USMLE Step 1
Genes associated with Multiple endocrine neoplasias (MEN)
1, 2A, 2B - MEN1 = MEN1 gene - MEN 2A & 2B = RET gene - Familial tumors of endocrine glands - autosomal dominant
Standard error of mean
How much variability exists between the the sample mean and the true population mean = standard deviation / square root of n (sample size) - SEM decreases as n increases
Different Phases of Drug Trials
I - small # of *healthy* volunteers - is it safe? II - small # of patients *with disease of interest* - does it work? III - *large* number of patients randomly assigned either to treatment under investigation or to best available treatment (or placebo) - is it as good or better? IV - postmarketing surveillance of patients after treatment approves - can it stay?
Prevalence
# of *existing* cases / total # of people in population - at point in time - prev*al*ence looks at *all* current cases Prevalent ~ incidence for short duration disease Prevalence > incidence for chronic diseases, due to large number of existing cases Prevalence ~ pretest probability
Incidence rate
# of *new* cases / # of people at risk - during specified time period - *Incidence* looks at new cases (*incidents*)
Compares group of ppl with disease to group without disease
*Case-control study* - looks for prior exposure or risk factor - "what happened?" - odds ratio (OR)
Compares group with given exposure or risk factor to group without exposure
*Cohort study* - does exposure affect likelihood of disease - can be prospective or historical - relative risk (RR)
Data from group = frequency of disease/related risk factors at particular point in time
*Cross-sectional study* - "what is happening?" - disease prevalence - shows risk factor association, but NOT causality
Genetic disorders associated with chromosome 18
*Edwards syndrome* (*E*lection age = *18*) - severe intellectual disability - rocker-bottom feet - micrognathia (small jaw) - low-set ears - clenched hands with overlapping fingers - prominent occiput - congenital heart disease - death before 1 year usually - 2nd most common trisomy that = live birth - PAPP-A & free beta-hCG decreased in first trimester - Quad screen = decreased alpha-fetoprotein, decreased beta-hCG, decreased estriol, decreased or normal inhibin A
Major symptoms of Myotonic type 1 muscular dystrophy
*My T*onia, *My T*esticles (testicular atrophy), *My T*oupee (frontal balding), *My T*icker (arrhythmia) - Autosomal Dominant - CTG trinucleotide repeat expansion in DMPK gene --> abnormal expression of myotonin protein kinase
Major Trinucleotide repeat expansion diseases
*Try* (nucleotide) *hunting* for *my fried eggs* (X) Huntington's = CAG Myotonic Dystrophy = CTG Friedreich ataxia = GAA Fragile X Syndrome = CGG
Duchenne muscular dystrophy is an X-linked disorder typically due to what type of mutation?
*frameshift* or nonsense - truncated dystrophin protein
What is increased in Down syndrome / trisomy 21?
- ALL & AML - first trimester: nuchal translucency & hypoplastic nasal bone, free beta-hCG - second trimester: beta-hCF, inhibin A
What is decreased in Edwards syndrome (trisomy 18)?
- PAPPA-A, free beta-hCG (first trimester) - alpha-fetoprotein, beta-hCG, estriol, inhibin A (quad screen)
Symptoms of B3/niacin excess
- facial flushing - induced by *prostaglandins*, not histamine - can avoid by taking *aspirin* with niacin - hyperglycemia - hyperuricemia
What's decreased in Down syndrome / trisomy 21?
- first trimester: serum PAPP-A - second trimester: alpha-fetoprotein, estriol
Robertsonian translocations are chromosomal translocations that commonly involve what chromosome pairs?
