USMLE Step 1 Quiz
Practice Inborn Errors Of Metabolism in USMLE Step 1 with focused quiz questions that help you check what you know, review explanations, and build confidence with test-style prompts.
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A 14-month-old infant is evaluated for developmental delay and failure to thrive. Laboratory results show markedly elevated plasma homocysteine levels but low methionine levels. A complete blood count reveals megaloblastic anemia. The patient improves with supplementation of methylcobalamin.
The enzyme responsible for converting homocysteine to methionine in this patient requires which of the following as a cofactor?
This quiz focuses on Inborn Errors Of Metabolism, giving you a quick way to practice the rules, question types, and explanations that matter most for USMLE Step 1.
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A 14-month-old infant is evaluated for developmental delay and failure to thrive. Laboratory results show markedly elevated plasma homocysteine levels but low methionine levels. A complete blood count reveals megaloblastic anemia. The patient improves with supplementation of methylcobalamin.
The enzyme responsible for converting homocysteine to methionine in this patient requires which of the following as a cofactor?
Explanation: The combination of elevated homocysteine, low methionine, and megaloblastic anemia that responds to methylcobalamin indicates a defect in the remethylation pathway. Methionine synthase converts homocysteine back to methionine and requires methylcobalamin (vitamin B12) as a cofactor. This can occur due to methionine synthase deficiency or defects in B12 metabolism. In contrast, cystathionine β-synthase deficiency causes elevation of both homocysteine and methionine and requires pyridoxine (vitamin B6).
A 9-month-old infant presents with failure to thrive, progressive loss of motor skills, and an enlarged abdomen. Physical examination reveals significant hepatosplenomegaly and a cherry-red spot on the macula. A bone marrow biopsy shows lipid-laden macrophages with a 'foamy' appearance.
The accumulation of which substance is responsible for this constellation of findings?
Explanation: The combination of neurodegeneration, prominent hepatosplenomegaly, and a cherry-red spot on the macula is characteristic of Niemann-Pick disease (Type A). This disorder is caused by a deficiency of the enzyme sphingomyelinase, which leads to the accumulation of sphingomyelin in lysosomes, creating 'foam cells' in various tissues.
A 5-day-old infant is brought to the emergency department with poor feeding, vomiting, and increasing lethargy over the past 48 hours. The parents note a sweet, sugary smell in the infant's urine. Laboratory studies show elevated plasma levels of leucine, isoleucine, and valine. If not managed promptly, this condition can lead to seizures, coma, and death.
This disorder is caused by a deficiency in which of the following enzymes?
Explanation: This infant has Maple Syrup Urine Disease (MSUD), an autosomal recessive disorder caused by a deficiency in the branched-chain α-ketoacid dehydrogenase complex. This enzyme is required for the degradation of the branched-chain amino acids (leucine, isoleucine, and valine), leading to their accumulation and the characteristic sweet-smelling urine.
A 6-month-old infant of Ashkenazi Jewish heritage presents with developmental arrest, having lost the ability to roll over. On examination, he has marked hypotonia, an exaggerated startle reflex, and a macular 'cherry-red' spot. Laboratory analysis reveals a deficiency in hexosaminidase A.
The pathophysiology of the neurologic deficits in this disease is most directly related to the accumulation of a substrate in which cellular organelle?
Explanation: The patient has Tay-Sachs disease, which is a classic example of a lysosomal storage disorder. The deficient enzyme, hexosaminidase A, is a lysosomal hydrolase. Its absence leads to the accumulation of its substrate, GM2 ganglioside, within the lysosomes of neurons, causing progressive neurodegeneration.
A 25-year-old man seeks evaluation for episodic, excruciating burning pain in his hands and feet, especially during times of stress or fever. He also reports a reduced ability to sweat. Physical examination reveals small, dark red, non-blanching skin lesions on his trunk and limbs. Urinalysis shows proteinuria, suggesting early renal disease.
