Random Flashcards

(57 cards)

1
Q

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

KEY FACTS

A

Feature Description

Gene Involved : APC tumor suppressor gene

Chromosome : Chromosome 5q21

Inheritance : Autosomal Dominant

Penetrance : 100% if untreated

Pathophysiology : Mutation in APC gene → defective β-catenin regulation → uncontrolled cell proliferation → formation of thousands of polyps

Cancer Risk Colorectal cancer by age ~40 unless prophylactic colectomy is done

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2
Q

FAP : PATHOLOGY

A

Feature Description

Histology : Multiple adenomatous colonic polyps (esp. tubular and villous adenomas)

Sequence Follows the adenoma-carcinoma sequence:

APC mutation (initiation)

KRAS mutation (progression)

p53 mutation (malignancy) |

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3
Q

FAP : CLINICAL FEATURES

A

Usually asymptomatic initially

Numerous colonic polyps by adolescence

Rectal bleeding, diarrhea, abdominal pain (later)

Colorectal cancer if untreated

Associated features depending on subtype (see below)

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4
Q

FAP: VARIANTS AND SYNDROMES

A

Syndrome Features

Gardner syndrome : FAP + osteomas, epidermoid cysts, dental abnormalities, desmoid tumors

Turcot syndrome : FAP + CNS tumors, especially
medulloblastoma (APC mutation)
or
glioblastoma (MMR mutation)

Attenuated FAP Fewer polyps (<100), later onset cancer, also APC-related

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5
Q

FAP: GENETICS + MOLECULAR

A

Gene Function Mutation Consequence

APC Tumor suppressor gene that regulates β-catenin Loss of function → β-catenin accumulates → ↑ transcription of proliferative genes

Two-hit hypothesis First hit: inherited APC mutation

Second hit: somatic mutation → polyp formation

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6
Q

FAP: MEMORIZATION TIPS

A

“APC is on 5 — Alive or Die”: APC mutation on chromosome 5 → if untreated, 100% chance of death by colon cancer

FAP = Family of Polyps – Think thousands of polyps inherited through family.

Gardner “gardens” tumors outside the colon (osteomas, cysts, etc.)

Turcot = Turban tumor (brain) – Associated with CNS tumors

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7
Q

WNT SIGNALING PATHWAY

A

State β-Catenin Status Result

No Wnt signal : Degraded by destruction complex (APC, Axin, GSK-3β) No gene transcription

Wnt signal ON : β-catenin stabilized → enters nucleus Activates gene transcription (cell proliferation, survival)

✅ USMLE Pearl:
APC gene is part of the β-catenin destruction complex.
If APC is mutated (e.g., FAP), β-catenin accumulates → ↑ transcription of oncogenes.
APC: adenomatous polyposis coli

CELL ADHESION
Anchors E-cadherin to the actin cytoskeleton

Important for tissue integrity and polarity

✅ Disruption → Loss of contact inhibition (a hallmark of cancer)

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8
Q

Beta catenin
STEP 1 MNEMONICS & TIPS

A

“B for both”:
β-catenin is used both in signaling and adhesion

“Beta-catenin builds and breaks”

Builds tissue via adhesion

Breaks cell cycle control via overactivation in cancer

“When APC is AWOL, β-catenin is out of control”
APC loss → β-catenin accumulation → uncontrolled proliferation

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9
Q

MISMATCH REPAIR (MMR) MUTATIONS
CLINICAL ASSOCIATION: LYNCH SYNDROME (HNPCC)

A

Feature Description

Also called Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Mutation: Germline mutation in MMR genes: MLH1, MSH2, MSH6, PMS2

Inheritance: Autosomal dominant

Mechanism: One inherited mutation + second somatic hit (Knudson’s two-hit hypothesis)

Key Cancers

Colorectal cancer (right-sided) – early onset, non-polypoid

** Endometrial cancer (most common extracolonic in women) **

Ovarian, gastric, urothelial, small bowel, pancreatic, brain (esp. glioblastoma)

Skin tumors (sebaceous neoplasms – Muir-Torre variant) |

✅ Mnemonic: “Lynch = MEGO”

