Disorders of urea cycle MCQs With Answer

Introduction: Disorders of urea cycle MCQs With Answer provide B. Pharm students a focused review of urea cycle disorders (UCD), hyperammonemia, diagnostic markers, enzyme defects (CPS1, OTC, ASS, ASL, ARG1), and pharmacologic management. This concise, SEO-friendly guide highlights key topics: pathophysiology, biochemical tests (ammonia, orotic acid, amino acids), emergency treatments (hemodialysis, sodium benzoate, sodium phenylbutyrate, carglumic acid), and long-term strategies including dietary protein modulation and liver transplantation. Ideal for exam prep and clinical pharmacy practice, these MCQs emphasize mechanism-based reasoning and drug therapy. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. Which enzyme catalyzes the first committed step of the urea cycle in mitochondria?

• Ornithine transcarbamylase (OTC)
• Carbamoyl phosphate synthetase I (CPS1)
• Argininosuccinate synthetase (ASS)
• Arginase (ARG1)

Correct Answer: Carbamoyl phosphate synthetase I (CPS1)

Q2. A male neonate presents with hyperammonemia and elevated urinary orotic acid. The most likely diagnosis is:

• CPS1 deficiency
• Ornithine transcarbamylase (OTC) deficiency
• Arginase deficiency
• NAGS deficiency

Correct Answer: Ornithine transcarbamylase (OTC) deficiency

Q3. Which urea cycle disorder is inherited in an X-linked recessive pattern?

• CPS1 deficiency
• OTC deficiency
• ASS deficiency
• ARG1 deficiency

Correct Answer: OTC deficiency

Q4. Elevated plasma citrulline is a characteristic biochemical finding in which disorder?

• Argininosuccinate lyase (ASL) deficiency
• Carbamoyl phosphate synthetase I (CPS1) deficiency
• Argininosuccinate synthetase (ASS) deficiency (citrullinemia type I)
• Ornithine transcarbamylase (OTC) deficiency

Correct Answer: Argininosuccinate synthetase (ASS) deficiency (citrullinemia type I)

Q5. Which metabolite is typically markedly elevated in arginase (ARG1) deficiency?

• Ornithine
• Arginine
• Carbamoyl phosphate
• Citrulline

Correct Answer: Arginine

Q6. Which therapy directly provides an alternative pathway for nitrogen excretion by conjugating with glycine to form hippurate?

• Sodium phenylbutyrate
• Sodium benzoate
• Lactulose
• Carglumic acid

Correct Answer: Sodium benzoate

Q7. Sodium phenylbutyrate acts as a prodrug and ultimately removes nitrogen by forming which urinary conjugate?

• Phenylacetylglutamine
• Hippurate
• Urea
• Ornithine sulfate

Correct Answer: Phenylacetylglutamine

Q8. Low orotic acid with severe hyperammonemia suggests deficiency of which enzyme or regulator?

• OTC
• CPS1 or NAGS
• ASS
• ASL

Correct Answer: CPS1 or NAGS

Q9. Which drug is a synthetic activator of CPS1 used in NAGS deficiency and some hyperammonemic states?

• Carglumic acid (N-carbamylglutamate)
• Sodium benzoate
• Sodium phenylbutyrate
• Arginine hydrochloride

Correct Answer: Carglumic acid (N-carbamylglutamate)

Q10. In acute severe hyperammonemia, the most rapid way to lower plasma ammonia is:

• Oral sodium benzoate
• Intravenous carglumic acid
• Hemodialysis
• Dietary protein restriction only

Correct Answer: Hemodialysis

Q11. Which amino acid is commonly supplemented in many proximal urea cycle defects to support residual urea cycle function?

• Leucine
• Arginine
• Methionine
• Phenylalanine

Correct Answer: Arginine

Q12. Which urea cycle defect typically presents later in childhood with progressive spasticity and episodic hyperammonemia rather than neonatal collapse?

• CPS1 deficiency
• OTC deficiency (male neonatal form)
• Arginase (ARG1) deficiency
• ASS deficiency

Correct Answer: Arginase (ARG1) deficiency

Q13. Which laboratory finding is most directly used to confirm hyperammonemia?