12, 14, 15, 21, 22 - balanced = no abnormal phenotype - unbalanced = miscarriage, stillbirth, chromosomal imbalance (Down syndrome, Patau syndrome)
CATCH-22 of 22qll deletion syndromes due to aberrant development of
3rd & 4th branchial pouches - Cleft palate - Abnormal faces - Thymic aplasia - Cardiac defects - Hypocalcemia
Genetic abnormality associated with Cri-du-chat syndrome
5 (46, XX or XY, 5p-)
Genetic abnormality associated with Williams syndrome
7 - congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)
Diagnostic Cl- concentration of Cystic Fibrosis
> 60 mEq/L in sweat - can present with contraction alkalosis & hypokalemia - ECF like a patient taking a loop diuretic (ECF H20/Na+ loss & K+/H+ wasting) - increased immunoreactive trypsiongen (newborn screening)
Genetic disorders associated with chromosome 16
ADPKD (PKD1) - 85% alpha-globin gene defects - alpha-thalassemia
Genetic disorders associated with chromosome 4
ADPKD (PKD2) - 15% Achondroplasia Huntington disease
Hypothesis of some difference of relationship
Alternative (H1) - ex. there is some difference between the disease and the risk factor in the population
All water soluble vitamins wash out easily except
B12 (cobalamin) & B9 (folate) - B12 stored in liver for ~3-4 years - B9 stored in liver for ~3-4 months
Synthesis of B3/niacin requires
B2 & B6
Used as cofactors in succinate dehydrogenase reaction in TCA cycle
B2/riboflavin
Essential component of coenzyme A & fatty acid synthase
B5/pantothenic acid
Cofactor for carboxylation enzymes (add 1-carbon group)
B7/biotin
Study population selected from hospital is less healthy than general population
Berkson bias - type of *Selection Bias*
Mutated gene associated with Cystic Fibrosis
CFTR gene on chromosome 7 Deletion of Phe508
What rxns is B7/biotin involved in?
Carboxylation reactions Pyruvate carboxylase = pyruvate (3C) --> OAA (4C) Acetyl-CoA carboxylase = acetyl-CoA (2C) --> malonyl-CoA (3C) Propionyl-CoA carboxylase = propionyl-CoA (3C) --> methylmalonyl-CoA (4C)
What gene is mutated in Familial adenomatous polyposis?
Chromosome 5q (APC gene) - 5 letters in "polyp" - colon covered with adenomatous polyps after puberty - progresses to colon cancer unless colon resected - autosomal dominant
Patau syndrome (trisomy 13) findings
Cleft li*p / p*alate, holo*p*rosencephaly, *p*olydactyly - *p*uberty (*13*) intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, congenital heart disease, cutis aplasia death within 1 year first trimester - decreased free beta-hCG, decreased PAPP-A
Draw out 2x2 diagnostic test table
Compares test results with actual presence of disease PPV = TP / (TP + FP) NPV = TN / (TN + FN) Sensitivity = TP / (TP + FN) Specificity = TN / (TN + FP)
Classic triad of Wernicke-Korsakoff syndrome
Confusion Ophthalmoplegia Ataxia
Genetic disorders associated with chromosome 5
Cri-du-chat syndrome Familial adenomatous polyposis
Hartnup disease
Deficiency of neutral AAs (tryptophan) transporters in proximal renal tubular cells & on enterocytes --> neutral aminoaciduria, decreased absorption from gut - decreased tryptophan for conversion to niacin --> pellagra-like symptoms - treatment = high-protein diet, nicotinic acid
Mutated gene associated with von Hippel-Lindau disease
Deletion of VHL gene (tumor suppressor) on chromosome 3 (3p) - 3 words for chromosome 3 - development of numerous tumors - both benign and malignant
Most common cause of genetic intellectual disability
Down syndrome / trisomy 21 - 95% due to meiotic nondisjunction - 4% due to unbalanced Robertsonian translocation (b/t 14 & 21) - 1% due to mosaicism
Dry vs. Wet beriberi
Dry - polyneuritis - symmetrical muscle wasting Wet - high-output cardiac failure (dilated cardiomyopathy) - edema
Major differences between Duchenne & Becker Muscular Dystrophies
Duchenne - onset before age 5 - *frameshift* or nonsense mutations Becker - onset in adolescence or early childhood - *non-frameshift* insertions in dystrophin gene = partially functional instead of truncated Both are X-linked recessive disorders
2nd most common trisomy resulting in live birth
Edwards syndrome (trisomy 18) - Election age (18)
Genetic disorders associated with chromosome 6
Hemochromatosis
Tendon xanthomas seen in what autosomal dominant disease?
