Inborn Errors of Amino Acid Metabolism — MCQs
Which enzyme deficiency leads to hyperhomocysteinemia?
Ammonia causes depletion of which of the following in TCA cycle?
Hyperammonaemia inhibits the TCA cycle by depleting which of the following?
An infant presented with vomiting, malnutrition, blue eyes, blonde hair & fair skin. On investigation, Guthrie test was positive. All are true regarding this disease EXCEPT:
In a patient with maple syrup urine disease, all of the following amino acids should be restricted in diet except?
A newborn presents with metabolic acidosis, high ammonia, and orotic acid in urine. Which enzyme deficiency is most likely?
A 5 year old child was brought to the physician with a history of black urine. There is no history of fever or any other complaints. There is no growth retardation and all the developmental milestones are normal. The child is suspected to have an enzyme defect for metabolism of an aromatic amino acid. What is the enzyme deficient
Most common enzyme deficiency in the urea cycle is:
A 45-year-old patient presents with joint pain and weakness and is known to have homocystinuria. Which vitamin is required in the treatment?
A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?
Inborn Errors of Amino Acid Metabolism Indian Medical PG Practice Questions and MCQs
Question 1: Which enzyme deficiency leads to hyperhomocysteinemia?
- A. Phenylalanine hydroxylase
- B. Glucose-6-phosphate dehydrogenase
- C. Galactose-1-phosphate uridyltransferase
- D. Methionine synthase (Correct Answer)
Explanation: ***Methionine synthase*** - **Methionine synthase** (also known as homocysteine methyltransferase) is critical for converting **homocysteine** back to **methionine** using **methyltetrahydrofolate (MTHF)** as a methyl donor. - A deficiency in this enzyme, or its cofactors like **vitamin B12** or **folate**, leads to the accumulation of homocysteine in the blood, resulting in **hyperhomocysteinemia**. *Phenylalanine hydroxylase* - Deficiency in **phenylalanine hydroxylase** causes **phenylketonuria (PKU)**, characterized by the accumulation of **phenylalanine** and its metabolites, not homocysteine. - This enzyme is responsible for converting **phenylalanine** to **tyrosine**. *Glucose-6-phosphate dehydrogenase* - Deficiency in **glucose-6-phosphate dehydrogenase (G6PD)** leads to **hemolytic anemia** in response to oxidative stress, as it impairs the production of **NADPH** in the **pentose phosphate pathway**. - It is not directly involved in homocysteine metabolism. *Galactose-1-phosphate uridyltransferase* - Deficiency in **galactose-1-phosphate uridyltransferase** is the cause of **classic galactosemia**, leading to the accumulation of **galactose-1-phosphate** and toxicity. - This enzyme is crucial for the metabolism of **galactose**, not homocysteine.
Question 2: Ammonia causes depletion of which of the following in TCA cycle?
- A. Malate
- B. Oxaloacetate
- C. Alpha-ketoglutarate (Correct Answer)
- D. Fumarate
Explanation: ***Alpha-ketoglutarate*** - Ammonia is detoxified in the brain by conversion to **glutamine**, a process that consumes **alpha-ketoglutarate** in the glutamate dehydrogenase reaction (alpha-ketoglutarate + NH3 + NADH <=> glutamate + NAD+). - The depletion of **alpha-ketoglutarate** in the TCA cycle impairs cellular respiration and ATP production, contributing to the neurological dysfunction seen in hyperammonemia. *Malate* - While malate is a component of the TCA cycle, its depletion is not a direct consequence of ammonia detoxification. - Ammonia metabolism primarily impacts the availability of alpha-ketoglutarate through the synthesis of glutamate and glutamine. *Oxaloacetate* - Although **oxaloacetate** is a key intermediate in the TCA cycle, its levels are not directly depleted by ammonia metabolism. - **Oxaloacetate** can be replenished through anaplerotic reactions, even if the TCA cycle is slightly inhibited due to alpha-ketoglutarate depletion. *Fumarate* - **Fumarate** is an intermediate of the TCA cycle and is not directly consumed or depleted by the ammonia detoxification pathway. - Its levels would only indirectly be affected if the overall flux of the TCA cycle is significantly reduced due to depletion of other intermediates.