M – MSI

E – Endometrial cancer

G – GI (colon, stomach, small bowel)

O – Ovarian cancer

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10
Q

VON HIPPEL–LINDAU (VHL) DISEASE
OVERVIEW

A

Feature Detail

Inheritance Autosomal Dominant

Gene VHL tumor suppressor gene

Chromosome Chromosome 3p25
Penetrance Nearly 100% by age 65

Key Mechanism Loss of VHL protein → failure to degrade HIF-1α → ↑ angiogenesis and tumor formation

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11
Q

von Hippel Lindau
MOLECULAR PATHOPHYSIOLOGY

A

Normal Function of VHL Consequence of Mutation

VHL protein tags HIF-1α for ubiquitination and degradation (under normoxia) HIF-1α accumulates → activates transcription of pro-angiogenic genes (VEGF, PDGF, EPO)

✅ Mnemonic:
“VHL = Very High Levels of HIF”

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12
Q

CLINICAL FEATURES (VHL-Associated Tumors)

A

Organ/System Tumor Type

CNS : Hemangioblastomas (cerebellum, retina, brainstem, spinal cord)

Kidney: Clear cell renal cell carcinoma (ccRCC) — bilateral, early onset

Adrenal gland: Pheochromocytoma (less common than in MEN 2)

Pancreas: Pancreatic cysts, neuroendocrine tumors

Eye : Retinal angiomas/hemangioblastomas – may lead to vision loss

Inner ear Endolymphatic sac tumors – hearing loss, vertigo

✅ VHL = multiple highly vascular tumors
✅ Hemangioblastomas + RCC + Pheo = classic triad tested

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13
Q

HIF-1alpha

A

CORE CONCEPT
Feature Details

What is HIF-1α? Transcription factor that responds to low oxygen (hypoxia)

Gene name HIF1A

Normal function Induces transcription of pro-angiogenic and glycolytic genes in hypoxic conditions

Key Target Genes

VEGF (vascular endothelial growth factor)

EPO (erythropoietin)

GLUT1, glycolytic enzymes

PDGF, TGF-α |

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14
Q

REGULATION of HIF-1alpha

A

Oxygen Level What Happens to HIF-1α

Normoxia (normal O₂) Hydroxylated by prolyl hydroxylase, recognized by VHL protein → ubiquitinated → degraded in proteasome

Hypoxia (low O₂) Hydroxylation inhibited → HIF-1α stabilizes → translocates to nucleus → dimerizes with HIF-1β → activates transcription

✅ USMLE Pearl: The VHL tumor suppressor gene negatively regulates HIF-1α under normoxia

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15
Q

HIF-1alpha
PATHOLOGY ASSOCIATIONS

A

Disease Role of HIF-1α

Von Hippel–Lindau disease (VHL) Mutation in VHL gene → failure to degrade HIF-1α → ↑ VEGF, EPO → hemangioblastomas, RCC, pheochromocytomas

Clear cell Renal Cell Carcinoma (ccRCC) Commonly shows upregulated HIF-1α due to VHL loss (even sporadically)

Tumors in general Many exploit HIF-1α to grow in hypoxic microenvironments

High-altitude adaptation ↑ HIF-1α → ↑ EPO → ↑ RBC production (secondary polycythemia)

✅ Mnemonic: HIF = Helps In Famine (oxygen famine)

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16
Q

BOARD-STYLE CLUES & APPLICATIONS

A

Young patient with bilateral RCC or hemangioblastomas → think VHL → think HIF-1α dysregulation

Tumors exploiting hypoxia to increase angiogenesis → likely using HIF-1α

High-altitude athlete with ↑ hematocrit → HIF-1α-mediated EPO response

📚 STEP 1 MNEMONICS
“HIF gets High In Fasted (hypoxic) cells”
→ HIF-1α is active during hypoxia, turns on survival pathways

“HIF makes blood and vessels”
→ ↑ EPO, ↑ VEGF

“VHL puts HIF on a leash”
→ If VHL is mutated, HIF-1α is unleashed, driving angiogenesis and tumor growth