• Elevated serum transaminases
• Elevated plasma ammonium (NH4+) concentration
• Low serum albumin
• Increased blood urea nitrogen (BUN)

Correct Answer: Elevated plasma ammonium (NH4+) concentration

Q14. Increased urinary orotic acid with hyperammonemia is due to diversion of carbamoyl phosphate into:

• Pyrimidine synthesis pathway
• Pentose phosphate pathway
• Urea cycle through increased arginine
• Fatty acid synthesis

Correct Answer: Pyrimidine synthesis pathway

Q15. HHH syndrome (hyperornithinemia-hyperammonemia-homocitrullinuria) is caused by a defect in:

• Ornithine translocase (mitochondrial transporter)
• Arginase enzyme
• CPS1 enzyme
• ASS enzyme

Correct Answer: Ornithine translocase (mitochondrial transporter)

Q16. In which urea cycle disorder would you expect markedly elevated argininosuccinic acid levels?

• ARG1 deficiency
• ASL (argininosuccinate lyase) deficiency
• ASS deficiency
• OTC deficiency

Correct Answer: ASL (argininosuccinate lyase) deficiency

Q17. Which of the following is a key acute management step for a neonate with suspected urea cycle disorder and hyperammonemia?

• Initiate high-protein feeding immediately
• Administer intravenous dextrose and lipid to provide non-protein calories
• Give oral ammonium chloride
• Delay treatment until genetic confirmation

Correct Answer: Administer intravenous dextrose and lipid to provide non-protein calories

Q18. Which pharmacologic agent is contraindicated as a definitive therapy for urea cycle disorders and is mainly used to treat hepatic encephalopathy caused by gut-derived ammonia?

• Lactulose
• Sodium benzoate
• Sodium phenylbutyrate
• Carglumic acid

Correct Answer: Lactulose

Q19. A female carrier of OTC deficiency may present with intermittent hyperammonemia due to:

• Complete inactivation of the OTC gene on both X chromosomes
• Skewed X-chromosome lyonization leading to predominance of mutant allele expression
• Autosomal dominant inheritance
• Only environmental triggers, never genetic factors

Correct Answer: Skewed X-chromosome lyonization leading to predominance of mutant allele expression

Q20. Which amino acid is often elevated in plasma in many urea cycle defects as a marker of nitrogen accumulation?

• Glutamine
• Valine
• Tyrosine
• Isoleucine

Correct Answer: Glutamine

Q21. Which enzyme deficiency typically shows low citrulline and elevated orotic acid levels?

• CPS1 deficiency
• OTC deficiency
• ASS deficiency
• ARG1 deficiency

Correct Answer: OTC deficiency

Q22. Chronic management of urea cycle disorders often includes which dietary approach?

• High-protein diet
• Protein restriction with essential amino acid supplementation
• Ketogenic diet
• High-fat, low-carbohydrate diet without protein changes

Correct Answer: Protein restriction with essential amino acid supplementation

Q23. Arginine supplementation is contraindicated in which urea cycle disorder?

• ASS deficiency
• ARG1 deficiency
• OTC deficiency
• ASL deficiency

Correct Answer: ARG1 deficiency

Q24. Which urea cycle enzyme deficiency can be treated effectively with liver transplantation as a cure?

• Only ARG1 deficiency
• Most severe hepatic urea cycle enzyme deficiencies such as OTC, CPS1, ASS
• Only mitochondrial transporter defects
• Urea cycle defects cannot be treated with transplantation

Correct Answer: Most severe hepatic urea cycle enzyme deficiencies such as OTC, CPS1, ASS

Q25. Which pharmacologic agent reduces nitrogen load by conjugating with glutamine to form phenylacetylglutamine?

• Sodium benzoate
• Sodium phenylbutyrate (phenylacetate derivative)
• Arginine
• Carglumic acid

Correct Answer: Sodium phenylbutyrate (phenylacetate derivative)

Q26. In CPS1 deficiency, which laboratory pattern is most likely?

• High ammonia, high orotic acid, high citrulline
• High ammonia, low orotic acid, low citrulline
• Normal ammonia, high citrulline
• High ammonia, high arginine

Correct Answer: High ammonia, low orotic acid, low citrulline

Q27. Which cofactor is essential for the functioning of carbamoyl phosphate synthetase I (CPS1) activity?

