Genetics & Biochemistry Mnemonics for USMLE Step 1
Genetics and biochemistry are two of the highest-yield, most mnemonic-friendly subjects on USMLE Step 1 — small enzyme names and inheritance patterns are easy to mix up under exam pressure, but they respond well to structured review. This set covers the metabolic and genetic disorders that come up most often, organized by topic so you can review one disease family at a time instead of a random grab-bag of trivia.
Glycogen Storage Diseases
Q: What causes Von Gierke’s disease, and what are its findings? A: Glucose-6-phosphatase deficiency (Type I glycogen storage disease). Presents with severe fasting hypoglycemia and increased glycogen storage in the liver.
Q: What causes Pompe’s disease, and what are its findings? A: Lysosomal acid alpha-1,4-glucosidase (acid maltase) deficiency — Type II glycogen storage disease. Causes cardiomegaly and systemic glycogen deposition, leading to early death. Mnemonic: “Pompe’s trashes the pump” — heart, liver, and muscle.
Q: What is the defect in Type III glycogen storage disease (Cori disease)? A: Deficiency of the debranching enzyme, amylo-1,6-glucosidase.
Q: What are the findings in McArdle’s disease, and what’s the underlying defect? A: Myophosphorylase (glycogen phosphorylase) deficiency — Type V glycogen storage disease. Glycogen accumulates in skeletal muscle; strenuous exercise causes myoglobinuria and painful cramps.
Q: Is there a mnemonic for the glycogen storage diseases? A: “Very Poor Carbohydrate Metabolism” — Von Gierke’s, Pompe’s, Cori’s, McArdle’s.
Lysosomal Storage Diseases (Sphingolipidoses)
Q: What disease results from buildup of sphingomyelin and cholesterol in reticuloendothelial and parenchymal cells? A: Niemann-Pick disease.
Q: What is the biochemical defect in Niemann-Pick disease, and how is it inherited? A: Sphingomyelinase deficiency, causing sphingomyelin accumulation; autosomal recessive.
Q: What causes Gaucher’s disease, and what are its findings? A: Beta-glucocerebrosidase deficiency, leading to glucocerebroside accumulation in the brain, liver, spleen, and bone marrow. Autosomal recessive. Characteristic finding: Gaucher cells, with a “crinkled paper” cytoplasm appearance on histology.
Q: What happens with absence of galactosylceramidase (galactocerebrosidase), and what disease results? A: Accumulation of galactocerebroside in the brain — Krabbe disease. Autosomal recessive. Clinical picture: optic atrophy, spasticity, early death.
Q: What results from absence of hexosaminidase A? A: GM2-ganglioside accumulation, characteristic of Tay-Sachs disease. Autosomal recessive. Most distinguishing exam finding: a cherry-red macula; affected children typically do not survive past early childhood. Carrier frequency is markedly higher among individuals of Ashkenazi Jewish descent than in the general population.
Q: What causes Fabry disease, and what’s the clinical consequence? A: Alpha-galactosidase A deficiency, causing accumulation of ceramide trihexoside — leads to renal failure. X-linked recessive.
Q: What is the defect in metachromatic leukodystrophy? A: Arylsulfatase A deficiency, causing sulfatide accumulation in the brain, kidney, liver, and peripheral nerves. Autosomal recessive.
Q: What are ganglioside, cerebroside, sphingomyelin, and sphingosine each made of? A:
Ganglioside = ceramide + oligosaccharide + sialic acid
Cerebroside = ceramide + glucose or galactose
Sphingomyelin = ceramide + phosphorylcholine
Sphingosine + fatty acid = ceramide
Amino Acid and Carbohydrate Metabolism Disorders
Q: What builds up in PKU, and what shows up in the urine? A: Phenylalanine accumulates due to deficient phenylalanine hydroxylase (or its tetrahydrobiopterin cofactor); phenylketones — phenylacetate, phenyllactate, and phenylpyruvate — appear in the urine. Tyrosine becomes an essential amino acid, since it can no longer be synthesized from phenylalanine.
