Urea cycle — MCQs
On this page
A 4-year-old boy presents with vomiting and one day of lethargy after a one week history of flu-like symptoms and low-grade fevers. The vomiting is nonbilious and nonbloody. The patient has had no other symptoms aside from mild rhinorrhea and cough. He has no past medical history, and is on no medications except for over-the-counter medications for his fever. His temperature is 98.5°F (36.9°C), pulse is 96/min, respirations are 14/min, and blood pressure is 108/80 mmHg. The patient appears lethargic and is oriented only to person. Otherwise, the physical exam is benign and the patient has no other neurologic symptoms. What is the mechanism of the most likely cause of this patient’s presentation?
A 3-year-old boy is seen in clinic. He was born at home without perinatal care. He was apparently normal at birth, but later developed failure to thrive and developmental delay. He also has a history of cataracts. His older brother had a myocardial infarction at the age of 18 and is rather lanky and tall in appearance. Laboratory testing of his urine showed an increase in the level of an amino acid. What is the most likely mechanism responsible for this boy's pathology?
A newborn boy develops projectile vomiting 48 hours after delivery. He is found to be lethargic, with poor muscle tone, and is hyperventilating. Within hours, he suffers important neurological deterioration, leading to seizures, coma, and, ultimately, death. An autopsy is performed and the pathology team makes a diagnosis of a rare genetic disorder that leads to low levels of N-acetylglutamate. Which of the following enzymes would be secondarily affected by this process?
A 3-week old boy is brought to the physician for the evaluation of lethargy, recurrent vomiting, and poor weight gain since birth. Physical examination shows decreased skin turgor and a bulging frontal fontanelle. Serum studies show an ammonia concentration of 170 μmol/L (N < 30) and low serum citrulline levels. The oral intake of which of the following nutrients should be restricted in this patient?
A 16-year-old boy presents with acute left-sided weakness. The patient is obtunded and can not provide any history other than his stomach hurts. The patient’s friend states that the patient has had episodes like this in the past and that “he has the same weird disease as his mom”. On physical examination, strength is 1 out of 5 in the left upper and lower extremities. A noncontrast CT scan of the head is normal. Laboratory tests reveal an anion gap metabolic acidosis. Which of the following is a normal function of the structure causing this patient’s condition?
A 40-year-old woman comes to the physician because of a 6-day history of painless blisters on her hands, forearms, and face. Some of the blisters have popped and released a clear fluid. She is otherwise healthy. She had been working the night shift as a security guard for the past few years and switched to the day shift 2 weeks ago. She started wearing a new metal wristwatch last week. Her mother had a similar rash in the past. Her only medication is an estrogen-based oral contraceptive. She drinks 2 beers every night and occasionally more on the weekends. She used intravenous heroin in the past but stopped 20 years ago. Vital signs are within normal limits. Examination shows bullae and oozing erosions in different stages of healing on her arms, dorsal hands, ears, and face. Oral examination shows no abnormalities. There are some atrophic white scars and patches of hyperpigmented skin on the arms and face. Further evaluation of this patient is most likely to show which of the following findings?
A 4-day-old male newborn delivered at 39 weeks' gestation is evaluated because of poor feeding, recurrent vomiting, and lethargy. Physical examination shows tachypnea with subcostal retractions. An enzyme assay performed on a liver biopsy specimen shows decreased activity of carbamoyl phosphate synthetase I. This enzyme plays an important role in the breakdown and excretion of amino groups that result from protein digestion. Which of the following is an immediate substrate for the synthesis of the molecule needed for the excretion of amino groups?
A 2-day-old male is seen in the newborn nursery for repeated emesis and lethargy. He was born at 39 weeks to a 24-year-old mother following an uncomplicated pregnancy and birth. He has been breastfeeding every 2 hours and has 10 wet diapers per day. His father has a history of beta-thalassemia minor. Laboratory results are as follows: Hemoglobin: 12 g/dL Platelet count: 200,000/mm³ Mean corpuscular volume: 95 µm³ Reticulocyte count: 0.5% Leukocyte count: 5,000/mm³ with normal differential Serum: Na+: 134 mEq/L Cl-: 100 mEq/L K+: 3.3 mEq/L HCO3-: 24 mEq/L Urea nitrogen: 1 mg/dL Creatinine: 0.6 mg/dL Ammonia: 150 µmol/L (normal: 50-80 µmol/L) Which of the following is the most likely diagnosis?
A 20-year-old male presents with confusion, asterixis, and odd behavior. Very early in the morning, his mother found him urinating on the floor of his bedroom. A detailed history taken from the mother revealed that he has been a vegetarian his entire life but decided to "bulk up" by working out and consuming whey protein several times a day. A blood test revealed increased levels of ammonia and orotic acid but a decreased BUN. The patient began hemodialysis and was given oral sodium benzoate and phenylbutyrate, which improved his condition. Gene therapy of the enzyme producing which product would correct his condition?
A 2-week-old boy presents to the emergency department because of unusual irritability and lethargy. The patient is admitted to the pediatric intensive care unit and minutes later develops metabolic encephalopathy. This progressed to a coma, followed by death before any laboratory tests are completed. The infant was born at home via vaginal delivery at 39 weeks' of gestation. His mother says that the symptoms started since the infant was 4-days-old, but since he only seemed ‘tired’, she decided not to seek medical attention. Further testing during autopsy shows hyperammonemia, low citrulline, and increased orotic acid. Which of the following enzymes is most likely deficient in this patient?