• N-acetylglutamate (NAG) as an allosteric activator
• Pyridoxal phosphate (PLP)
• Tetrahydrofolate (THF)
• Biotin

Correct Answer: N-acetylglutamate (NAG) as an allosteric activator

Q28. Which of the following is a recognized adverse effect of chronic sodium phenylbutyrate therapy?

• Severe hypokalemia as a common effect
• Unpleasant body/urine odor and potential neurotoxicity at high doses
• Direct hepatotoxicity in all patients
• Hyperammonemia exacerbation

Correct Answer: Unpleasant body/urine odor and potential neurotoxicity at high doses

Q29. In urea cycle disorders, increased plasma alanine often reflects:

• Increased hepatic urea synthesis
• Transamination of excess ammonia into amino acids as nitrogen carriers
• Primary defect in alanine transaminase only
• Decreased muscle protein breakdown

Correct Answer: Transamination of excess ammonia into amino acids as nitrogen carriers

Q30. Which diagnostic test is most useful to distinguish between OTC deficiency and CPS1 deficiency?

• Serum transaminase levels
• Plasma citrulline concentration and urinary orotic acid
• Serum creatinine
• Liver biopsy for glycogen content

Correct Answer: Plasma citrulline concentration and urinary orotic acid

Q31. Which urea cycle disorder causes accumulation of argininosuccinic acid and may present with trichorrhexis nodosa and brittle hair?

• ASS deficiency
• ASL deficiency (argininosuccinic aciduria)
• ARG1 deficiency
• OTC deficiency

Correct Answer: ASL deficiency (argininosuccinic aciduria)

Q32. The primary site of the urea cycle enzymes is:

• Kidney cortex
• Pancreas
• Liver hepatocytes (mitochondria and cytosol)
• Muscle sarcoplasm

Correct Answer: Liver hepatocytes (mitochondria and cytosol)

Q33. Which neonatal sign is most specific for severe hyperammonemia due to a urea cycle disorder?

• Hypoglycemia only
• Lethargy progressing to coma without significant liver enzyme elevation
• Jaundice with conjugated bilirubin elevation
• Hypertension

Correct Answer: Lethargy progressing to coma without significant liver enzyme elevation

Q34. A pharmacist counseling a family on sodium benzoate should explain its mechanism of action as:

• Stimulating CPS1 activity directly
• Conjugating with glycine to form hippurate for renal excretion of nitrogen
• Enhancing urea cycle enzyme expression genetically
• Blocking intestinal ammonia production

Correct Answer: Conjugating with glycine to form hippurate for renal excretion of nitrogen

Q35. Which laboratory marker would be decreased in many urea cycle disorders due to impaired urea synthesis?

• Plasma ammonia
• Blood urea nitrogen (BUN)
• Plasma glutamine
• Urinary orotic acid

Correct Answer: Blood urea nitrogen (BUN)

Q36. Which of the following is true about ornithine transcarbamylase (OTC) deficiency presentation in heterozygous females?

• They are always asymptomatic carriers
• They may range from asymptomatic to severely symptomatic due to X-inactivation
• They present only after age 50
• They have a consistent phenotype identical to affected males

Correct Answer: They may range from asymptomatic to severely symptomatic due to X-inactivation

Q37. The role of argininosuccinate lyase (ASL) in the urea cycle is to:

• Convert citrulline to argininosuccinate
• Split argininosuccinate into arginine and fumarate
• Hydrolyze arginine to urea and ornithine
• Form carbamoyl phosphate from NH3 and CO2

Correct Answer: Split argininosuccinate into arginine and fumarate

Q38. Which gene testing or molecular diagnostic approach is most appropriate for definitive diagnosis of OTC deficiency?

• Chromosomal karyotype
• Sequencing of the OTC gene and deletion/duplication analysis
• Serum enzyme assay for OTC activity in plasma
• Urine amino acid analysis only

Correct Answer: Sequencing of the OTC gene and deletion/duplication analysis

Q39. Which statement about carglumic acid is correct?