Q: What are the clinical findings and treatment for PKU? A: Mental retardation, fair skin, eczema, and a musty body odor. Treatment: reduce phenylalanine intake (including avoiding aspartame) and supplement tyrosine.
Q: What is alkaptonuria, and what does it look like clinically? A: A deficiency of homogentisic acid oxidase in the tyrosine degradation pathway. Causes dark urine (from alkapton bodies) and dark connective tissue, sometimes with joint pain. Generally a benign condition.
Q: What is the defect in homocystinuria, and what are the findings? A: A defect in cystathionine synthase — either an outright enzyme deficiency, or reduced affinity of the enzyme for its cofactor, pyridoxal phosphate (vitamin B6). Homocysteine and methionine accumulate in the blood, and cysteine becomes an essential amino acid. Clinical findings: mental retardation, osteoporosis, and lens dislocation.
Q: How is homocystinuria treated? A: For the enzyme-deficiency form: decrease methionine and increase cysteine intake. For the B6-responsive form (reduced cofactor affinity): supplement vitamin B6.
Q: What is the defect in maple syrup urine disease? A: Decreased branched-chain alpha-ketoacid dehydrogenase, blocking degradation of the branched-chain amino acids isoleucine, valine, and leucine. Causes CNS defects, mental retardation, and death if untreated; urine has a characteristic maple syrup smell.
Q: What causes cystinuria, and what’s the complication? A: An inherited defect in the renal tubular transporter for cystine, ornithine, lysine, and arginine (mnemonic: COLA). Leads to excess cystine in the urine and a risk of cystine kidney stones. Management centers on high fluid intake and urinary alkalinization, with cystine-binding agents reserved for refractory stone formers.
Q: What’s the difference between essential fructosuria and fructose intolerance? A: Essential fructosuria is a benign, asymptomatic defect in fructokinase — fructose simply appears in blood and urine. Fructose intolerance is an autosomal recessive deficiency of aldolase B, causing hypoglycemia, jaundice, and cirrhosis. Mechanism: fructose-1-phosphate accumulates and traps phosphate, which inhibits glycogenolysis and gluconeogenesis. Treatment is to reduce both fructose and sucrose intake.
Q: What causes galactosemia, and what are the findings? A: Absence of galactose-1-phosphate uridyltransferase, leading to accumulation of toxic galactitol. Presents with cataracts, hepatosplenomegaly, and mental retardation. Treatment: exclude galactose and lactose from the diet.
Q: What causes lactose intolerance, and how is it managed? A: Lactase deficiency. Symptoms include bloating, cramping, and osmotic diarrhea. Managed by avoiding dairy or taking lactase supplements. It’s age-dependent and more prevalent in Black and Asian populations.
Q: What happens in pyruvate dehydrogenase deficiency? A: Pyruvate and alanine back up, causing lactic acidosis, along with neurologic defects. Since the metabolic block is downstream of pyruvate, a ketogenic diet (which bypasses the defective step) is used therapeutically. Often seen in alcoholics due to associated thiamine (B1) deficiency.
Q: Which amino acids are purely ketogenic? A: Lysine and leucine.
Core Biosynthesis Facts
Q: What are creatine and urea both made from? A: Arginine.
Q: What is glycine used to synthesize? A: Porphyrin, which is then used to make heme.
Q: What is histamine synthesized from? A: Histidine.
Q: What three compounds can be made from tryptophan? A: Niacin, serotonin, and melatonin.
Q: What is NAD/NADP synthesized from? A: Niacin.
Q: What biological compounds are derived from phenylalanine? A: Tyrosine, thyroxine, DOPA, dopamine, norepinephrine, epinephrine, and melanin.
Q: What do melanin and norepinephrine have in common? A: Both are derived from dopamine, via the pathway phenylalanine → tyrosine → DOPA → dopamine.
Q: What do thyroxine and DOPA have in common? A: Both are derived from tyrosine.