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17
Q

Tuberous sclerosis : overview

A

Feature Detail

Inheritance Autosomal Dominant

Genes TSC1 (hamartin, chromosome 9q34)

TSC2 (tuberin, chromosome 16p13)
Function TSC1 and TSC2 form a complex that inhibits mTOR → suppresses cell growth/proliferation

Mechanism Mutation → mTOR disinhibition → ↑ cell proliferation → hamartoma formation

Penetrance High (variable expressivity)

✅ Mnemonic: “TSC = Too many Soft Cell tumors”

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18
Q

Tuberous sclerosis
NEUROLOGIC FEATURES (VERY HIGH YIELD)

A

Manifestation Description

Cortical tubers Hamartomas in cortex → seizures, developmental delay

Subependymal nodules Benign growths near ventricles

Subependymal giant cell astrocytoma (SEGA) May obstruct foramen of Monro → hydrocephalus

Infantile spasms Seizures in infants, associated with poor prognosis

Intellectual disability Common, variable severity

✅ USMLE Pearl: TS is a leading cause of childhood seizures + mental retardation

PATHOPHYSIOLOGY
Normal In TSC
TSC1/2 → inhibit mTOR pathway → control cell growth TSC1/2 loss → unchecked mTOR activation → hamartomas in multiple organs

✅ Step 1 Focus: Dysregulated mTOR is central to tumor syndromes like TSC

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19
Q

NEUROLOGIC FEATURES (VERY HIGH YIELD)

A

Manifestation Description

Cortical tubers Hamartomas in cortex → seizures, developmental delay

Subependymal nodules Benign growths near ventricles

Subependymal giant cell astrocytoma (SEGA) May obstruct foramen of Monro → hydrocephalus

Infantile spasms Seizures in infants, associated with poor prognosis

Intellectual disability Common, variable severity

✅ USMLE Pearl: TS is a leading cause of childhood seizures + mental retardation

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20
Q

DERMATOLOGIC FEATURES (CLASSIC STEP 1 FINDINGS)

A

Finding Description

Hypomelanotic macules (“ash leaf spots”) Hypopigmented patches, visible with Wood’s lamp

Facial angiofibromas (adenoma sebaceum) Red papules in malar region (butterfly distribution)

Shagreen patch Thick, leathery skin on lower back

Ungual fibromas Flesh-colored tumors near or under fingernails

✅ Mnemonic: “Ash-leaf on the face, shagreen on the base”

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21
Q

BRUTON AGAMMAGLOBULINEMIA (X-LINKED)
CLINICAL PRESENTATION

A

Age Symptoms
Usually begins after 6 months of age - Recurrent bacterial infections: otitis media, pneumonia, sinusitis

Especially from encapsulated organisms (e.g., Strep pneumo, H. influenzae, Neisseria)

Enteroviral infections (e.g., polio, coxsackie) due to lack of neutralizing antibodies

Giardia lamblia infections (due to ↓ IgA) |

✅ Classic Step 1 Clue: Male infant with recurrent sinopulmonary infections starting after 6 months

STEP 1 RAPID RECALL
✅ X-linked recessive → affects boys

✅ Mutation in BTK → arrested pre-B cell maturation

✅ ↓ B cells, ↓ all immunoglobulins

✅ Recurrent bacterial infections (especially encapsulated organisms)

✅ Onset after 6 months

✅ IVIG therapy

✅ Avoid live vaccines

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22
Q

MAJOR GENETIC TYPES

A

Type Mutation Inheritance T B NK

X-linked SCID (most common) IL2RG gene (common γ-chain) X-linked recessive ↓ ↓ ↓

Adenosine deaminase (ADA) deficiency ADA gene Autosomal recessive ↓ ↓ ↓

JAK3 deficiency JAK3 gene Autosomal recessive ↓ ↓ ↓

RAG1/RAG2 deficiency Failure of V(D)J recombination Autosomal recessive ↓ ↓ Normal

IL-7R deficiency IL-7 receptor gene Autosomal recessive ↓ Normal Normal

✅ Most forms → T-cell deficiency leads to nonfunctional B cells, even if present

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23
Q

SCID: CLINICAL PRESENTATION

24
Q

Tight Junctions (Zonula Occludens)

A

High-Yield Features:
• Function:
• Seal adjacent cells together near the apical surface.
• Prevent paracellular movement of solutes.
• Maintain cell polarity by separating apical and basolateral surfaces.
• Composition:
• Key proteins: Claudins and Occludins (very testable).
• Linked to actin cytoskeleton via ZO-1 protein (Zonula Occludens-1).
• Location:
• Found in epithelial and endothelial cells.
• Especially prominent in intestinal mucosa, blood-brain barrier, and renal tubules.