This genetic disorder, characterized by a deficiency of α-galactosidase A, follows which pattern of inheritance?
Explanation: This patient's symptoms of acroparesthesias, hypohidrosis, angiokeratomas, and renal dysfunction are classic for Fabry disease. It is a lysosomal storage disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of globotriaosylceramide. Fabry disease is inherited in an X-linked recessive pattern.
A 2-week-old infant is brought to the pediatrician for a follow-up visit. The mother notes that the infant has developed an unusual musty or 'mouse-like' odor in his urine and sweat. The infant has fair skin and light-colored hair, which is much lighter than his parents'. If left untreated, this child is at high risk for severe intellectual disability and seizures. This condition is caused by a deficiency in phenylalanine hydroxylase.
Which of the following amino acids becomes essential for this patient?
Explanation: This patient has classic phenylketonuria (PKU), caused by a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Since the body can no longer synthesize tyrosine from phenylalanine, tyrosine becomes an essential amino acid and must be supplied in the diet. Phenylalanine is the amino acid that accumulates and must be restricted. Tryptophan and methionine are unrelated essential amino acids.
A 45-year-old man presents with severe, long-standing joint pain, particularly in his spine and large joints. Physical examination reveals dark, blackish spots on the sclerae of his eyes and bluish-black discoloration of his ear cartilage. He mentions that his urine turns black if left standing for several hours. This condition is caused by a deficiency in an enzyme involved in the degradation pathway of tyrosine.
A deficiency of which of the following enzymes is responsible for this patient's condition?
Explanation: The patient's presentation of ochronosis (dark pigment deposition in connective tissue), debilitating arthritis, and urine that darkens upon exposure to air is classic for alkaptonuria. This autosomal recessive disorder is caused by a deficiency of homogentisate oxidase, leading to the accumulation of homogentisic acid.
A 3-day-old male infant presents with tachypnea, vomiting, and progressive lethargy. Laboratory evaluation reveals a markedly elevated serum ammonia level and respiratory alkalosis. Further analysis of his urine shows significantly elevated orotic acid levels. The infant's father had a brother who died in infancy with similar symptoms.
A deficiency in which of the following urea cycle enzymes best explains these findings?
Explanation: This patient presents with hyperammonemia, characteristic of a urea cycle defect. The key finding is the elevated orotic acid. Ornithine transcarbamylase (OTC) deficiency, an X-linked recessive disorder, leads to the accumulation of carbamoyl phosphate in the mitochondria. This excess carbamoyl phosphate leaks into the cytosol and enters the pyrimidine synthesis pathway, resulting in orotic aciduria. Deficiencies in other urea cycle enzymes do not typically cause orotic aciduria.
A 10-day-old infant is brought to the clinic for jaundice, vomiting, and poor weight gain since starting breastfeeding. Physical examination reveals hepatomegaly and bilateral cataracts. Urinalysis is positive for reducing substances, but a urine glucose oxidase test is negative. The infant is at increased risk for E. coli sepsis.
A deficiency of which enzyme is the most likely cause of this infant's condition?
Explanation: This is a classic presentation of classic galactosemia, an autosomal recessive disorder caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). This leads to the accumulation of toxic metabolites, including galactose-1-phosphate and galactitol. Galactose-1-phosphate accumulation causes liver damage, while galactitol accumulation in the lens causes cataracts. Galactokinase deficiency causes cataracts but not the severe systemic symptoms.
A 7-month-old infant is brought to the emergency department after an episode of vomiting and lethargy that occurred shortly after being fed fruit puree for the first time. Laboratory studies show hypoglycemia, hyperuricemia, and elevated liver enzymes. The parents report similar, but milder, episodes when he was given sweetened water.
This condition is caused by a deficiency in which of the following enzymes?