Question 3: Hyperammonaemia inhibits the TCA cycle by depleting which of the following?
- A. succinate
- B. α-ketoglutarate (Correct Answer)
- C. malate
- D. fumarate
Explanation: ***a keto glutarate*** - **Hyperammonemia** leads to the depletion of **α-ketoglutarate** through its amination to form **glutamate** by glutamate dehydrogenase and subsequently glutamine by glutamine synthetase. - The removal of **α-ketoglutarate** from the TCA cycle impairs its ability to produce energy and essential intermediates, contributing to neurological dysfunction in hyperammonemia. *succinate* - **Succinate** is an intermediate in the TCA cycle, but its depletion is not the primary mechanism by which hyperammonemia inhibits the cycle. - The direct consumption of **α-ketoglutarate** for ammonia detoxification is the more direct and significant impact. *malate* - **Malate** is another intermediate in the TCA cycle but is downstream from **α-ketoglutarate**. - Its depletion is a consequence of overall TCA cycle inhibition, not the initial cause mediated by hyperammonemia. *fumarate* - **Fumarate** is also a TCA cycle intermediate and is produced after succinate. - Its levels would be affected by the overall inhibition of the cycle, but it is not the direct target or substrate for ammonia detoxification that depletes the cycle.
Question 4: An infant presented with vomiting, malnutrition, blue eyes, blonde hair & fair skin. On investigation, Guthrie test was positive. All are true regarding this disease EXCEPT:
- A. Phenyl acetate positive in urine
- B. Mental retardation is present
- C. Hypopigmentation due to tryptophan deficiency (Correct Answer)
- D. Due to PAH enzyme defect
Explanation: ***Hypopigmentation due to tryptophan deficiency*** - The characteristic **hypopigmentation** (fair skin, blonde hair, blue eyes) in **phenylketonuria (PKU)** is due to **tyrosine deficiency**, not tryptophan deficiency. - **Phenylalanine hydroxylase (PAH)** deficiency leads to accumulation of phenylalanine, which cannot be converted to **tyrosine**. - **Tyrosine** is the precursor for **melanin synthesis** via the enzyme **tyrosinase**, so tyrosine deficiency results in decreased melanin production and hypopigmentation. *Phenyl acetate positive in urine* - In **phenylketonuria (PKU)**, **phenylalanine** accumulates and is shunted to alternative metabolic pathways, leading to the production and excretion of **phenylacetate, phenylpyruvate, and phenyllactate** in the urine. - The presence of these metabolites gives the urine a characteristic **mousey or musty odor**. *Mental retardation is present* - If **phenylketonuria (PKU)** is left untreated, the accumulation of **phenylalanine** is neurotoxic and leads to severe, **irreversible intellectual disability** and **developmental delay**. - Early detection through newborn screening (the **Guthrie test** detects elevated blood phenylalanine) and dietary phenylalanine restriction are crucial to prevent this outcome. *Due to PAH enzyme defect* - **Phenylketonuria (PKU)** is primarily caused by a deficiency in the enzyme **phenylalanine hydroxylase (PAH)**, which is responsible for converting phenylalanine to tyrosine. - This **autosomal recessive genetic disorder** leads to the accumulation of phenylalanine in the blood and tissues, causing the clinical manifestations.
Question 5: In a patient with maple syrup urine disease, all of the following amino acids should be restricted in diet except?
- A. Methionine (Correct Answer)
- B. Isoleucine
- C. Leucine
- D. Valine
Explanation: ***Methionine*** - **Maple syrup urine disease (MSUD)** is a disorder affecting the metabolism of **branched-chain amino acids (BCAAs)**: leucine, isoleucine, and valine. - Therefore, methionine, which is not a BCAA, typically does not need to be restricted and is, in fact, an **essential amino acid** crucial for protein synthesis. *Isoleucine* - **Isoleucine** is a branched-chain amino acid (BCAA) whose metabolism is impaired in MSUD due to a deficiency in **branched-chain alpha-keto acid dehydrogenase complex**. - Accumulation of isoleucine and its corresponding alpha-keto acid is toxic and must be **restricted in the diet**. *Leucine* - **Leucine** is another branched-chain amino acid (BCAA) that cannot be properly metabolized in MSUD. - High levels of leucine and its metabolites are particularly **neurotoxic** and contribute to the characteristic neurological symptoms, necessitating strict dietary restriction. *Valine* - **Valine** is the third branched-chain amino acid (BCAA) whose breakdown is defective in MSUD. - Dietary restriction of valine is essential to prevent its accumulation, which can lead to metabolic crises and **developmental delays**.