Urea cycle US Medical PG Practice Questions and MCQs
Question 1: A 4-year-old boy presents with vomiting and one day of lethargy after a one week history of flu-like symptoms and low-grade fevers. The vomiting is nonbilious and nonbloody. The patient has had no other symptoms aside from mild rhinorrhea and cough. He has no past medical history, and is on no medications except for over-the-counter medications for his fever. His temperature is 98.5°F (36.9°C), pulse is 96/min, respirations are 14/min, and blood pressure is 108/80 mmHg. The patient appears lethargic and is oriented only to person. Otherwise, the physical exam is benign and the patient has no other neurologic symptoms. What is the mechanism of the most likely cause of this patient’s presentation?
- A. Deficient erythrocyte enzyme
- B. Chemical ingestion
- C. Bacterial infection
- D. Irreversible enzyme inhibition (Correct Answer)
- E. Reversible enzyme inhibition
Explanation: ***Irreversible enzyme inhibition*** - This presentation is highly suggestive of **Reye syndrome**, which is associated with **aspirin use** in children with viral illnesses. Aspirin (acetylsalicylic acid) **irreversibly inhibits cyclooxygenase (COX) enzymes** by acetylating a serine residue at the active site. - While aspirin's primary mechanism is COX inhibition, **Reye syndrome** involves **mitochondrial dysfunction** in hepatocytes, leading to impaired fatty acid beta-oxidation, hyperammonemia, hepatic steatosis, and **encephalopathy**. This explains the vomiting, lethargy, and altered mental status after flu-like symptoms. - The key connection is that aspirin acts through **irreversible enzyme inhibition**, making this the correct mechanistic classification for the causative agent. *Reversible enzyme inhibition* - While some aspects of Reye syndrome involve mitochondrial enzyme dysfunction, aspirin itself does **not** act through reversible competitive inhibition—it **irreversibly acetylates** COX enzymes. - Reversible inhibition would imply the drug effect could be easily overcome by increasing substrate concentration, which is not the case with aspirin's mechanism. *Deficient erythrocyte enzyme* - This mechanism is associated with conditions like **glucose-6-phosphate dehydrogenase (G6PD) deficiency**, which primarily causes **hemolytic anemia** with jaundice and pallor. - While G6PD deficiency can be triggered by certain medications, it does not typically present with the **encephalopathy** and liver dysfunction seen in this patient. *Chemical ingestion* - While aspirin is technically a chemical, the question asks about the **mechanism** rather than the route of exposure. The specific mechanism is irreversible enzyme inhibition. - The history of **flu-like symptoms** and use of over-the-counter fever medications strongly suggests aspirin-associated Reye syndrome rather than accidental toxic ingestion. *Bacterial infection* - A severe bacterial infection (e.g., **bacterial meningitis** or **sepsis**) could cause lethargy and vomiting, but the clinical picture (normal vital signs, benign physical exam, no fever) is not typical for acute bacterial infection. - The association with a recent **viral illness** and potential over-the-counter medication use strongly favors Reye syndrome, a non-infectious etiology.
Question 2: A 3-year-old boy is seen in clinic. He was born at home without perinatal care. He was apparently normal at birth, but later developed failure to thrive and developmental delay. He also has a history of cataracts. His older brother had a myocardial infarction at the age of 18 and is rather lanky and tall in appearance. Laboratory testing of his urine showed an increase in the level of an amino acid. What is the most likely mechanism responsible for this boy's pathology?
- A. Hereditary defect of renal amino acid transporter
- B. Inability to degrade branched chain amino acids
- C. Cystathionine synthase deficiency (Correct Answer)
- D. Deficiency of homogentisic acid oxidase
- E. Deficiency of phenylalanine hydroxylase
Explanation: ***Cystathionine synthase deficiency*** - The constellation of **developmental delay, failure to thrive, cataracts**, and a history of **myocardial infarction** in an older sibling with a **marfanoid habitus** points to **homocystinuria**. - **Cystathionine synthase deficiency** is the most common cause of homocystinuria, leading to an **accumulation of homocysteine** and methionine, which can be detected in urine. *Hereditary defect of renal amino acid transporter* - Conditions like **cystinuria** involve defective renal transport of specific amino acids (cystine, ornithine, lysine, arginine) but typically present with **kidney stones**, not cataracts or thrombotic events. - This defect would lead to elevated levels of the affected amino acids in the urine but does not explain the systemic features observed. *Inability to degrade branched chain amino acids* - This describes **Maple Syrup Urine Disease**, characterized by the inability to metabolize **leucine, isoleucine, and valine**. - It presents with symptoms like **poor feeding, lethargy, seizures, and a distinctive sweet odor** in urine, which are not detailed here, and generally has a more acute and severe neonatal presentation without a typical marfanoid habitus or thrombotic events. *Deficiency of homogentisic acid oxidase* - This deficiency causes **alkaptonuria**, an inborn error of tyrosine metabolism. - It is characterized by **dark urine** upon standing, **ochronosis** (darkening of connective tissues), and **arthropathy**, none of which are consistent with the patient's symptoms. *Decreased in phenylalanine hydroxylase* - This is the enzyme deficient in **phenylketonuria (PKU)**, which leads to the accumulation of **phenylalanine**. - PKU typically presents with **intellectual disability, seizures, fair skin, and a musty odor** if untreated, but generally does not involve cataracts or thrombotic events.
Question 3: A newborn boy develops projectile vomiting 48 hours after delivery. He is found to be lethargic, with poor muscle tone, and is hyperventilating. Within hours, he suffers important neurological deterioration, leading to seizures, coma, and, ultimately, death. An autopsy is performed and the pathology team makes a diagnosis of a rare genetic disorder that leads to low levels of N-acetylglutamate. Which of the following enzymes would be secondarily affected by this process?