Familial hypercholesterolemia - elevated LDL - defective or absent LDL receptor - autosomal dominant
What gene is mutated in Achondroplasia?
Fibroblast growth factor receptor 3 (FGFR3) - inhibits chondrocyte proliferation - Autosomal Dominant
Major symptoms of Fragile X syndrome
Fragile X = eXtra large testes, jaw, ears - 2nd most common cause of genetic intellectual disability (after Down syndrome) - post-pubertal macroorchidism - long face with large jaw - large everted ears - autism - mitral valve prolapse
Genetic disorders associated with chromosome 9
Friedreich ataxia
Symptoms of B3/niacin deficiency
Glossitis Pellagra - can be caused by Hartnup disease, Malignant carcinoid syndrome (increased tryptophan metabolism), & isoniazid (decreased B6) - The *3 D's* of B*3* = *D*iarrhea, *D*ementia, *D*ermatitis = C3/C4 dermatome circumferential "broad collar" rash = Casal necklace, hyperpigmentation of sun-exposed limbs
Vitamin A used to treat cystic acne
Isotretinoin
Early detection is confused with increased survival
Lead-time bias - early detection makes it seem as though survival has increased, but the natural history of the disease has not changed
How to lower and increase the cutoff points
Lower = B --> A = increased FP, decreased FN = increased Se*n*sitivity, increased *N*PV = decreased S*p*ecificity, decreased *P*PV Raising = B --> C = increased FN, decreased FP = increased S*p*ecificity, increased *P*PV = decreased Se*n*sitivity, decreased *N*PV
Most affected by outliers
Mean = sum of values / total number of values
Positive skew
Mean > Median > Mode Asymmetry with longer tail on right
Result of Vitamin A / Retinol deficiency
Nyctalopia - night blindness Xerosis cutis - dry, scaly skin Keratomalacia - corneal degeneration Bitot spots on conjunctiva Immunosuppression
Gene mutated in Li-Fraumeni syndrome
TP53 - AKA: SBLA syndrome = sarcoma, breast, leukemia, adrenal gland - multiple malignancies at early age - autosomal dominant
Least affected by outliers
Mode = most common value
Mutated gene seen in Neurofibromatosis type 1 (von Recklinghausen disease)
NF1 gene on chromosome 17 - 17 letters in von Recklinghausen - neurocutaneous disorder - cafe-au-lait spots, lisch nodules - autosomal dominant
Mutated gene associated with Neurofibromatosis type 2
NF2 gene on chromosome 22 - type 2 = 22
Negative Predictive Value (NPV)
NPV = TN / (TN + FN) - proportion of negative test results that are true negative - probability that person with negative test does not have disease - varies *inversely* with prevalence or pretest probability
Genetic disorders associated with chromosome 17
Neurofibromatosis type 1 BRCA1
Genetic disorders associated with chromosome 22
Neurofibromatosis type 2 DiGeorge syndrome (22q11)
When does: mean = median = mode?
Normal distribution
Hypothesis of no difference or relationship
Null (H0) - ex. no association between disease & risk factor in population - Type I error = stating that there is an effect or difference when none exists - null hypothesis incorrectly rejected in of alternative hypothesis
X-linked recessive disorders - mnemonic
Oblivious Female Will Often Give Her Boys Her x-Linked Disorders Ornithine transcarbamylase deficiency Fabry disease Wiskott-Aldrich syndrome Ocular albinism G6PD deficiency Hunter syndrome Bruton agammaglobulinemia Hemophilia A & B Lesch-Nyhan syndrome Duchenne (and Becker) muscular dystrophy
What gene is mutated in Autosomal dominant polycystic kidney disease?
PKD1 - chromosome *16* - 16 letters in "polycystic kidney" - 85% PKD2 - chromosome 4 Autosomal dominant
Positive Predictive Value (PPV)
PPV = TP / (TP + FP) - proportion of positive test results that are true positive - probability that person with positive test has disease - varies *directly* with pretest probabiltiyt
Genetic disorders associated with chromosome 13
Patau syndrome Wilson disease Retinoblastoma (RB1) BRCA2
Genetic disorders associated with chromosome 15
Prader-Willi syndrome Angelman syndrome Marfan syndrome
TPP of Vitamin B1 / thiamine is a cofactor for what dehydrogenase reactions?