Explanation: This patient has hereditary fructose intolerance, an autosomal recessive disorder caused by a deficiency of aldolase B. Upon ingestion of fructose, fructose-1-phosphate accumulates, which depletes intracellular phosphate stores and inhibits glycogenolysis and gluconeogenesis, leading to severe hypoglycemia and liver damage. Fructokinase deficiency (essential fructosuria) is a benign condition.
A 4-month-old infant is noted to have a protuberant abdomen and delayed growth. Physical examination reveals massive hepatomegaly and doll-like facial features. Laboratory tests performed after a 4-hour fast show severe hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. A liver biopsy shows an accumulation of glycogen.
A deficiency in which of the following enzymes is the most likely cause of this patient's condition?
Explanation: This is a classic presentation of Von Gierke disease (Glycogen Storage Disease Type I), caused by a deficiency of glucose-6-phosphatase. This enzyme is required for the final step of both glycogenolysis and gluconeogenesis. Its deficiency leads to severe fasting hypoglycemia and a shunt of metabolic intermediates towards lactate (lactic acidosis), uric acid (hyperuricemia), and lipid synthesis (hyperlipidemia).
An 8-month-old infant is brought to the emergency department with lethargy and seizures. The parents report he had a viral illness with poor oral intake for the past 24 hours. Laboratory results show severe hypoglycemia, low to absent ketones in the urine, elevated liver enzymes, and hyperammonemia. Urine organic acid analysis shows dicarboxylic aciduria.
A defect in which of the following metabolic pathways is the most likely cause of this presentation?
Explanation: The clinical picture of hypoketotic hypoglycemia during a period of fasting is a hallmark of a fatty acid oxidation disorder, most commonly Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. During fasting, the body relies on β-oxidation to produce acetyl-CoA for ketone body synthesis and ATP for gluconeogenesis. A defect in this pathway prevents ketone production and impairs gluconeogenesis, leading to severe hypoglycemia.
An 8-month-old infant of Ashkenazi Jewish descent is evaluated for developmental regression. The parents state he has lost the ability to sit up on his own. Physical examination shows hypotonia, an exaggerated startle response to sound, and a prominent cherry-red spot on the macula. Hepatosplenomegaly is notably absent.
This neurodegenerative disorder is caused by the accumulation of which of the following substances due to an enzyme deficiency?
Explanation: This is a classic presentation of Tay-Sachs disease, a lysosomal storage disorder caused by a deficiency of the enzyme hexosaminidase A. This deficiency leads to the accumulation of GM2 ganglioside, primarily in the neurons of the central nervous system. The lack of hepatosplenomegaly helps distinguish it from Niemann-Pick disease, which can also present with a cherry-red spot.
A 22-year-old woman presents with chronic fatigue, bone pain, and a tendency to bruise easily. Physical examination reveals massive splenomegaly. A complete blood count shows pancytopenia. A bone marrow aspirate is performed, and microscopy reveals large macrophages with a 'crinkled tissue paper' or 'wrinkled silk' appearance.
A deficiency in which of the following enzymes is responsible for this patient's condition?
Explanation: The presentation of bone pain, hepatosplenomegaly, and pancytopenia, along with the characteristic lipid-laden macrophages ('Gaucher cells') in the bone marrow, is diagnostic of Gaucher disease. This is the most common lysosomal storage disorder and is caused by a deficiency of the enzyme glucocerebrosidase (β-glucosidase), leading to the accumulation of glucocerebroside.
A 12-year-old boy is evaluated for poor vision. His ophthalmologic exam reveals downward and inward dislocation of the lenses. He is exceptionally tall for his age with long, thin limbs and fingers. His medical history is significant for a deep vein thrombosis last year. He has mild intellectual disability. Lab studies show elevated homocysteine and methionine levels.
A deficiency of which of the following enzymes is the most common cause of this condition?