Clinical Correlates:
• Pathogens targeting tight junctions:
• Clostridium perfringens enterotoxin and Vibrio cholerae disrupt tight junctions → leads to leaky epithelium and watery diarrhea.
• H. pylori targets ZO-1 → disrupts gastric epithelium.

Tips:
• If the question asks about maintaining selective permeability or blood–brain barrier integrity → choose tight junctions.
• Associated diseases: Think paracellular leaks and loss of barrier function.

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Gap Junctions
High-Yield Features: • Function: • Allow direct communication between cells. • Permit passage of ions, small molecules, and electrical signals. • Critical for synchronization of cellular activities (e.g., heart, uterus). • Composition: • Made of connexins → 6 connexins form a connexon (hemichannel). • Two connexons from adjacent cells align to form a complete channel. • Location: • High in cardiac myocytes, smooth muscle, astrocytes, osteocytes, and uterine myometrium. Clinical Correlates: • Mutations in connexins → associated with: • Charcot-Marie-Tooth disease (CMTX1) – connexin-32. • Congenital deafness – connexin-26. • Labor onset: Estrogen increases gap junction formation in uterine smooth muscle → allows coordinated contractions. Tips: • Think electrical/chemical coupling and rapid signal transmission. • For questions about synchronous contraction (heart, uterus, GI) → choose gap junctions.
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CELL CYCLE BASICS
Phase Events Key Checkpoints/Proteins G1 Cell grows; prepares for DNA synthesis p53, Rb, cyclin D/CDK4 S DNA replication Cyclin A/CDK2 G2 Check DNA; prep for mitosis Cyclin B/CDK1 M Mitosis (cell division) Spindle checkpoint, APC/C G0 Quiescent (non-dividing) Stable cells (e.g., neurons) Mnemonic: "Go Sally Go Make Children" = G1 → S → G2 → M → Cytokinesis
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CELL CYCLE REGULATORS
Protein Function Clinical Relevance p53 Activates p21 → inhibits CDK → halts G1/S Mutated in >50% cancers Rb Blocks E2F (needed for S phase) Retinoblastoma, Osteosarcoma Cyclins/CDKs Drive cell cycle forward Overactive in cancers CDK inhibitors (p21, p27, p16) Suppress cycle progression Tumor suppressors
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KEY ONCOGENES (gain-of-function → cancer)
Gene Product Associated Cancer ABL Tyrosine kinase CML (t(9;22) BCR-ABL) MYC (c-MYC) Transcription factor Burkitt lymphoma (t(8;14)) HER2/neu (ERBB2) Receptor tyrosine kinase Breast cancer RAS GTPase Colon, lung, pancreatic cancer RET Tyrosine kinase receptor MEN 2A/2B, medullary thyroid carcinoma BRAF Serine/threonine kinase Melanoma, hairy cell leukemia ✅ Oncogenes = 1-hit sufficient for cancer ✅ Often involved in growth signaling or cell cycle promotion
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KEY TUMOR SUPPRESSOR GENES (loss-of-function → cancer)
Gene Normal Role Associated Cancers TP53 DNA damage sensor, activates apoptosis (via BAX) Li-Fraumeni syndrome, many cancers RB G1/S checkpoint inhibitor (E2F blocker) Retinoblastoma, osteosarcoma BRCA1/2 DNA repair (homologous recombination) Breast/ovarian cancer APC Inhibits β-catenin/WNT pathway Familial adenomatous polyposis (FAP) VHL Degrades HIF-1α → suppress angiogenesis VHL disease, RCC WT1/WT2 Urogenital development Wilms tumor ✅ Tumor suppressors = 2-hit hypothesis ✅ Often regulate cell cycle, DNA repair, or apoptosis
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APOPTOSIS PATHWAYS (HIGH-YIELD)
1. Intrinsic (Mitochondrial) Pathway Triggered by: DNA damage, hypoxia, stress Key proteins: BAX/BAK = pro-apoptotic BCL-2 = anti-apoptotic Cytochrome c release → activates caspase 9 → caspase cascade 2. Extrinsic (Death Receptor) Pathway Triggered by: FAS-FASL (e.g., cytotoxic T-cell) TNF-α Activates caspase 8 → caspase cascade ✅ BCL-2 overexpression → blocks apoptosis → seen in follicular lymphoma (t(14;18))
