Step 1 Biochemistry: 8 High-Yield Practice Questions
Biochemistry is ~15% of USMLE Step 1. Focus on enzyme deficiencies, lysosomal storage diseases, amino acid metabolism, and DNA repair mechanisms. These 8 questions target the most frequently tested biochemistry concepts.
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Q1Lysosomal Storage Diseases
A 1-year-old child develops progressive neurodegeneration, hepatosplenomegaly, and cherry-red spot on fundoscopy. Bone marrow biopsy shows 'Niemann-Pick cells' — large foamy macrophages. The deficient enzyme is:
Explanation: Niemann-Pick disease: sphingomyelinase deficiency → sphingomyelin accumulation in macrophages (foamy cells) and neurons. Type A: severe neurodegenerative form with cherry-red spot and death by age 3. Type B: milder, hepatosplenomegaly without neurodegeneration. Gaucher = glucocerebrosidase; Tay-Sachs = hexosaminidase A (no hepatosplenomegaly); Fabry = alpha-galactosidase A (peripheral neuropathy, renal failure).
Q2Amino Acid Metabolism
A newborn has increased serum phenylalanine detected on newborn screen. The child has a normal BH4 (tetrahydrobiopterin) level. This is most consistent with:
Explanation: Classic PKU: autosomal recessive deficiency of phenylalanine hydroxylase (PAH) → phenylalanine accumulates → phenylketones in urine (musty smell), intellectual disability, fair skin, eczema (phenylalanine inhibits tyrosine → melanin synthesis). Normal BH4 rules out dihydropteridine reductase deficiency. Treatment: phenylalanine-restricted diet + sapropterin (BH4) for some variants. BH4 itself is the cofactor for PAH — if BH4 is deficient, PAH cannot function even if structurally normal.
Q3Organic Acid Disorders
A 45-year-old man has recurrent kidney stones (calcium oxalate) and renal failure. His urine shows oxalate crystals. Liver biopsy shows abnormal peroxisomes. The deficient enzyme is:
Explanation: Primary hyperoxaluria type 1: autosomal recessive deficiency of alanine-glyoxylate aminotransferase (AGT), a peroxisomal enzyme. Glyoxylate cannot be converted to glycine → excess glyoxylate converted to oxalate → calcium oxalate stones, nephrocalcinosis, systemic oxalosis. Treatment: liver transplant (replaces the enzyme) ± kidney transplant. Pyridoxine (B6) helps some variants by stabilizing residual AGT activity.
Q4Nucleotide Metabolism
A child is found to have megaloblastic anemia, orotic aciduria, and NO hyperammonemia. The most likely enzyme deficiency is:
Explanation: Orotic aciduria WITHOUT hyperammonemia = UMP synthase deficiency (hereditary orotic aciduria). The urea cycle is intact (no hyperammonemia), but pyrimidine synthesis is blocked. Orotic acid accumulates and spills into urine. Megaloblastic anemia from inadequate pyrimidine synthesis for DNA replication. Treatment: uridine supplementation (bypasses the block). OTC deficiency = most common urea cycle defect, causes orotic aciduria WITH hyperammonemia (orotic acid accumulates from excess carbamoyl phosphate shunted to pyrimidine synthesis).
Q5Mitochondrial Disorders
A patient has progressive cerebellar ataxia, posterior column dysfunction, and cardiomyopathy beginning in the second decade of life. Echocardiogram shows hypertrophic cardiomyopathy. Frataxin gene mutations are identified. The metabolic consequence is:
Explanation: Friedreich's ataxia: autosomal recessive, GAA trinucleotide repeat expansion in frataxin gene. Frataxin normally binds iron in mitochondria to facilitate iron-sulfur cluster assembly for the electron transport chain. Frataxin deficiency → free iron accumulates in mitochondria → Fenton reaction → excess reactive oxygen species (free radical damage) → selective damage to dorsal root ganglia, spinocerebellar tracts, corticospinal tracts, and heart. Classic: ataxia + cardiomyopathy + absent ankle reflexes (posterior column/spinocerebellar).
Q6Amino Acid Metabolism
A 25-year-old woman with recurrent miscarriages and DVT is found to have elevated homocysteine, decreased methionine, and homocystine in urine. The most likely enzyme deficiency is:
Explanation: Homocystinuria from cystathionine beta-synthase (CBS) deficiency: autosomal recessive; homocysteine cannot be converted to cystathionine → homocysteine accumulates → homocystine in urine. Features: Marfanoid habitus, lens dislocation (DOWNWARD — opposite Marfan which is upward), intellectual disability, premature atherosclerosis and thromboembolism. Treatment: pyridoxine (B6, CBS cofactor), methionine-restricted diet + cysteine supplementation, betaine (remethylates homocysteine). MTHFR mutations cause milder hyperhomocysteinemia without homocystinuria.
Q7DNA Repair
A patient with Lynch syndrome has colon cancer. His tumor cells were sent for microsatellite instability (MSI) testing — result: MSI-high. The defective cellular process is:
Explanation: Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC): autosomal dominant mutations in DNA mismatch repair (MMR) genes — MLH1, MSH2, MSH6, PMS2. MMR corrects base-pair mismatches and small insertions/deletions made during replication. Loss of MMR → microsatellite instability (repeated DNA sequences accumulate mutations). Microsatellite instability-high (MSI-H) tumors respond well to immune checkpoint inhibitors (pembrolizumab). Nucleotide excision repair defects → xeroderma pigmentosum (UV-induced mutations).
Q8Carbohydrate Metabolism
A 6-month-old has failure to thrive, jaundice, cataracts, and E. coli sepsis. Reducing substances are found in urine but glucose is absent. The enzyme deficiency is:
Explanation: Classic galactosemia: GALT deficiency → galactose-1-phosphate accumulates in liver (cirrhosis, jaundice), brain (intellectual disability), lens (cataracts — galactitol accumulation), kidney (Fanconi syndrome). E. coli sepsis in neonates is a classic association — galactose-1-phosphate impairs neutrophil function. Reducing substances in urine = galactose (glucose absent — Clinitest positive but glucose oxidase negative). Treatment: lactose and galactose elimination diet. Galactokinase deficiency: milder, causes only cataracts (galactitol accumulates but galactose-1-phosphate does not).
Which lysosomal storage disease has a cherry-red macula?
Tay-Sachs and Niemann-Pick disease (type A) both cause cherry-red macular spots, while Gaucher disease does not. The cherry-red macula occurs because the fovea centralis (which lacks ganglion cells) retains its normal red color while surrounding retinal ganglion cells are destroyed by lipid accumulation, making the fovea appear bright red by contrast. Key distinction: Tay-Sachs has NO hepatosplenomegaly; Niemann-Pick A has prominent hepatosplenomegaly.
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