- A. Argininosuccinate lyase
- B. Carbamoyl phosphate synthetase I (Correct Answer)
- C. Argininosuccinate synthetase
- D. Ornithine transcarbamylase
- E. Arginase
Explanation: ***Carbamoyl phosphate synthetase I*** - **N-acetylglutamate** is an **obligate activator** for **Carbamoyl phosphate synthetase I (CPS I)**, the rate-limiting enzyme of the **urea cycle**. Low levels of N-acetylglutamate directly impair CPS I activity. - Reduced CPS I activity leads to a severe **urea cycle disorder**, causing **hyperammonemia**, which manifests with lethargy, poor muscle tone, hyperventilation, neurological deterioration, seizures, coma, and death in newborns. *Argininosuccinate lyase* - This enzyme is involved downstream in the **urea cycle**, catalyzing the cleavage of **argininosuccinate** into **arginine** and **fumarate**. - Its activity is not directly regulated by **N-acetylglutamate**, so it would not be secondarily affected in the same manner as CPS I. *Argininosuccinate synthetase* - This enzyme acts after CPS I and ornithine transcarbamylase in the **urea cycle**, synthesizing **argininosuccinate** from **citrulline** and **aspartate**. - Its function is independent of **N-acetylglutamate** levels, making it unlikely to be secondarily affected. *Ornithine transcarbamylase* - This enzyme catalyzes the second step of the **urea cycle**, forming **citrulline** from **ornithine** and **carbamoyl phosphate**. - While essential for the urea cycle, its activity is not directly modulated by **N-acetylglutamate**; rather, it depends on the availability of carbamoyl phosphate produced by CPS I. *Arginase* - This is the final enzyme in the **urea cycle**, converting **arginine** to **ornithine** and **urea**. - Its activity is not directly or indirectly regulated by **N-acetylglutamate**, nor is it the enzyme primarily affected in this presentation.
Question 4: A 3-week old boy is brought to the physician for the evaluation of lethargy, recurrent vomiting, and poor weight gain since birth. Physical examination shows decreased skin turgor and a bulging frontal fontanelle. Serum studies show an ammonia concentration of 170 μmol/L (N < 30) and low serum citrulline levels. The oral intake of which of the following nutrients should be restricted in this patient?
- A. Gluten
- B. Lactose
- C. Fructose
- D. Protein (Correct Answer)
- E. Vitamin A
Explanation: ***Protein*** - Elevated **ammonia** and low **citrulline** levels indicate a **urea cycle disorder**, which impairs the body's ability to excrete nitrogenous waste from protein metabolism. - Restricting **protein intake** limits the production of ammonia, thereby reducing the toxic burden on the system and preventing further neurological damage. *Gluten* - **Gluten restriction** is primarily indicated for **celiac disease**, which presents with gastrointestinal symptoms like diarrhea, malabsorption, and poor weight gain, but not directly with hyperammonemia or urea cycle dysfunction. - While malabsorption can cause poor weight gain, the specific metabolic derangements here point away from celiac disease. *Lactose* - **Lactose intolerance** or **galactosemia** would necessitate **lactose restriction**. Symptoms usually include vomiting, diarrhea, and failure to thrive, but they do not typically present with the extreme hyperammonemia seen here. - Galactosemia specifically would show elevated galactose and galactose-1-phosphate, not ammonia. *Fructose* - **Hereditary fructose intolerance** requires **fructose restriction**. It generally presents with vomiting, hypoglycemia, and liver dysfunction (jaundice, hepatomegaly) upon exposure to fructose, not primarily with hyperammonemia. - The metabolic pathway for fructose metabolism does not directly generate ammonia in the quantities seen with urea cycle disorders. *Vitamin A* - **Vitamin A restriction** is not a primary treatment for any known inborn error of metabolism or hyperammonemia. - While deficiencies or toxicities of vitamins can occur, they do not present with the specific metabolic profile described (high ammonia, low citrulline).
Question 5: A 16-year-old boy presents with acute left-sided weakness. The patient is obtunded and can not provide any history other than his stomach hurts. The patient’s friend states that the patient has had episodes like this in the past and that “he has the same weird disease as his mom”. On physical examination, strength is 1 out of 5 in the left upper and lower extremities. A noncontrast CT scan of the head is normal. Laboratory tests reveal an anion gap metabolic acidosis. Which of the following is a normal function of the structure causing this patient’s condition?
- A. Regulation of blood glucose
- B. Synthesis of fatty acids
- C. Production of bile acids
- D. Metabolism of purines
- E. Conversion of ammonia to urea (Correct Answer)
Explanation: ***Conversion of ammonia to urea*** - The patient's presentation with **acute neurological deficits**, **abdominal pain**, and **anion gap metabolic acidosis** with a normal head CT, along with family history, is highly suggestive of a **urea cycle disorder (UCD)**. - The **urea cycle** primarily functions in the **liver** to convert **toxic ammonia** into less toxic urea for excretion. *Regulation of blood glucose* - While regulation of blood glucose is a vital **liver function**, it does not directly relate to the primary metabolic derangement (ammonia accumulation) seen in UCDs. - **Hypoglycemia** can occur in some UCDs, but it's not the defining feature of the neurological crisis. *Synthesis of fatty acids* - **Fatty acid synthesis** primarily occurs in the liver and adipose tissue, but its dysfunction is not the direct cause of the patient's acute symptoms. - While liver dysfunction can impact lipid metabolism, it is not the central pathological process in UCDs. *Production of bile acids* - **Bile acid production** is a critical function of the liver for fat digestion and absorption, but it is not directly impaired in urea cycle disorders. - Bile acid synthesis disorders would present with different clinical features, such as **cholestasis** and fat malabsorption. *Metabolism of purines* - **Purine metabolism** occurs in various tissues, and its dysfunction can lead to conditions like **gout** or **Lesch-Nyhan syndrome**, which differ from the presented symptoms. - Abnormalities in purine metabolism are not the core defect in urea cycle disorders.
