sx: anemia, acute/chronic pain, jaundice, splenomegaly
Tx:
- Hydroxyurea
- Butyrate
- Narcotics
- Transfusion
- PCN ppx
- Hydration
- Immunizations
- At physio pH, Glu is -1 and V is 0 so he charge will increase by 2 (dimers). We should use pH 7 to separate them. HbA will travel faster than HbS
- Can use allele-specific dot blotting to detect
- BPG and low pH –> agreggation bc stablize T state
- Glycosylation interferes with BPG binding –> less aggreg
Sickle Cell Trait
Heterozygous
- HbA, HbS (Small amounts HbA2, HbF, HbA1c)
- Usually asymptomatic except in renal medulle
Sickle Cell Anemia
Homozygous
- Autosomal recessive disorder
- Increased BPG –> stable deoxy –> sickling
- Low pH –> shift curve to left –> stable deoxy –> more sickling
- Glycosylation of N-terminal AA will interfere with BPG binding -> stable oxy –> decrease aggregation
HbC
B6 Gly –> Lys
- Causes intracellular crystallization of the protein and cation leak - efflux of potassium, resulting in dehydration
- Also has infection protection effect
- No change in allostery so no change in BPG, Bohr
- mild hemolytic disorder
Need pH
Cystic Fibrosis (CF)
CFTR d508 mutation
- Mutation in the CF transmembrane receptor protein that causes the protein to fold slowly. As a result, the protein is captured by the proteolytic system and degraded.
- A small amount escapes and can fold.
- Effect is depleted amounts of critical transporter
- Can use Allele-specific PCR to determine if gene mutation exists.
Alzheimer’s Disease
Accumulation of aberrant AB peptide in plaques.
- Normal proteins unfold and associate to form insoluble aggregates that are toxic and cause neuronal cell death.
- Amyloid Disease
Lou Gehrig’s Disease (ALS)
Agreggation of SOD with other cellular proteins leads to death of lateral nerves.
- Normal proteins unfold and associate to form insoluble aggregates that are toxic and cause neuronal cell death.
Parkinsons
- Normal proteins unfold and associate to form insoluble aggregates that are toxic and cause neuronal cell death.
- Amyloid Disease
- Mutation in UchLI (Ub carboxy terminal hydrolase? )
- Parkin is an E3 enzyme –> mutations cause early onset PD
Prion Disease
Protein induced conformational change of native structure; transmissible.
CJD - BSE beef
Familial insomnia?
Kuru - ritual cannibalistic activities
Huntington MJD (Machado Joseph Disease)
Trinucleotide Expansion Disease:
- CAG repeats (glutamine) undergo extensive expansion to cause altered function or aggregation.
MJD - Ataxin 3 mutation (proteasome subunit that an bind Ub chains)
HPV
E6 mutation degrades p53 –> cancers
E6AP is termed a Hect E3 ligase
XP (Madura)
Xpc protein is a DNA damage-binding protein that is degraded by the proteosome
Fanconi anemia
- Defect in DNA repair
Proteasome is required for activating a DNA damage response
Von hippel-Lindau syndrome
Failure to degrade Hif-1
mini tumors all over body
Hypoxia
Symptoms (in order of increasing altitude)
- Altered night vision
- Dizziniess or tingling
- LoC
- Acute decompression
EPO Doping
You don’t need much EPO physiologically so may not show up at all on electrophoresis.
Diseases to detect on Western Blot
- Duchenne muscular dystrophy
- HIV
- Lyme
- HBV
- HSV
HIV
ELISA
- Antibodies developed by human vs AIDS detected
DX:
ELISA –> (+) –> Western –> (+) –> Positive
–> (-) –> Negative
Western Blot
Positive: Bands at p31 OR p24 AND gp160 OR gp120
Negative: no bands
Indeterminant: Bands present but pattern not right
MI
ELISA
- Release of troponin into circulation after MI
- Immobilized antibody recognizes troponin T
p53 (MDM2)
In response to cellular stress, MDM2, an E3 ubiquitin ligase, promotes p53 ubiquitination and degradation by the proteasome.
p53 and MDM2 co-immunoprecipiated out together.
