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