Question 6: A 40-year-old woman comes to the physician because of a 6-day history of painless blisters on her hands, forearms, and face. Some of the blisters have popped and released a clear fluid. She is otherwise healthy. She had been working the night shift as a security guard for the past few years and switched to the day shift 2 weeks ago. She started wearing a new metal wristwatch last week. Her mother had a similar rash in the past. Her only medication is an estrogen-based oral contraceptive. She drinks 2 beers every night and occasionally more on the weekends. She used intravenous heroin in the past but stopped 20 years ago. Vital signs are within normal limits. Examination shows bullae and oozing erosions in different stages of healing on her arms, dorsal hands, ears, and face. Oral examination shows no abnormalities. There are some atrophic white scars and patches of hyperpigmented skin on the arms and face. Further evaluation of this patient is most likely to show which of the following findings?
- A. Elevated anti-transglutaminase antibodies
- B. Elevated anti-varicella zoster virus antibodies
- C. Positive skin patch test
- D. Increased urinary uroporphyrin (Correct Answer)
- E. Elevated anti-Smith antibodies
Explanation: ***Increased urinary uroporphyrin*** - This patient's presentation with **painless blisters** on sun-exposed areas (hands, forearms, face), worsened by sun exposure (implied by night shift to day shift change), a positive family history, and scarring/hyperpigmentation is classic for **Porphyria Cutanea Tarda (PCT)**. - **PCT** is characterized by a deficiency in **hepatic uroporphyrinogen decarboxylase**, leading to an accumulation of **uroporphyrinogen** and **uroporphyrin I and III** isomers, which are excreted in urine and stool, making **increased urinary uroporphyrin** a key diagnostic finding. *Elevated anti-transglutaminase antibodies* - This finding is associated with **celiac disease**, which can manifest with **dermatitis herpetiformis** (pruritic, vesicular rash). - However, **dermatitis herpetiformis** is typically very itchy, and the patient does not report pruritus, nor does her rash pattern fully align with it. *Elevated anti-varicella zoster virus antibodies* - While reflecting prior exposure or vaccination to **varicella zoster virus (VZV)**, this would not explain new-onset, widespread painless blisters in a healthy adult. - **Reactivation of VZV (shingles)** typically presents as a painful, unilateral, dermatomal vesicular rash. *Positive skin patch test* - A positive skin patch test indicates a **Type IV hypersensitivity reaction** to a specific allergen, commonly seen in **allergic contact dermatitis**. - While the patient started wearing a new metal wristwatch, explaining a localized rash, her widespread blisters on the face and forearms point away from a simple contact dermatitis. *Elevated anti-Smith antibodies* - **Anti-Smith antibodies** are highly specific for **Systemic Lupus Erythematosus (SLE)**, which can present with various skin manifestations, including photosensitive rashes. - However, the characteristic **flaccid bullae and erosions** seen in this patient are not typical of SLE, and there are no other systemic symptoms suggestive of lupus.
Question 7: A 4-day-old male newborn delivered at 39 weeks' gestation is evaluated because of poor feeding, recurrent vomiting, and lethargy. Physical examination shows tachypnea with subcostal retractions. An enzyme assay performed on a liver biopsy specimen shows decreased activity of carbamoyl phosphate synthetase I. This enzyme plays an important role in the breakdown and excretion of amino groups that result from protein digestion. Which of the following is an immediate substrate for the synthesis of the molecule needed for the excretion of amino groups?
- A. N-acetylglutamate
- B. Homocysteine
- C. Phenylalanine
- D. Valine
- E. Aspartate (Correct Answer)
Explanation: ***Aspartate*** - The question describes a case of **carbamoyl phosphate synthetase I (CPS I)** deficiency, which leads to **hyperammonemia** due to impaired urea cycle function. - The urea cycle is responsible for excreting **amino groups** as urea; one of the key molecules directly incorporated into the urea molecule is **aspartate**, which donates an amino group to form **argininosuccinate**. *N-acetylglutamate* - **N-acetylglutamate** is an essential activator of **carbamoyl phosphate synthetase I (CPS I)**, the enzyme deficient in this patient. - While crucial for the urea cycle's regulation, it is an **allosteric activator** rather than a direct substrate for the synthesis of molecules needed for amino group excretion. *Homocysteine* - **Homocysteine** is an intermediate in **methionine metabolism** and is primarily associated with cardiovascular disease and neurological issues when elevated. - It plays no direct role as a substrate in the urea cycle for the excretion of amino groups. *Phenylalanine* - **Phenylalanine** is an **essential amino acid** that is a precursor to tyrosine and neurotransmitters. - Its metabolism is separate from the urea cycle, and it is not a direct substrate for ammonia excretion in this pathway. *Valine* - **Valine** is a **branched-chain amino acid (BCAA)** primarily catabolized in muscles and used for energy. - It is not a direct substrate in the urea cycle, which processes nitrogen from various amino acids into urea for excretion.
Question 8: A 2-day-old male is seen in the newborn nursery for repeated emesis and lethargy. He was born at 39 weeks to a 24-year-old mother following an uncomplicated pregnancy and birth. He has been breastfeeding every 2 hours and has 10 wet diapers per day. His father has a history of beta-thalassemia minor. Laboratory results are as follows: Hemoglobin: 12 g/dL Platelet count: 200,000/mm³ Mean corpuscular volume: 95 µm³ Reticulocyte count: 0.5% Leukocyte count: 5,000/mm³ with normal differential Serum: Na+: 134 mEq/L Cl-: 100 mEq/L K+: 3.3 mEq/L HCO3-: 24 mEq/L Urea nitrogen: 1 mg/dL Creatinine: 0.6 mg/dL Ammonia: 150 µmol/L (normal: 50-80 µmol/L) Which of the following is the most likely diagnosis?
