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?
Q12
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?
Q13
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?
Q14
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?
Q15
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?
Q16
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?
Q17
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?
Urea cycle US Medical PG Practice Questions and MCQs
Question 11: 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 12: 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 13: 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 14: 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 15: 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 16: 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 17: 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.
