Free USMLE Step 1 Multisystem practice questions

The combination of a clonal plasma cell population, a monoclonal free lambda light chain, nephrotic-range proteinuria, hepatomegaly, macroglossia, and periorbital purpura is AL (primary) amyloidosis. In AL amyloidosis a plasma cell dyscrasia (myeloma or MGUS) oversecretes free immunoglobulin light chains, most often lambda. These light chains misfold into insoluble beta-pleated sheet fibrils that resist proteolysis and accumulate extracellularly in heart, kidney, tongue, nerve, liver, and skin, which is why the illness crosses organ systems. Congo red staining with apple-green birefringence confirms amyloid of any type, so the precursor must be identified separately by free light chain studies, immunofixation, and tissue mass spectrometry before treatment, which here is directed at the plasma cell clone. Macroglossia and periorbital purpura (from fragile amyloid-laden vessels) are close to specific for AL.

B. Serum amyloid A is the precursor in AA (secondary) amyloidosis, driven by chronic inflammation such as rheumatoid arthritis, inflammatory bowel disease, tuberculosis, or familial Mediterranean fever; this patient has no chronic inflammatory disease. C. Transthyretin deposits in hereditary and wild-type ATTR amyloidosis, which cause cardiomyopathy and neuropathy but not macroglossia, purpura, or a light chain clone. D. Beta2-microglobulin accumulates only after years of hemodialysis and deposits in joints and tendons, causing carpal tunnel syndrome. E. Islet amyloid polypeptide (amylin) is a localized amyloid confined to pancreatic islets in type 2 diabetes and causes no systemic deposits.

Fever and headache after a tick bite in the southeastern United States in summer, followed by a rash that begins on the wrists and ankles, involves the palms and soles, and spreads centrally, is Rocky Mountain spotted fever. Rickettsia rickettsii, carried by Dermacentor ticks, is an obligate intracellular bacterium that preferentially infects vascular endothelial cells (and underlying smooth muscle) of small vessels throughout the body.

The organism enters endothelial cells, escapes the phagosome, and spreads from cell to cell by actin-based motility, injuring each cell it infects. The result is a widespread small-vessel vasculitis with increased vascular permeability: fluid and albumin leak into tissues, causing edema, hypoalbuminemia, hypovolemia, and hypotension; local thrombosis and bleeding make the rash petechial; and platelet consumption causes thrombocytopenia. Damage in the brain, lungs, heart, and kidneys explains encephalitis, pneumonitis, myocarditis, and renal failure, and hyponatremia is common. Doxycycline is given at any age, because delayed treatment carries high mortality.

A. Immune complex vasculitis (type III) occurs in serum sickness and IgA vasculitis; RMSF damage results from direct infection of endothelium. C. Superantigens cause toxic shock syndrome, with a diffuse erythroderma that later desquamates. D. Exfoliative toxins that cleave desmoglein-1 cause staphylococcal scalded skin syndrome. E. Septic emboli cause the splinter hemorrhages and Janeway lesions of infective endocarditis rather than a centripetally spreading rash.

The polymerase chain reaction amplifies DNA. It requires a DNA template, two primers that flank the target, deoxynucleotides, and a heat-stable DNA polymerase (Taq, from the hot spring organism Thermus aquaticus), which survives the repeated 95 C denaturation steps. Flaviviruses such as dengue have a single-stranded RNA genome, so there is no DNA for Taq to copy. Reverse transcriptase must first be added to synthesize complementary DNA (cDNA) from the viral RNA template; the reaction is then called reverse transcription PCR, and it is how RNA viruses including dengue, SARS-CoV-2, HIV, and hepatitis C virus are detected. If fluorescence is read during each cycle, the assay also quantifies starting template, as in viral load testing. Note the distinct abbreviations: reverse transcription PCR makes RNA amplifiable, whereas real-time (quantitative) PCR measures how much target was present; the two are often combined.

A. RNA synthesis from a DNA template is transcription, carried out by RNA polymerase; that is the wrong direction for making an amplifiable DNA copy of a viral RNA genome. B. Joining DNA fragments through phosphodiester bonds is the function of DNA ligase, used in cloning and in Okazaki fragment maturation, not in PCR setup. C. Relaxing supercoils by transient strand cleavage is the action of topoisomerase; heat, not an enzyme, separates the strands in PCR. E. Methylation of cytosine in CpG islands regulates gene expression and is exploited in methylation-sensitive assays, but it plays no role in amplifying an RNA genome.

Neonatal hypotonia with poor feeding followed by hyperphagia, obesity, small hands and feet, and developmental delay is Prader-Willi syndrome. Genes in 15q11-q13 such as SNRPN are imprinted so that the maternal copies are methylated and silent and only the paternal copies are expressed; disease occurs when no active paternal copy is present.