- A. Phenylketonuria
- B. Orotic aciduria
- C. Alkaptonuria
- D. Ornithine transcarbamylase deficiency (Correct Answer)
- E. Beta-thalassemia minor
Explanation: ***Ornithine transcarbamylase deficiency*** - The combination of **lethargy**, vomiting (emesis), and **significantly elevated ammonia levels** in a neonate strongly points to a **urea cycle disorder**, with ornithine transcarbamylase (OTC) deficiency being the most common. - This X-linked disorder leads to a buildup of ammonia due to the inability to convert carbamoyl phosphate and ornithine into citrulline, a crucial step in the urea cycle. *Phenylketonuria* - Characterized by the inability to metabolize **phenylalanine**, leading to its accumulation and neurological damage if untreated. - Typically presents with developmental delay, seizures, and a musty odor, not acute hyperammonemia and vomiting in the neonatal period. *Orotic aciduria* - A rare metabolic disorder caused by a defect in **pyrimidine synthesis**, leading to accumulation of **orotic acid**. - Presents with megaloblastic anemia, developmental delay, and failure to thrive, but not typically with severe neonatal hyperammonemia. *Alkaptonuria* - An autosomal recessive disorder of **tyrosine metabolism** where homogentisic acid oxidase is deficient, leading to a buildup of **homogentisic acid**. - Characterized by dark urine when exposed to air, ochronosis (bluish-black pigmentation of cartilage), and early-onset osteoarthritis; it does not cause acute neonatal illness with hyperammonemia. *Beta-thalassemia minor* - This is an **inherited blood disorder** causing mild anemia, often asymptomatic, due to reduced or absent beta-globin chain production. - While the father has this condition, the infant's symptoms of lethargy, vomiting, and hyperammonemia are **not consistent** with beta-thalassemia minor.
Question 9: A 20-year-old male presents with confusion, asterixis, and odd behavior. Very early in the morning, his mother found him urinating on the floor of his bedroom. A detailed history taken from the mother revealed that he has been a vegetarian his entire life but decided to "bulk up" by working out and consuming whey protein several times a day. A blood test revealed increased levels of ammonia and orotic acid but a decreased BUN. The patient began hemodialysis and was given oral sodium benzoate and phenylbutyrate, which improved his condition. Gene therapy of the enzyme producing which product would correct his condition?
- A. Citrulline (Correct Answer)
- B. Fructose-1-phosphate
- C. Homocysteine
- D. Phenylalanine
- E. Uridine monophosphate
Explanation: ***Citrulline*** - The clinical presentation (confusion, asterixis, bizarre behavior, high ammonia, low BUN, high orotic acid, improvement with sodium benzoate and phenylbutyrate) is classic for a **urea cycle disorder**, specifically **ornithine transcarbamylase (OTC) deficiency**. - OTC catalyzes the conversion of ornithine and carbamoyl phosphate to citrulline. A deficiency in OTC leads to a buildup of carbamoyl phosphate, which is then shunted to the pyrimidine synthesis pathway, leading to increased orotic acid. Therefore, gene therapy for the enzyme producing citrulline (OTC) would address the underlying defect. *Fructose-1-phosphate* - This is an intermediate in **fructose metabolism**. Disorders related to this, such as **hereditary fructose intolerance**, are not associated with hyperammonemia or orotic aciduria in this manner. - Symptoms typically involve hypoglycemia, vomiting, and liver dysfunction upon fructose ingestion. *Homocysteine* - Elevated homocysteine levels are characteristic of **homocystinuria**, which is due to defects in methionine metabolism, often involving **cystathionine beta-synthase** or enzymes in the folate/B12 pathways. - Homocystinuria presents with developmental delay, skeletal abnormalities, and thromboembolic events, distinct from the patient's symptoms. *Phenylalanine* - Elevated phenylalanine is the hallmark of **phenylketonuria (PKU)**, an inherited disorder of amino acid metabolism where the body cannot process **phenylalanine**. - PKU primarily causes neurological issues if untreated, but not typically hyperammonemia or orotic aciduria. *Uridine monophosphate* - While orotic acid is a precursor to uridine monophosphate in pyrimidine synthesis, a direct gene therapy for the enzyme producing uridine monophosphate is not the primary intervention for the underlying urea cycle disorder. - The high orotic acid is a consequence of the urea cycle blockade, not the primary defect itself.
Question 10: A 2-week-old boy presents to the emergency department because of unusual irritability and lethargy. The patient is admitted to the pediatric intensive care unit and minutes later develops metabolic encephalopathy. This progressed to a coma, followed by death before any laboratory tests are completed. The infant was born at home via vaginal delivery at 39 weeks' of gestation. His mother says that the symptoms started since the infant was 4-days-old, but since he only seemed ‘tired’, she decided not to seek medical attention. Further testing during autopsy shows hyperammonemia, low citrulline, and increased orotic acid. Which of the following enzymes is most likely deficient in this patient?