Red Blood Cell Enzyme Defects and Hemoglobinopathies
Q: Why are red blood cells especially vulnerable to glycolytic enzyme deficiencies? A: RBCs have no mitochondria, so they rely entirely on anaerobic glycolysis for ATP.
Q: Which glycolytic enzyme deficiencies cause hemolytic anemia? A: Hexokinase, glucose-phosphate isomerase, aldolase, triose-phosphate isomerase, phosphoglycerate kinase, enolase, and pyruvate kinase — pyruvate kinase deficiency is the most clinically significant and common of this group.
Q: What is the biochemical effect of G6PD deficiency? A: Reduced NADPH, which is needed to regenerate reduced glutathione — the molecule that detoxifies free radicals and peroxides. The rate-limiting enzyme of the hexose monophosphate shunt is glucose-6-phosphate dehydrogenase itself.
Q: What triggers hemolysis in G6PD deficiency, and what’s seen on the smear? A: Oxidizing agents — fava beans, sulfonamides, primaquine, and antituberculosis drugs (e.g., isoniazid) — trigger hemolytic anemia. Heinz bodies (precipitated, denatured hemoglobin) are seen on peripheral smear. Inheritance is X-linked recessive, and it’s more common in Black, Mediterranean, and Southeast Asian populations.
Q: What causes sickle cell anemia, and what’s the clinical picture? A: An autosomal recessive single missense mutation in the beta-globin gene, most common among individuals of African descent. Patients present with recurrent painful vaso-occlusive crises and increased susceptibility to infection (from functional asplenia).
Connective Tissue and Structural Protein Disorders
Q: A child presents with multiple fractures and blue sclerae — what’s the diagnosis? A: Osteogenesis imperfecta — a disorder of abnormal Type I collagen synthesis. The sclera appears blue because thinned connective tissue over the choroid lets the underlying vascular pigment show through.
Q: What’s the genetic mechanism of osteogenesis imperfecta? A: A COL1A1 gene mutation causing a dominant-negative effect — one abnormal allele disrupts collagen assembly enough to cause disease even though a normal allele is still present. The most common form is autosomal dominant, and it’s frequently mistaken for child abuse given the fracture pattern.
Q: A patient has hyperextensible skin, a bleeding tendency, and hypermobile joints — what’s the diagnosis? A: Ehlers-Danlos syndrome, caused by faulty collagen synthesis. It’s now recognized as a family of 13 subtypes (per the 2017 International Classification), with inheritance patterns ranging from autosomal dominant (the most common forms) to autosomal recessive and X-linked, depending on subtype.
Q: What’s the clinical picture of cystic fibrosis, and how is it inherited? A: Autosomal recessive, from loss-of-function mutations in the CFTR chloride channel gene. Presents with recurrent pulmonary infections, exocrine pancreatic insufficiency, and infertility in men. More common in white/Caucasian populations, rare in Asian populations.
Q: What’s the genetic mechanism and clinical picture of Duchenne muscular dystrophy? A: X-linked recessive, caused by loss-of-function mutations in the dystrophin gene. Presents with progressive muscle weakness and degeneration.
Q: What causes albinism, and what’s the associated risk? A: A congenital deficiency of tyrosinase, which prevents synthesis of melanin from tyrosine within existing melanocytes. Increases the risk of skin cancer.
Neurofibromatosis, Fragile X, Down Syndrome, and Mitochondrial Disease
Q: What are the characteristic findings in neurofibromatosis, and how is it inherited? A: Multiple café-au-lait spots, neurofibromas, and increased tumor susceptibility. Autosomal dominant, from loss-of-function mutations in a tumor-suppressor signaling protein (neurofibromin); roughly half of cases represent new mutations.
Q: What is the genetic mechanism and phenotype of Fragile X syndrome? A: X-linked, caused by progressive expansion of an unstable trinucleotide repeat that silences the gene encoding an RNA-binding protein (FMRP). Phenotype: intellectual disability, characteristic facial features, and macroorchidism (enlarged testes).