Explanation: The combination of marfanoid habitus, ectopia lentis (lens dislocation, typically downward), intellectual disability, and thromboembolism is characteristic of classic homocystinuria. This autosomal recessive disorder is most commonly caused by a deficiency of cystathionine β-synthase, which requires pyridoxine (vitamin B6) as a cofactor. The deficiency leads to an accumulation of homocysteine and its precursor, methionine.
A 30-year-old asymptomatic woman is found to have a substance in her urine that tests positive with a copper reduction test but negative with a glucose oxidase test. She has no history of cataracts, liver disease, or hypoglycemia. Further investigation reveals that she has a benign genetic condition related to carbohydrate metabolism.
A deficiency in which of the following enzymes is the most likely diagnosis?
Explanation: This patient has essential fructosuria, a benign autosomal recessive condition caused by a deficiency of fructokinase. This enzyme is responsible for the first step of fructose metabolism. Its absence prevents fructose from being metabolized in the liver, leading to its excretion in the urine. Because fructose is a reducing sugar, it gives a positive copper reduction test (detects reducing substances), but the glucose-specific glucose oxidase test is negative. The condition is asymptomatic.
A 1-year-old child is brought to the ophthalmologist for poor vision. An examination reveals bilateral cataracts. The child has no other significant medical problems, such as jaundice, hepatomegaly, or developmental delay. Urinalysis is positive for reducing substances. The parents are counseled to avoid milk products.
The formation of cataracts in this patient is due to the action of which enzyme on excess galactose?
Explanation: This patient has galactokinase deficiency. In this condition, galactose cannot be phosphorylated to galactose-1-phosphate. The excess galactose is shunted into an alternative pathway where the enzyme aldose reductase converts it to galactitol. Galactitol is an osmotically active alcohol that accumulates in the lens, causing swelling and cataract formation. Unlike classic galactosemia, the more toxic galactose-1-phosphate does not accumulate, so systemic symptoms are absent.
A 4-month-old infant presents with jaundice, failure to thrive, and a progressively enlarging abdomen. The parents note a persistent 'boiled cabbage' odor from the infant. Laboratory studies show markedly elevated α-fetoprotein, conjugated hyperbilirubinemia, and prolonged prothrombin time. Urine analysis shows elevated succinylacetone.
This disorder is caused by a deficiency of an enzyme in the degradation pathway of which amino acid?
Explanation: This is a presentation of hereditary tyrosinemia type I, an autosomal recessive disorder caused by a deficiency of fumarylacetoacetate hydrolase, the final enzyme in the tyrosine degradation pathway. This leads to the accumulation of toxic metabolites, particularly succinylacetone, which causes severe liver and kidney damage. The cabbage-like odor is due to accumulated tyrosine metabolites.
A 2-year-old boy is brought for evaluation of developmental delay, choreoathetosis, and spasticity. His mother reports that he has begun compulsively biting his own fingers and lips. She also notes 'orange sand' in his diapers. Laboratory studies reveal hyperuricemia.
This X-linked recessive disorder is caused by a severe deficiency of which of the following enzymes?
Explanation: This patient has Lesch-Nyhan syndrome, an X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT is a key enzyme in the purine salvage pathway. Its absence leads to increased degradation of purines into uric acid (hyperuricemia) and increased de novo purine synthesis. The neurologic features and self-mutilation are characteristic.
A 4-month-old infant is evaluated for extreme irritability, developmental delay, and increasing muscle rigidity. Physical exam reveals hypertonia, hyperreflexia, and optic atrophy. An MRI of the brain shows extensive white matter disease. A biopsy of a peripheral nerve would most likely reveal multinucleated globoid cells.
A deficiency of which of the following enzymes is responsible for this condition?
Explanation: This is a classic presentation of Krabbe disease, also known as globoid cell leukodystrophy. It is a severe, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme galactocerebrosidase. This leads to the accumulation of galactocerebroside and the toxic metabolite psychosine, which destroys myelin-producing cells and results in the characteristic globoid cells (macrophages containing undigested lipid) in nervous tissue.