- A. Branched-chain alpha-ketoacid dehydrogenase
- B. Propionyl-CoA carboxylase
- C. Homogentisic acid dioxygenase
- D. Ornithine transcarbamylase (Correct Answer)
- E. Cystathionine beta-synthase
Explanation: **Ornithine transcarbamylase** - **Hyperammonemia**, **low citrulline**, and **increased orotic acid** are classic findings in **Ornithine Transcarbamylase (OTC) deficiency**. OTC is an X-linked urea cycle disorder. - The rapid progression to **metabolic encephalopathy** and death in a neonate with these laboratory findings is highly characteristic of severe OTC deficiency, often presenting in the first few days of life. *Branched-chain alpha-ketoacid dehydrogenase* - Deficiency of this enzyme causes **Maple Syrup Urine Disease**, characterized by elevated **branched-chain amino acids** and their corresponding ketoacids in blood and urine. - While it can cause neurological symptoms, it does not typically present with the specific constellation of **hyperammonemia**, low citrulline, and high orotic acid. *Propionyl-CoA carboxylase* - Deficiency of this enzyme leads to **Propionic acidemia**, a type of organic acidemia, characterized by **propionic acid accumulation** and often **metabolic acidosis**, ketosis, and hyperammonemia. - However, it would not typically cause **low citrulline** or isolated **elevated orotic acid** as seen in urea cycle disorders. *Homogentisic acid dioxygenase* - Deficiency of this enzyme causes **Alkaptonuria**, an inborn error of metabolism characterized by the accumulation of **homogentisic acid**. - This condition is usually benign in infancy, with symptoms appearing later in life such as **dark urine** on standing and **ochronosis** (darkening of cartilage). It does not present with acute hyperammonemia or metabolic encephalopathy. *Cystathionine beta-synthase* - Deficiency of this enzyme causes **homocystinuria**, an inborn error of methionine metabolism, leading to elevated **homocysteine** and methionine. - Clinical features include **ectopia lentis**, skeletal abnormalities, and intellectual disability, but not usually acute neonatal hyperammonemia or the specific findings of low citrulline and high orotic acid.
Question 11: A 2-day-old male newborn is brought to the physician because he became somnolent and felt cold after breastfeeding. Pregnancy and delivery were uncomplicated. He was born at 40 weeks' gestation and weighed 3538 g (7 lb 13 oz); he currently weighs 3311 g (7 lb 5 oz). Examination shows generalized hypotonia. Serum studies show an ammonia concentration of 150 μmol/L (N < 50 μmol/L). Which of the following is the most likely cause of the patient's neurological symptoms?
- A. Increased α-ketoglutarate concentration
- B. Increased glutamate concentration
- C. Increased succinyl-CoA concentration
- D. Decreased acylcarnitine concentration
- E. Decreased γ-aminobutyric acid concentration (Correct Answer)
Explanation: ***Decreased γ-aminobutyric acid concentration*** - The elevated **ammonia** concentration in this patient crosses the **blood-brain barrier** and is detoxified in astrocytes by converting glutamate to glutamine (via glutamine synthetase). - This detoxification process depletes neuronal **glutamate** pools, which subsequently reduces the synthesis of **GABA** (gamma-aminobutyric acid), since GABA is synthesized from glutamate via glutamic acid decarboxylase. - The depletion of glutamate and GABA, combined with **energy depletion** from impaired TCA cycle function (due to α-ketoglutarate depletion) and direct **ammonia neurotoxicity**, contribute to the neurological symptoms including **somnolence** and **hypotonia**. - Hyperammonemia causes complex neurotransmitter imbalances and metabolic disruption that result in the observed neurological dysfunction. *Increased α-ketoglutarate concentration* - In hyperammonemia, **α-ketoglutarate** is converted to glutamate (by glutamate dehydrogenase) and then to glutamine (by glutamine synthetase) to detoxify ammonia. - This leads to **depletion of α-ketoglutarate**, not an increase, which impairs the **TCA cycle** and reduces cerebral energy production, contributing significantly to neurological symptoms. *Increased glutamate concentration* - Neuronal **glutamate** concentration is actually **decreased** in hyperammonemia due to its conversion into glutamine to trap ammonia in astrocytes. - This depletion of the key excitatory neurotransmitter and its role in energy metabolism contributes to neurological dysfunction. *Increased succinyl-CoA concentration* - **Succinyl-CoA** is a TCA cycle intermediate that is not directly affected by hyperammonemia. - The primary metabolic disturbance involves the glutamate-glutamine cycle and depletion of α-ketoglutarate, not accumulation of succinyl-CoA. *Decreased acylcarnitine concentration* - **Acylcarnitines** are markers of fatty acid oxidation disorders, not urea cycle disorders. - This presentation with isolated hyperammonemia, somnolence, and hypotonia is classic for a **urea cycle disorder**, where acylcarnitine levels are typically normal.
Question 12: A 3-day-old female infant presents with poor feeding, lethargy, vomiting after feeding, and seizures. Labs revealed ketoacidosis and elevated hydroxypropionic acid levels. Upon administration of parenteral glucose and protein devoid of valine, isoleucine, methionine, and threonine, and carnitine, the infant began to recover. Which of the following enzymes is most likely deficient in this infant?
- A. Branched-chain ketoacid dehydrogenase
- B. Propionyl-CoA carboxylase (Correct Answer)
- C. Cystathionine synthase
- D. Phenylalanine hydroxylase
- E. Homogentisate oxidase
Explanation: ***Propionyl-CoA carboxylase*** - The presence of **ketoacidosis** and elevated **hydroxypropionic acid** levels is characteristic of propionic acidemia, which is caused by a deficiency in **propionyl-CoA carboxylase**. - The therapeutic benefit from a diet restricted in **valine, methionine, threonine**, and **isoleucine** (precursors of propionyl-CoA) along with carnitine supplementation further supports this diagnosis. *Branched-chain ketoacid dehydrogenase* - A deficiency in this enzyme leads to **Maple Syrup Urine Disease**, characterized by elevated **branched-chain ketoacids** and associated with a distinctive sweet odor in urine. - While it causes neurotoxicity and poor feeding, the specific finding of elevated **hydroxypropionic acid** points away from this diagnosis. *Cystathionine synthase* - Deficiency in **cystathionine synthase** causes **homocystinuria**, leading to elevated **homocysteine** levels. - Symptoms include developmental delay, ectopia lentis, and skeletal abnormalities, but not typically elevated **hydroxypropionic acid** or severe neonatal ketoacidosis in this manner. *Phenylalanine hydroxylase* - This enzyme is deficient in **phenylketonuria (PKU)**, resulting in high levels of **phenylalanine** and its metabolites. - PKU is typically associated with intellectual disability, seizures, and a musty odor, but not ketoacidosis or elevated **hydroxypropionic acid**. *Homogentisate oxidase* - A deficiency in this enzyme causes **alkaptonuria**, characterized by the accumulation of **homogentisic acid**. - This condition is usually benign in infancy, primarily manifesting as dark urine upon standing and later developing into ochronosis and arthritis, without acute neonatal ketoacidosis or elevated **hydroxypropionic acid**.