Q: What is the genetic cause and phenotype of Down syndrome? A: Trisomy 21. Phenotype includes intellectual disability, growth retardation, dysmorphic features, and internal organ anomalies, especially cardiac defects. Risk increases with advanced maternal age.
Q: How is Leber’s hereditary optic neuropathy inherited? A: Mitochondrial inheritance.
Q: If a father has a mitochondrial myopathy, what fraction of his children will be affected? A: None — mitochondrial DNA, and mitochondrial disease, is inherited exclusively through the mother.
Q: If a mother is affected by a mitochondrial disease, what fraction of her children can be affected? A: All of her offspring can potentially be affected.
DNA Repair Disorders
Q: What’s the defect in xeroderma pigmentosum? A: Defective nucleotide excision repair, leaving the cell unable to repair thymidine (pyrimidine) dimers caused by UV light — these dimers form on the same DNA strand, not on opposing strands. Autosomal recessive. Presents with photosensitivity, dry skin, and a markedly increased risk of melanoma and other skin cancers.
Q: What DNA damage can’t be repaired in ataxia-telangiectasia? A: Damage from ionizing radiation (X-rays) — the underlying defect is in the ATM gene, involved in double-strand break repair.
Q: What’s the underlying issue in Bloom syndrome? A: A DNA repair defect (BLM helicase), causing sensitivity to radiation and genomic instability.
Q: What triggers problems in Fanconi anemia? A: DNA cross-linking agents — the condition stems from a defect in the DNA repair pathway that handles this type of damage.
Q: What does “loss of heterozygosity” mean, and why does it matter for cancer? A: It’s the loss of the remaining normal allele in a gene pair — classically, a tumor suppressor gene. Per Knudson’s two-hit hypothesis, a patient who inherits or develops one mutated allele won’t develop the associated cancer until the second, normal allele is also lost or inactivated.
Genetics Principles and Population Genetics
Q: Who does an autosomal dominant defect affect within a family? A: Both males and females equally.
Q: What kind of defects do autosomal recessive disorders usually involve, and how many generations do they typically affect? A: Usually enzyme deficiencies, and typically only one generation in a family (affected siblings, unaffected parents).
Q: What’s distinctive about X-linked recessive inheritance? A: No male-to-male transmission, and disease tends to be more severe in males. About half of the sons of a carrier (heterozygous) mother will be affected.
Q: What is genetic imprinting? A: A phenomenon where the phenotype differs depending on whether the mutated gene copy was inherited from the mother or the father.
Q: What is incomplete penetrance? A: When not every individual carrying a disease-causing genotype actually shows the phenotype.
Q: What is variable expressivity? A: When the severity and nature of the phenotype differs from person to person, even among those with the same genotype.
Q: What is pleiotropy? A: When a single gene affects more than one phenotypic trait. Autosomal dominant conditions are often pleiotropic.
Q: What is genetic anticipation? A: A pattern where disease severity worsens, or age of onset gets earlier, in each successive generation — classically seen in trinucleotide repeat disorders.
Q: What is linkage disequilibrium? A: The tendency for specific alleles at two linked loci to occur together in a population more often than would be expected by chance alone.
Q: What is a dominant-negative mutation? A: A mutation where the abnormal gene product actively interferes with the function of the normal product from the other allele — so a single mutant allele disrupts function even though a normal allele is still present.
Q: What’s the Hardy-Weinberg equation, and what do its terms mean? A: p² + 2pq + q² = 1, where p and q are the frequencies of the two alleles at a locus (and p + q = 1). The term 2pq represents heterozygote frequency in the population.
Q: What are the four assumptions behind Hardy-Weinberg equilibrium? A: No new mutation at the locus, no selection for or against any genotype, random mating, and no migration into or out of the population.
Q: If both parents are carriers of the same autosomal recessive condition, what percentage of their children will be affected? A: 25%.