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DNA REPAIR PATHWAYS
Pathway Damage Type Associated Disorder Base excision repair Small, non-bulky lesions Defective in mutations of MYH Nucleotide excision repair Bulky adducts (e.g., thymidine dimers) Xeroderma pigmentosum Mismatch repair Replication errors Lynch syndrome (MMR genes: MLH1, MSH2, etc.) Non-homologous end joining (NHEJ) dsDNA breaks Ataxia-telangiectasia, Fanconi anemia Homologous recombination dsDNA breaks (error-free) BRCA1/2, Fanconi anemia
33
SIGNALING PATHWAYS (USMLE FAVORITES)
Pathway Uses Example Ligands Tyrosine kinase (RTK) Cell growth, MAPK/PI3K Insulin, EGFR, PDGF, FGF JAK/STAT Cytokines → transcription GH, prolactin, EPO, IL-2 G-protein (cAMP) Second messenger TSH, ACTH, LH, FSH, PTH, glucagon G-protein (IP₃/DAG) Calcium release GnRH, TRH, angiotensin II Steroid receptor (intracellular) Direct gene regulation Cortisol, estrogen, testosterone, vitamin D, T3/T4 ✅ Mutations in these pathways → uncontrolled growth or endocrine cancers
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STEP 1 MNEMONICS & TIPS
“p53 = guardian of the genome” → halts the cycle at G1/S, activates BAX for apoptosis “APC = Anti-Polyposis Control” → blocks WNT/β-catenin “Rb = Restricts cycle at G1/S” “Two-hit” = Tumor suppressors “One-hit” = Oncogenes Ras-GTP = ON, Ras-GDP = OFF ✅ STEP 1 RAPID RECALL ✅ Oncogenes = gain-of-function, 1-hit (e.g., RAS, MYC, ABL, HER2) ✅ Tumor suppressors = loss-of-function, 2-hit (e.g., p53, Rb, BRCA1/2) ✅ Apoptosis: Intrinsic = BAX/BCL-2, Extrinsic = FAS/TNF ✅ Cell cycle: Cyclins/CDKs push, p53/Rb inhibit ✅ DNA repair: Match pathway to disease (e.g., MMR = Lynch, NER = XP)
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Hypertrophic obstructive cardiomyopathy (HOCM) : diagnostic
The diagnosis can be confirmed by echocardiography, which typically shows systolic anterior motion of the mitral valve, asymmetrical septal hypertrophy, and a septal wall thickness of >15 mm. Doppler studies show increased left ventricular outflow tract pressure gradients.
36
X-linked sideroblastic anemia
Glycine + succinyl-CoA → aminolevulinic acid This reaction, which is the first and rate-limiting step of heme synthesis, is catalyzed by δ-aminolevulinic acid synthase. A deficiency of this enzyme leads to insufficient heme production, which results in iron overload and perinuclear accumulation of iron-loaded mitochondria (i.e., ringed sideroblasts
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Fragile X
A defect in the expression of the FMR1 gene leads to CGG repeat expansions, which are responsible for fragile X syndrome, the second most common genetic cause of intellectual disability (after trisomy 21).
38
Cystinuria
Recurrent radiolucent nephrolithiasis in a young adult with a positive urine cyanide nitroprusside test is consistent with cystinuria Hexagon-shaped crystals on urinalysis would be consistent with cystine stones caused by cystinuria.
39
Acute promyelocytic leukemia (M3)
A chromosomal t(15;17) translocation is characteristic of acute promyelocytic leukemia (M3), which would explain this patient's B symptoms (low-grade fever, fatigue) and signs of coagulopathy (easy bruising, fibrinogen). Retinoic acid binds its nuclear receptors to stimulate histone acetylation, which promotes gene expression that regulates the maturation and proliferation of granulocytes.
40
Rb gene mutations
Patients with inherited retinoblastoma gene mutations (Rb gene mutations) have a significantly increased risk of developing osteosarcomas.
41
Estrogen deficiency in Turner patients