• It is an amino acid supplement used in ARG1 deficiency
• It activates CPS1 by mimicking N-acetylglutamate and is used in NAGS deficiency
• It binds ammonia directly in the gut
• It is a gene therapy product for OTC deficiency

Correct Answer: It activates CPS1 by mimicking N-acetylglutamate and is used in NAGS deficiency

Q40. In chronic management, monitoring which parameter is critical to assess metabolic control in UCD patients?

• Serum sodium only
• Plasma ammonia, plasma amino acid profile, and growth/nutritional status
• Urinary glucose
• Serum cholesterol

Correct Answer: Plasma ammonia, plasma amino acid profile, and growth/nutritional status

Q41. Which urea cycle disorder often shows orotic aciduria but normal blood citrulline levels?

• OTC deficiency
• CPS1 deficiency
• ASS deficiency
• ARG1 deficiency

Correct Answer: OTC deficiency

Q42. Which of the following non-pharmacologic emergency interventions is recommended in acute hyperammonemia?

• High-protein diet to induce urea cycle activity
• Stop protein intake temporarily and provide intravenous calories (dextrose ± lipids)
• Immediate oral administration of arginine for all patients
• Delay dialysis for 72 hours

Correct Answer: Stop protein intake temporarily and provide intravenous calories (dextrose ± lipids)

Q43. Which urea cycle enzyme defect is most likely to cause hypotonia, seizures, and coma in the first few days of life?

• Mild arginase deficiency presenting in adolescence
• Severe OTC or CPS1 deficiency presenting neonatally
• Late onset ASS deficiency only in adults
• HHH syndrome only in middle age

Correct Answer: Severe OTC or CPS1 deficiency presenting neonatally

Q44. Phenylacetic acid derived drugs used in UCDs primarily function by:

• Directly activating urea cycle enzymes
• Conjugating with glutamine to facilitate renal excretion of nitrogen
• Inhibiting intestinal protein digestion
• Increasing hepatic production of urea

Correct Answer: Conjugating with glutamine to facilitate renal excretion of nitrogen

Q45. Which of the following is true regarding newborn screening for urea cycle disorders?

• All UCDs are reliably detected on routine newborn screening in every country
• Some UCDs like ASS and ASL may be detected by elevated citrulline on tandem mass spectrometry, but others may be missed
• Newborn screening measures plasma ammonia directly
• Screening is unnecessary because UCDs never present in the neonatal period

Correct Answer: Some UCDs like ASS and ASL may be detected by elevated citrulline on tandem mass spectrometry, but others may be missed

Q46. Which metabolite accumulates in NAGS deficiency, and what is the best specific therapy?

• High citrulline; treat with sodium benzoate
• Low N-acetylglutamate; treat with carglumic acid
• High arginine; treat with arginine restriction
• High orotic acid; treat with uridine

Correct Answer: Low N-acetylglutamate; treat with carglumic acid

Q47. Which of the following is an important counseling point for families when using sodium benzoate therapy long-term?

• No monitoring is required once therapy starts
• Monitor for sodium load, carnitine depletion, and ensure adherence to dosing schedule
• It cures the genetic defect permanently
• It should be mixed only with high-protein foods

Correct Answer: Monitor for sodium load, carnitine depletion, and ensure adherence to dosing schedule

Q48. Which urea cycle intermediate is produced in the cytosol and transported into mitochondria for continuation of the cycle?

• Carbamoyl phosphate
• Arginine
• Ornithine transported into mitochondria after being regenerated in cytosol
• Citrulline produced in mitochondria and transported out to cytosol

Correct Answer: Citrulline produced in mitochondria and transported out to cytosol

Q49. A pharmacology student asks which drug used in UCDs is a prodrug converted in vivo to phenylacetate; the correct answer is:

• Sodium benzoate
• Sodium phenylbutyrate
• Carglumic acid
• Arginine hydrochloride

Correct Answer: Sodium phenylbutyrate

Q50. Which long-term complication is most associated with poorly controlled urea cycle disorders despite therapy?

• Chronic renal failure only
• Neurocognitive impairment, developmental delay, and intellectual disability
• Primary pulmonary hypertension as the main feature
• Type 1 diabetes mellitus

Correct Answer: Neurocognitive impairment, developmental delay, and intellectual disability

G S Sachin

I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.

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