Question 13: A 6-year-old boy is brought to the pediatrician by his mother for diarrhea and a skin rash. His mother reports that he had a cough, sore throat, and runny nose 1 week ago. Although his upper respiratory symptoms improved after two days, he started having multiple watery bowel movements 3 days ago. He also developed a red pruritic rash on his arms, legs, and neck at that time. His mother also reports that he has had similar symptoms in the past that have occurred after the boy gets sick. His temperature is 98.8°F (37.1°C), blood pressure is 109/68 mmHg, pulse is 92/min, and respirations are 19/min. The child is alert and oriented to person but not place or time. He is unable to count to 10 even though his mother says he can normally count to 100 easily. He walks with a wide-based gait. An erythematous patchy rash is noted on his upper and lower extremities bilaterally. A complete blood count and basic metabolic panel are within normal limits. A urinalysis reveals elevated levels of neutral amino acids. Which of the following is the most appropriate acute treatment for this patient?
- A. Phenylbutyrate
- B. Tryptophan
- C. Nicotinic acid (Correct Answer)
- D. Pyridoxine
- E. Tyrosine
Explanation: ***Nicotinic acid*** - The patient's symptoms (diarrhea, dermatitis, neurological deficits, and the history of recurrent episodes after illness) are classic for **Hartnup disease**, which involves impaired absorption of neutral amino acids, including tryptophan. - **Tryptophan** is a precursor to **niacin (vitamin B3)**. Therefore, supplementation with **nicotinic acid** (a form of niacin) is the most appropriate acute treatment to alleviate the symptoms of pellagra-like rash and neurological dysfunction. *Phenylbutyrate* - **Phenylbutyrate** is used in the treatment of **urea cycle disorders** to reduce ammonia levels by conjugating with glutamine. - This patient's symptoms are not consistent with a urea cycle disorder, and their ammonia levels are not indicated to be elevated. *Tryptophan* - While **tryptophan** malabsorption is the underlying defect leading to niacin deficiency in Hartnup disease, directly supplementing tryptophan is less efficient than supplementing its downstream product, **niacin**. - High doses of tryptophan can also lead to other issues, and providing the readily usable form of the vitamin is more direct and effective. *Pyridoxine* - **Pyridoxine (vitamin B6)** is a coenzyme involved in many metabolic pathways, including amino acid metabolism, but it is not directly indicated for Hartnup disease. - Deficiencies in pyridoxine typically present with different neurological and dermatological symptoms, such as **sideroblastic anemia** or **peripheral neuropathy**. *Tyrosine* - **Tyrosine** is a non-essential amino acid that is a precursor to neurotransmitters and thyroid hormones. - While it is a neutral amino acid, its malabsorption in Hartnup disease does not directly lead to the pellagra-like symptoms, and supplementation with tyrosine itself is not the primary treatment.
Question 14: A 4-day-old boy is brought to the physician because of somnolence, poor feeding, and vomiting after his first few breast feedings. He appears lethargic. His respiratory rate is 73/min. Serum ammonia is markedly increased. Genetic analysis shows deficiency in N-acetylglutamate synthase. The activity of which of the following enzymes is most likely directly affected by this genetic defect?
- A. Ornithine translocase
- B. Carbamoyl phosphate synthetase I (Correct Answer)
- C. Argininosuccinase
- D. Argininosuccinate synthetase
- E. Arginase
Explanation: ***Carbamoyl phosphate synthetase I*** - **N-acetylglutamate** (NAG) is an essential allosteric activator of **carbamoyl phosphate synthetase I (CPS I)**, the rate-limiting enzyme of the urea cycle. - A deficiency in **N-acetylglutamate synthase** directly leads to a lack of NAG, significantly impairing CPS I activity and causing severe hyperammonemia. *Ornithine translocase* - This enzyme is responsible for transporting **ornithine** into the mitochondria for the urea cycle. - While a defect in **ornithine translocase** also causes hyperammonemia, it is due to accumulation of ornithine and upstream substrates, not a defect in N-acetylglutamate synthase. *Argininosuccinase* - Also known as **argininosuccinate lyase**, this enzyme cleaves argininosuccinate into arginine and fumarate. - A deficiency would lead to accumulation of **argininosuccinate**, and while it is a urea cycle disorder, it is not directly affected by N-acetylglutamate synthase deficiency. *Argininosuccinate synthetase* - This enzyme catalyzes the condensation of **citrulline** and **aspartate** to form argininosuccinate. - A defect in **argininosuccinate synthetase** causes citrullinemia but is not directly regulated by N-acetylglutamate. *Arginase* - **Arginase** is the final enzyme in the urea cycle, hydrolyzing arginine to form urea and ornithine. - A deficiency would lead to hyperargininemia, which typically presents later in childhood and is not directly affected by N-acetylglutamate.
Question 15: A 2-day-old male infant is brought to the emergency department by ambulance after his parents noticed that he was convulsing and unresponsive. He was born at home and appeared well initially; however, within 24 hours he became increasingly irritable and lethargic. Furthermore, he stopped feeding and began to experience worsening tachypnea. This continued for about 6 hours, at which point his parents noticed the convulsions and called for an ambulance. Laboratories are obtained with the following results: Orotic acid: 9.2 mmol/mol creatinine (normal: 1.4-5.3 mmol/mol creatinine) Ammonia: 135 µmol/L (normal: < 50 µmol/L) Citrulline: 2 µmol/L (normal: 10-45 µmol/L) Which of the following treatments would most likely be beneficial to this patient?