Ovarian dysgenesis is one of the most common features of Turner syndrome. Since the ovaries are the predominant source of estrogen, many patients with Turner syndrome are estrogen deficient, which results in increased osteoclast activity, decreased osteoblast activity, and bone reabsorption. Patients with Turner syndrome are therefore at increased risk for osteoporosis and pathologic fractures. Almost all patients with Turner syndrome require exogenous estrogen and progesterone replacement to prevent complications of sex hormone deficiency.
42
HOX genes
Expression of a HOX gene normally transcribed only cranially HOX genes are involved in the patterning of an embryo along the head-tail axis – i.e., they encode the characteristic positions of body parts, ensuring development at correct locations.
43
Variable expressitivity
a pedigree that looks like incomplete penetrance (as with this question), but the diagnosis in the family is NF1, choose variable expressivity, not incomplete penetrance.
44
Heteroplasmy
Heteroplasmy is a phenomenon seen in mitochondrial disorders, an inheritance pattern characterized by strict maternal transmission (i.e., mothers transmit disease to sons and daughters; fathers never transmit disease), where varying amounts of diseased mitochondria are passed to the next generation, resulting in offspring with disease of varying severity.
45
Abacavir
Abacavir is known to a cause a hypersensitivity-like reaction in patients with HLA B*5701 positivity. Screening for this HLA haplotype is required prior to commencement of abacavir.
46
Heteroplasmy
HETEROPLASMY Feature Detail Definition Presence of both normal and mutated mitochondrial DNA (mtDNA) within the same cell Inheritance pattern Mitochondrial (maternal) inheritance only Mechanism Each mitochondrion has multiple copies of mtDNA → a mixture of mutated and normal mitochondria is passed on to offspring Result Variable expression of disease among offspring, depending on proportion of mutated mtDNA in each tissue Clinical consequence Variable severity even within the same family (due to random distribution of mtDNA at fertilization) High-yield examples Leber Hereditary Optic Neuropathy (LHON) MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) Myoclonic Epilepsy with Ragged Red Fibers (MERRF) | ✅ Step 1 Clue: “Two siblings inherit the same mitochondrial mutation, but only one shows symptoms” → Heteroplasmy ✅ Mnemonic: “Heteroplasmy = Heterogeneous mitochondrial expression”
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Pleiotropy
Feature Detail Definition One gene → multiple phenotypic effects in different organ systems Mechanism The gene product is involved in multiple pathways or tissues Result A single genetic mutation causes a wide range of symptoms affecting many systems High-yield examples Phenylketonuria (PKU) – intellectual disability, fair skin, musty odor Marfan syndrome – tall stature, lens dislocation, aortic aneurysm Neurofibromatosis type 1 – skin, eyes, nervous system Cystic fibrosis – lungs, pancreas, GI, reproductive tract | ✅ Step 1 Clue: “A single gene mutation causes symptoms in the skeleton, eye, and cardiovascular system” → Pleiotropy ✅ Mnemonic: “Pleiotropy = Plenty of problems from one gene”
48
Von Willebrand factor
Von Willebrand factor (vWF) helps enable platelet adhesion by bridging glycoprotein Ib on platelets to vascular endothelium. The ristocetin assay will be abnormal in patients with impaired platelet adhesion. This means vWD and Bernard-Soulier disease (deficiency of GpIb) both have abnormal ristocetin assays. Glanzmann thrombasthenia is deficiency of glycoprotein IIb/IIIa on platelets, resulting in impaired aggregation. The ristocetin assay is normal in Glanzmann thrombasthenia.
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Cystic fibrosis
The misfolded CFTR chloride channel remains sequestered within the rough endoplasmic reticulum (i.e., it is not transported to the cell surface). CFTR channel is cAMP-mediated and ATP-gated.