The usual cause is a deletion of the paternal 15q11-q13 region, but here FISH shows two copies, which excludes a deletion. A purely maternal methylation pattern means both chromosome 15s came from the mother, that is maternal uniparental disomy: two silenced maternal copies leave the child functionally without paternal gene expression. Uniparental disomy usually arises by trisomy rescue after maternal meiotic nondisjunction, which is why it is linked to advanced maternal age. Hypothalamic dysfunction explains the hyperphagia, hypogonadism, and short stature.

B. Paternal uniparental disomy leaves two silenced paternal UBE3A copies and causes Angelman syndrome, with a purely paternal methylation pattern. C. A maternal deletion also causes Angelman syndrome and would show only one copy on FISH. D. A maternal UBE3A point mutation causes Angelman syndrome with normal methylation. E. FMR1 silencing causes fragile X syndrome, which does not produce neonatal hypotonia with later hyperphagic obesity.

Gastrointestinal symptoms followed by fever, myositis with a high creatine kinase, periorbital edema, subconjunctival and splinter hemorrhages, and marked eosinophilia in a cluster of people who ate undercooked bear meat is trichinellosis. Trichinella larvae encysted in muscle of pork or wild game (bear, walrus, wild boar) are released by gastric digestion, mature into adult worms in the small intestine (causing the early enteric phase), and the females release new larvae. These larvae travel through lymphatics and blood to striated muscle, where each enters a muscle fiber, transforms it into a nurse cell, and coils and encysts, later calcifying. Tissue invasion by a helminth explains the striking eosinophilia, and vasculitis-like injury produces the hemorrhages and periorbital edema. Treatment is albendazole or mebendazole, often with corticosteroids.

A. Cysticerci with a scolex are larvae of Taenia solium acquired by ingesting eggs; they cause neurocysticercosis with seizures rather than acute febrile myositis. B. Macrophages packed with amastigotes indicate Leishmania, which involves the reticuloendothelial system and skin. C. Perifascicular atrophy with perivascular inflammation is the pattern of dermatomyositis, an autoimmune myopathy without eosinophilia or a food exposure. D. Bradyzoite tissue cysts without inflammation indicate latent Toxoplasma, which does not cause this acute eosinophilic illness.

The yellow fat-burning powder is 2,4-dinitrophenol (DNP), an illicit weight-loss agent and a classic uncoupler of oxidative phosphorylation. DNP is a lipid-soluble weak acid that picks up protons in the intermembrane space and releases them in the matrix, carrying H+ back across the inner mitochondrial membrane without passing through ATP synthase.

The proton gradient therefore collapses while the electron transport chain is no longer held back by it. Electron flow and oxygen consumption rise, NADH and FADH2 are oxidized faster, and fat stores are burned, but ATP synthesis falls and the energy of the gradient is released as heat. This explains the severe hyperthermia, tachycardia, tachypnea and diaphoresis. As ATP falls, cells increase glycolysis, producing lactic acidosis, and muscle rigidity reflects ATP depletion. Salicylate overdose and thermogenin (UCP1) in brown fat work by the same principle.

A. Rotenone inhibits complex I, which stops electron flow; oxygen consumption falls rather than rises.

B. Cyanide, carbon monoxide and azide inhibit complex IV; they also lower oxygen consumption, producing a high venous oxygen saturation, not hypermetabolism.

C. Oligomycin blocks ATP synthase; the gradient builds up until electron transport stalls, so oxygen consumption decreases.

D. Arsenic inhibits pyruvate dehydrogenase by binding lipoic acid, causing lactic acidosis with vomiting and rice-water diarrhea, but it does not increase oxygen use or generate this degree of heat.

High fever, hypotension, diffuse sunburn-like erythroderma, mucosal hyperemia, and involvement of several organ systems (gastrointestinal, muscle with high CK, renal, platelets) in a menstruating girl using tampons, with negative blood cultures and coagulase-positive staphylococci on the tampon, is staphylococcal toxic shock syndrome, caused by TSST-1. Desquamation of the palms and soles would follow in 1 to 2 weeks.

TSST-1 is a superantigen. A normal protein antigen is processed, and a peptide sits in the groove of an MHC class II molecule, where it is recognized by the rare T cells with a matching receptor. A superantigen is not processed; it clamps the outside of the MHC class II molecule to the Vβ region of the T-cell receptor, so every T cell bearing certain Vβ families is activated, up to a large fraction of all T cells. This polyclonal activation releases huge amounts of IL-1, IL-2, TNF-α, and IFN-γ, which cause fever, capillary leak, shock, and multiorgan injury. Blood cultures are usually negative because toxin is absorbed from a local site. Treatment is source removal plus an antistaphylococcal agent with clindamycin to shut off toxin synthesis.

A. ADP-ribosylation of EF-2 is the action of diphtheria toxin and Pseudomonas exotoxin A.

B. Protein A binds the Fc region of IgG, but it prevents opsonization and complement activation rather than causing shock.