Question 6: A newborn presents with metabolic acidosis, high ammonia, and orotic acid in urine. Which enzyme deficiency is most likely?
- A. Arginase
- B. Glutamine synthetase
- C. Ornithine transcarbamylase (Correct Answer)
- D. CPS-1
Explanation: ***Ornithine transcarbamylase*** - Deficiency of **ornithine transcarbamylase (OTC)**, a key enzyme in the urea cycle, leads to the accumulation of **carbamoyl phosphate**. - **Carbamoyl phosphate** is then shunted to the pyrimidine synthesis pathway, leading to increased production and excretion of **orotic acid** in the urine, along with **hyperammonemia** and **metabolic acidosis**. *Arginase* - **Arginase deficiency** in the urea cycle primarily causes increased **arginine levels** and **hyperammonemia**, but it does not typically lead to the accumulation of orotic acid. - The effects are often more chronic with gradual onset of symptoms, rather than severe neonatal presentation with orotic aciduria. *Glutamine synthetase* - **Glutamine synthetase** catalyzes the synthesis of glutamine from glutamate and ammonia, playing a crucial role in **ammonia detoxification**. - A deficiency would impair ammonia detoxification and lead to **hyperammonemia**, but it would not directly cause **orotic aciduria**. *CPS-1* - **Carbamoyl phosphate synthetase I (CPS-1)** deficiency is the first step of the urea cycle and leads to severe **hyperammonemia** due to the inability to form carbamoyl phosphate. - Unlike OTC deficiency, **CPS-1 deficiency** does not involve the buildup of carbamoyl phosphate; hence, **orotic acid levels** would be low or normal, not high.
Question 7: A 5 year old child was brought to the physician with a history of black urine. There is no history of fever or any other complaints. There is no growth retardation and all the developmental milestones are normal. The child is suspected to have an enzyme defect for metabolism of an aromatic amino acid. What is the enzyme deficient
- A. Homogentisate dehydrogenase
- B. Homogentistae oxidase (Correct Answer)
- C. Tyrosine Transaminase
- D. Tryptophan Hydroxylase
- E. Phenylalanine Hydroxylase
Explanation: ***Homogentistae oxidase*** - The presentation of a child with **black urine** (alkaptonuria) in the absence of other symptoms is characteristic of a deficiency in **homogentisate oxidase**. - This enzyme is crucial in the catabolism of **tyrosine**, and its deficiency leads to the accumulation of **homogentisic acid**, which oxidizes upon exposure to air, turning urine black. *Homogentisate dehydrogenase* - This enzyme is not a recognized component of the **tyrosine degradation pathway** in humans. - The correct enzyme involved in the breakdown of **homogentisate** is an oxidase, not a dehydrogenase, in this context. *Tyrosine Transaminase* - A deficiency in **tyrosine transaminase** (tyrosinemia type II) would lead to elevated tyrosine levels and typically presents with symptoms affecting the eyes, skin, and intellectual disability, not primarily black urine. - This condition is characterized by **ocular findings** (corneal ulcers), **skin lesions**, and **neurological symptoms**. *Tryptophan Hydroxylase* - This enzyme is involved in the synthesis of **serotonin** and **melatonin** from tryptophan, a different amino acid pathway. - A deficiency or abnormality in **tryptophan hydroxylase** would not cause black urine but could lead to neurological or mood disorders. *Phenylalanine Hydroxylase* - A deficiency in **phenylalanine hydroxylase** causes **phenylketonuria (PKU)**, which affects phenylalanine metabolism, not tyrosine metabolism directly. - PKU typically presents with **intellectual disability**, **musty odor**, **fair skin**, and **seizures** if untreated, not black urine.