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MOST TESTED X-LINKED RECESSIVE DISORDERS
Disease High-Yield Clues Mechanism Bruton Agammaglobulinemia Recurrent bacterial infections after 6 months BTK gene – failed B-cell maturation ***( Bruton, bacterial, BTK gene, B cells)*** Wiskott-Aldrich Syndrome Eczema + infections + thrombocytopenia WAS gene – T-cell cytoskeleton defect Hemophilia A & B Bleeding, joint hemorrhage, ↑ aPTT Factor VIII or IX deficiency Duchenne Muscular Dystrophy (DMD) Gower sign, calf pseudohypertrophy, early death Dystrophin (frameshift or nonsense) Becker Muscular Dystrophy Similar to DMD, later onset Dystrophin (in-frame mutation) G6PD Deficiency Hemolysis with fava beans, sulfa drugs, infection ↓ G6PD → ↓ NADPH → oxidative stress Lesch-Nyhan Syndrome Self-mutilation, gout, aggression HGPRT deficiency – ↑ uric acid Ornithine Transcarbamylase (OTC) Deficiency Hyperammonemia, vomiting, coma Urea cycle defect, ↑ orotic acid Hunter Syndrome Coarse face, developmental delay, no corneal clouding Iduronate sulfatase defect Red-Green Color Blindness Can't distinguish red and green Opsin gene defect
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Dystrophin
Dystrophin is a protein required for maintaining the integrity of the muscle cell by linking its cytoskeleton to the extracellular matrix.
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Mutations in BRCA genes
result in defective recombinational double-stranded DNA repair. This process normally involves the repair of DNA using complementary strands from homologous dsDNA. Base excision repair involves the removal of a single mutated base. This is the answer on the USMLE if the stem mentions glycosylases (i.e., glycosylase enzymes are required for this process).
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Nucleotide excision repair
Nucleotide excision repair involves the removal of bulky DNA distortions, namely pyrimidine- pyrimidine dimers due to UV exposure. This is the answer on the USMLE for xeroderma pigmentosa.
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Mismatch repair
Mismatch repair involves the removal of an incorrect base inserted during DNA synthesis. The template strand is methylated; the newly synthesized strand is unmethylated. Mismatch repair enzymes identify the newly synthesized strand due to its lack of methylation and remove/replace the incorrect base. Defects in mismatch repair are sometimes referred to as “microsatellite instability.”
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Slipped-strand mispairing
Slipped-strand mispairing is the answer on USMLE if there is an insertion or deletion of bases within strands of tandem repeats.
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Disease Translocation Genes Involved Key Points CML (Chronic Myelogenous Leukemia) t(9;22) (Philadelphia chromosome) BCR-ABL Activates tyrosine kinase → uncontrolled proliferation; tx: imatinib Burkitt lymphoma t(8;14) c-MYC on 8, Ig heavy chain on 14 Rapid growth, "starry sky" histology Follicular lymphoma t(14;18) BCL-2 on 18, Ig heavy chain on 14 BCL-2 = anti-apoptotic; indolent course Mantle cell lymphoma t(11;14) Cyclin D1 on 11, Ig heavy chain on 14 Promotes G1 → S cell cycle transition AML (M3 subtype – APL) t(15;17) PML-RARA fusion Treat with ATRA (all-trans retinoic acid) Ewing sarcoma t(11;22) EWS-FLI1 Small blue cells; diaphysis of long bones Ewing sarcoma variant t(21;22) EWS-ERG Less common ALCL (Anaplastic Large Cell Lymphoma) t(2;5) ALK gene ALK = tyrosine kinase Focus on: CML: t(9;22), BCR-ABL Burkitt: t(8;14), MYC Follicular: t(14;18), BCL-2 Mantle: t(11;14), Cyclin D1 APL: t(15;17), PML-RARA
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