Pyruvate dehydrogenase ATP: Alpha-ketoglutarate dehydyogenase, Transketolase, Pyruvate dehydrogenase - links glycolysis to TCA cycle alpha-ketoglutarate dehydrogenase - TCA cycle Transketolase - HMP shunt Branched-chain ketoacid dehydrogenase
Value desirable for ruling *out* disease
Sensitivity = True-positive rate = 100% - TP / (TP + FN) = 1 - FN = 0 - all negatives must be TNs - indicates low false-negative rate - used for screening in diseases with low prevalence = TP / (TP + FN) = 1 - false-negative rate *SN-N-OUT* = highly *S*e*N*sitive test, when *N*egative, rules *OUT* disease
Value desirable for ruling *in* disease
Specificity = True-negative rate = 100% - TN / (TN + FP) = 1 - FP = 0 - all positives must be TPs - indicates low false-positive rate = TN / (TN + FP) = 1 - false-positive rate *SP-P-IN* = highly *SP*ecific test, when *P*ositive, rules *IN* disease
Symptoms of B2/riboflavin deficiency
The *2 C's* of B*2* - *C*heilosis = inflammation of lips, scaling & fissures at corners of mouth - *C*orneal vascularization
Associated molecule of B9 -
folate
Pyridoxal phosphate (PLP) / derivative of pyridoxine (B6) is a cofactor used in what rxns?
Transamination - ALT & AST Decarboxylation Glycogen phosphorylase Synthesis of: cystathionine heme niacin histamine NTs - ST, Epi, NE, Dopamine, GABA
Additional blinding of researchers analyzing data
Triple-blind
Autosomal dominant disease associated with numerous benign hamartomas
Tuberous sclerosis - variable expression
Fat-soluble vitamin that treats measles & AML subtype M3
Vitamin A (retinol)
Where do symptoms begin in Duchenne muscular dystrophy?
Weakness begins in pelvic girdle muscles - progresses superiorly - pseudohypertrophy of calf muscles due to dibrofatty replacement of muscle
Genetic disorders associated with chromosome 7
Williams syndrome Cystic fibrosis
Genetic disorders associated with chromosome 11
Wilms tumor beta-globin gene defects - sickle cell disease - beta-thalassemia
Is a complicated medical condition in which there is formation of multiple tumors in the pancreas or the duodenum. These tumors are called Gastrinomas
Zollinger Ellison syndrome - gastrin remains elevated after secretin administered (normally inhibits gastrin release) - may be associated with MEN1
Vitamin A used to treat acute promyelocytic leukemia
all-trans retinoic acid
Associated molecule of B7 -
biotin
Associated molecule of B12 -
cobalamin
Symptoms of B6/pyridoxine deficiency
convulsions hyperirritability peripheral neuropathy sideroblastic anemias
Symptoms of B5/pantothenic acid deficiency
dermatitis enteritis alopecia adrenal insufficiency
B3/niacin used to treat
dyslipidemia - lowers levels of VLDL - raises levels of HDL
What tissues are affected first when there is B1/thiamine deficiency?
highly aerobic tissues - brain, heart - impaired glucose breakdown --> ATP depletion
Diagnosis of B1/thiamine deficiency made by
increase in RBC transketolase activity after B1 administration
B6/pyridoxine deficiency seen in peripheral neuropathy inducible by
isoniazid & oral contraceptives
What is required before isotretinoin (vitamin A derivative) is prescribed?
negative pregnancy test + 2 forms of contraception
Associated molecule of B3 -
niacin: NAD+
Associated molecule of B5 -
pantothenic acid: CoA
Associated molecule of B6 -
pyridoxine: PLP
Associated molecule of B2 -
riboflavin: FAD, FMN
Associated molecule of B1 -
thiamine: TPP
DiGeorge syndrome involves what defects?
thymic, parathyroid, cardiac defects
B3/niacin derived from
tryptophan synthesis requires B2 & B6
Genetic disorders associated with chromosome 3
von Hippel-Lindau disease renal cell carcinoma