C. Groove presentation of processed peptide is conventional antigen presentation, which activates only a few clones.

D. LPS is endotoxin of gram-negative bacteria; S. aureus is gram-positive and lacks it.

Early-onset hyperphagia and severe obesity in a child with an affected parent, tall stature with advanced bone age, marked hyperinsulinemia, normal pigmentation, normal cortisol and a leptin level appropriate to fat mass is the picture of MC4R deficiency, the most common monogenic cause of obesity. It is usually caused by a heterozygous loss-of-function mutation with dominant (often codominant) inheritance, which fits the father's history.

In the arcuate nucleus, leptin activates POMC neurons, which cleave POMC into alpha-MSH. Alpha-MSH acts on MC4R in the paraventricular nucleus to produce satiety and increase energy expenditure, while AgRP antagonizes the same receptor. Halving MC4R signaling removes this final common satiety step, so hunger is high even though leptin, POMC and alpha-MSH are all present. Accelerated linear growth and increased lean mass are characteristic features that distinguish it from the recessive defects upstream. The MC4R agonist setmelanotide is approved for defects upstream of the receptor (POMC, PCSK1 and leptin receptor deficiency), not for MC4R deficiency itself.

A. Leptin deficiency is recessive and gives undetectable leptin with hypogonadism and T-cell dysfunction. C. POMC deficiency adds neonatal ACTH deficiency (hypoglycemia, cholestasis, low cortisol) and red hair with pale skin from lost MC1R stimulation. D. Leptin receptor deficiency is recessive, with present or high leptin, hypogonadotropic hypogonadism and no increase in linear growth. E. Prohormone convertase 1 deficiency is recessive and presents in infancy with malabsorptive diarrhea, hypoglycemia and high proinsulin.

Severe fasting hypoglycemia with massive hepatomegaly, lactic acidosis, hypertriglyceridemia, hyperuricemia, and no response to glucagon is von Gierke disease (glycogen storage disease type I), autosomal recessive deficiency of glucose-6-phosphatase. Without the final dephosphorylation step, the liver cannot release free glucose from either glycogenolysis or gluconeogenesis, so glucose-6-phosphate accumulates in hepatocytes. The trapped intermediate spills into three pathways, which explains the whole laboratory picture: into glycolysis, generating lactate; into lipogenesis, generating triglyceride; and into the pentose phosphate pathway, where ribose-5-phosphate feeds PRPP and accelerates de novo purine synthesis, raising uric acid production. The elevated lactate compounds the problem by competing with urate for proximal tubular organic anion secretion, so renal urate clearance falls. Children can develop gout and urate nephropathy. Treatment is frequent glucose feeding and nocturnal cornstarch, with avoidance of fructose and galactose, which also enter at glucose-6-phosphate.

A. Urea cycle failure causes hyperammonemia with encephalopathy and does not raise uric acid, which is a purine, not a protein nitrogen, end product. B. Hypoxanthine-guanine phosphoribosyltransferase deficiency is Lesch-Nyhan syndrome, an X-linked disorder with hyperuricemia, choreoathetosis, intellectual disability, and self-mutilation, not hepatomegaly with hypoglycemia. C. ATP depletion by trapped fructose-1-phosphate, with degradation of adenine nucleotides to urate, occurs in hereditary fructose intolerance and after fructose infusion; this child's hypoglycemia occurs with fasting rather than after fructose ingestion, and her glycogen-laden liver points to a glycogenosis. D. Glomerular filtration is initially normal in von Gierke disease; renal injury is a late consequence of urate and glomerular hyperfiltration rather than the cause of the hyperuricemia.

Three probabilities must be multiplied.

The man's carrier risk is 2/3. His sister is affected, so both parents are obligate carriers. Among their children, the outcomes are 1/4 affected, 1/2 carrier and 1/4 noncarrier. Because he is known to be unaffected, the affected outcome is excluded, leaving carrier (2 of 3 remaining parts) and noncarrier (1 of 3).

The partner's carrier risk is about 1/25. Disease frequency q² = 1/2,500, so q = 1/50. For a rare autosomal recessive disease p is close to 1, so carrier frequency 2pq is approximately 2q = 1/25.

Two carriers have a 1/4 chance of an affected child in each pregnancy.

Risk = 2/3 × 1/25 × 1/4 = 2/300 = 1/150.

The Hardy-Weinberg approach assumes random mating, no selection, mutation or migration, and a large population. Carrier testing of both partners (CFTR sequencing) would replace these estimates with actual genotypes.

A. 1 in 100 assumes the man is certainly a carrier (1 × 1/25 × 1/4), ignoring that he could be a noncarrier. C. 1 in 200 uses a 1/2 carrier risk for the man (1/2 × 1/25 × 1/4), which is the carrier probability for any child of two carriers but ignores that his being unaffected removes the affected outcome from consideration. D. 1 in 625 multiplies two population carrier frequencies (1/25 × 1/25) and omits both the family history and the 1/4 transmission factor. E. 1 in 2,500 is simply the population birth prevalence, which ignores his affected sister.