HER2
IHC
- higher levels of protein, mRNA, and DNA
Altitude Sickness
- Use acetazolamide to promote excretion of bicarb in kidneys –> stabilize T state –> inc oxygen delivery to tissues
Carbon Monoxide Poisoning
- CO has 250x greater affinity for Hb than O2
- Produces cherry red discoloration of skin and organs
- Tx with 100% O2 or hyperbaric O2
HbA1c
Sugars bind to free amines on Hb
- -> commonly N-terminus of B cain
- -> irreversible
Methemoglobinemia
- Elevated (>1%) methemoglobin –> oxidized
- Can be induced by Abx
- inherited by mutations in CYPb5
- HbM mutations effect these interactions
Cyanide Poisoning
Tx
- amyl nitrate –> oxidizes Hb which readily binds CN
- produces cyanohemogbloin
- Keeps HCN from binding to CYPC oxidase –> critical for cellular respiration
Progeria
Can be caused by mutations in lamins
- Nuclear lamina - structure composed of specific intermediate filament proteins, the lamins. THey form a dense felt-like area under the nuclear membrane as seen by EM –> helps maintain nuclear structure
Salmonella typhimurium
Causes food poisoning Tx: - Inactivation of DNA adenine methylase (dam) - Blocks virulence genes - Induces immune response
HSV Tx
Nucleoside analoogs are used in antiviral and anticancer therapy
Acyclovir –> analog of deoxyguanosine
HIV Tx
- AZT(zidovudine) is an analog of deoxythymidine
- Incorporated into DNA during replication, but blocks further DNA synthesis
Actinomycin D
Dactinomycin
Intercalate into minor groove of DNA double helix interfering with DNA and RNA synthesis
Quinolones
Campothecin
Adriamycin/Etoposide
Quinolones
- Inhibit DNA gyrase
- Novobiocin, nalidixic acid?!??!
- no SE -_-
Campothecin - Topo I
Adriamycin/Etoposide - Topo II
HSV helicase-primase
Inhibitors of these enzymes recently developed
- stabilize interaction of helicase-primase with viral DNA
- inhibit progression of HSV DNA replication
Telomerase
DNA damage sensors (p53) induce cell growth arrest if there is genomic instability due to telomere fusion, etc.
In cancers, telomerase can be reactivated and coupled with loss of p53.
Dyskeratosis congenita
Caused by reduced telomerase activity
- Affects precursor cells in highly prolif tissues
- -> hair, epithelium, intestines, skin, BM, sperm
- pts generally die from BM failure
Hutchinson-Gilford progeria
Rare inherited condition
- Show accelerated telomere shortening
- Alopecia, aged skin, short, atherslcerosis
- Pts die from MI before 20yo
Adenomatous colorectal polyposis syndrome
Defect in BER
- mutation in gene coding glycosylase
- high risk for colon cancer
Cisplatin
Forms bulky intra-strand adducts with DNA
- Tumor cells deficient in NER are very sensitive to this drug
Rifampicin
Inhibits RNA polymerase
TFIIH Mutation
Can cause:
- XP
- trichothiodystrophy (TTD)
- Cockayne syndrome (CS)
alpha-amantin
binds tightly to RNAPII and inhibits elongation
- like rifampicin
Tamoxifen
Estrogen antagonist
- breast tumors rely on estrogen pathways for proliferation, but inhibited here
Hypothyroidism
- Selenocysteine is encoded by UGA stop codon that has been “recoded” to allow Sec-tRNA binding
- The SBP2 protein is required for this recoding process
- Rare mutations can cause hypothyroidism bc of reduced Sec incorporation –> dec deiodinases
Diptheria
Toxin targets translation by modifying the elongation factor responsible for translocation, eEF2.