- A. Galactose avoidance
- B. Aspartame avoidance
- C. Benzoate administration (Correct Answer)
- D. Uridine administration
- E. Fructose avoidance
Explanation: ***Benzoate administration*** - This patient presents with hyperammonemia (135 µmol/L), elevated orotic acid (9.2 mmol/mol creatinine), and **low citrulline (2 µmol/L)**, which is the classic triad for **ornithine transcarbamylase (OTC) deficiency**. - The low citrulline distinguishes OTC deficiency from other urea cycle defects, while elevated orotic acid results from accumulation of carbamoyl phosphate that gets shunted into pyrimidine synthesis. - **Sodium benzoate** is a nitrogen scavenger that conjugates with glycine to form hippurate, which is excreted renally, providing an alternative pathway for nitrogen disposal and reducing toxic ammonia levels. - This is a life-saving acute treatment for hyperammonemia in urea cycle disorders. *Galactose avoidance* - This is the treatment for **galactosemia**, a disorder of galactose metabolism caused by galactose-1-phosphate uridyltransferase deficiency. - Galactosemia presents with hepatomegaly, jaundice, cataracts, intellectual disability, and hypoglycemia after milk feeding. - The patient's hyperammonemia and elevated orotic acid pattern is incompatible with galactosemia. *Aspartame avoidance* - This is relevant for **phenylketonuria (PKU)** dietary management, as aspartame contains phenylalanine. - PKU presents with developmental delay, intellectual disability, musty odor, and eczema, with elevated phenylalanine levels. - Ammonia and orotic acid are normal in PKU, making this diagnosis inconsistent with the lab findings. *Uridine administration* - **Uridine** treats **hereditary orotic aciduria** (UMP synthase deficiency), which presents with megaloblastic anemia, growth retardation, and developmental delays. - While orotic acid is elevated in both conditions, hereditary orotic aciduria has **normal ammonia** and the primary pathology is impaired pyrimidine synthesis, not ammonia disposal. - This patient's life-threatening hyperammonemia requires immediate nitrogen scavenging, which uridine does not provide. *Fructose avoidance* - This treats **hereditary fructose intolerance** (aldolase B deficiency), which causes hypoglycemia, vomiting, hepatomegaly, and jaundice after fructose ingestion. - The presentation is triggered by dietary fructose exposure and does not cause hyperammonemia or elevated orotic acid. - The patient's metabolic profile is inconsistent with a fructose metabolism disorder.
Question 16: You are examining a 3-day-old newborn who was delivered vaginally without any complications. The newborn presents with vomiting, hyperventilation, lethargy, and seizures. Blood work demonstrates hyperammonemia, elevated glutamine levels, and decreased blood urea nitrogen. A CT scan demonstrates cerebral edema. Defects in which of the following enzymes would result in a clinical presentation similar to this infant?
- A. Carbamoyl phosphate synthetase I (Correct Answer)
- B. Homogentisate oxidase
- C. Cystathionine synthase
- D. Branched-chain ketoacid dehydrogenase
- E. Phenylalanine hydroxylase
Explanation: **Carbamoyl phosphate synthetase I** - **Carbamoyl phosphate synthetase I (CPSI)** deficiency is a severe **urea cycle disorder** that typically presents in the neonatal period with **hyperammonemia**, **vomiting**, **lethargy**, **seizures**, and **hyperventilation**. - The enzyme CPSI catalyzes the first step of the urea cycle, which is crucial for detoxifying ammonia, leading to **elevated glutamine** and **decreased blood urea nitrogen** when defective. *Homogentisate oxidase* - Deficiency in **homogentisate oxidase** causes **alkaptonuria**, a disorder of tyrosine metabolism. - This condition is characterized by **dark urine** upon standing, **ochronosis** (bluish-black discoloration of cartilage and connective tissue later in life), and **arthropathy**, not hyperammonemia or acute neonatal crisis. *Cystathionine synthase* - A defect in **cystathionine synthase** leads to **homocystinuria**, an inherited disorder of methionine metabolism. - Symptoms include **ectopia lentis**, **skeletal abnormalities**, **thromboembolic events**, and **developmental delay**, not acute neonatal hyperammonemic encephalopathy. *Branched-chain ketoacid dehydrogenase* - Deficiency in **branched-chain ketoacid dehydrogenase** causes **maple syrup urine disease (MSUD)**, a disorder of branched-chain amino acid metabolism. - While it can present with vomiting, lethargy, and seizures in neonates, it is characterized by a distinctive **maple syrup odor** in urine and elevated branched-chain amino acids, not hyperammonemia and low BUN. *Phenylalanine hydroxylase* - A deficiency in **phenylalanine hydroxylase** causes **phenylketonuria (PKU)**, an amino acid metabolism disorder. - PKU typically presents with intellectual disability, seizures, and a musty odor if untreated, but generally does not manifest as an acute neonatal crisis with hyperammonemia, as seen in urea cycle defects.
Practice by Chapter
Overview and purpose of urea cycle
Practice Questions
Urea cycle reactions and enzymes
Practice Questions
Nitrogen sources and transport forms
Practice Questions
Compartmentalization between mitochondria and cytosol
Practice Questions
Energy requirements of urea cycle
Practice Questions
Regulation of urea cycle
Practice Questions
Integration with TCA cycle
Practice Questions
Hyperammonemia causes and effects
Practice Questions
Urea cycle disorders
Practice Questions
Alternative nitrogen excretion pathways
Practice Questions
Diagnostic markers of urea cycle function
Practice Questions
Want unlimited practice?
Get full access to all questions, explanations, and performance tracking.
Start For Free