Question 8: Most common enzyme deficiency in the urea cycle is:
- A. Ornithine transcarbamoylase (OTC) deficiency (Correct Answer)
- B. Arginase deficiency
- C. Carbamoyl phosphate synthase I deficiency
- D. Argininosuccinate synthetase deficiency
Explanation: ***Ornithine transcarbamoylase (OTC)*** - **OTC deficiency** is the most common and often the most severe inherited disorder of the **urea cycle**, leading to a buildup of ammonia. - It is an **X-linked recessive** disorder, predominantly affecting males, though carrier females can also exhibit symptoms. *Arginase deficiency* - This deficiency affects the final step of the urea cycle, leading to the accumulation of **arginine** and its precursors. - It is less common than OTC deficiency and typically presents with a later onset and milder symptoms. *Carbamoyl phosphate synthase I deficiency* - **CPS I deficiency** is a severe form of urea cycle disorder but is less common than OTC deficiency. - It results in the inability to synthesize **carbamoyl phosphate**, a crucial substrate for the urea cycle, leading to severe hyperammonemia. *Argininosuccinate synthetase deficiency* - This deficiency, also known as **citrullinemia type I**, leads to the accumulation of **citrulline** in the blood. - While it is a significant urea cycle disorder, it is not as frequently encountered as OTC deficiency.
Question 9: A 45-year-old patient presents with joint pain and weakness and is known to have homocystinuria. Which vitamin is required in the treatment?
- A. Vitamin B6 (Correct Answer)
- B. Vitamin B12
- C. Vitamin B7
- D. Vitamin B1
- E. Vitamin B9
Explanation: ***Vitamin B6*** - **Homocystinuria** is often caused by a deficiency in the enzyme **cystathionine beta-synthase**, which requires **pyridoxal phosphate (active form of B6)** as a cofactor. - Supplementation with high-dose **vitamin B6** can help some patients by increasing the residual activity of the enzyme, thereby reducing **homocysteine levels**. - This is the **primary treatment** for **B6-responsive homocystinuria** (approximately 50% of cases respond to B6 therapy). *Vitamin B12* - Vitamin B12 is a cofactor for the enzyme **methionine synthase**, which converts homocysteine back to methionine. - While it plays a role in homocysteine metabolism, **vitamin B6** is typically the primary treatment for homocystinuria caused by **cystathionine beta-synthase deficiency**. *Vitamin B9* - Vitamin B9 (folic acid) works together with **vitamin B12** as a cofactor in the **remethylation pathway** via methionine synthase. - While folate supplementation may help lower homocysteine levels, it is **not the primary treatment** for classical homocystinuria due to cystathionine beta-synthase deficiency. - **Vitamin B6** remains the first-line vitamin therapy for enzyme deficiency-related homocystinuria. *Vitamin B7* - Vitamin B7, or **biotin**, is a cofactor for carboxylase enzymes and is involved in fatty acid synthesis and gluconeogenesis. - It has no direct role in the metabolism of **homocysteine** or the treatment of homocystinuria. *Vitamin B1* - Vitamin B1, or **thiamine**, is essential for carbohydrate metabolism and nerve function. - It is not involved in the metabolic pathways that regulate **homocysteine levels** or the treatment of homocystinuria.
Question 10: A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?
- A. Low-phenylalanine diet (Correct Answer)
- B. Avoidance of ascorbic acid
- C. Vitamin D supplementation
- D. High-protein diet
- E. Tetrahydrobiopterin (BH4) supplementation
Explanation: ***Low-phenylalanine diet*** - The patient's symptoms (developmental delay, musty body odor, fair skin) and high **phenylalanine levels** are classic for **phenylketonuria (PKU)**. - Management primarily involves a strict **low-phenylalanine diet** to prevent further neurological damage. - This is the **cornerstone of PKU management** and must be initiated as early as possible. *Tetrahydrobiopterin (BH4) supplementation* - While **BH4 (sapropterin)** can be beneficial in some patients with **BH4-responsive PKU** (a subset of PKU cases), it is not first-line management. - BH4 testing is performed after diagnosis, but dietary restriction remains the primary treatment. - Not all PKU patients respond to BH4, and it's used as an adjunct, not a replacement for dietary management. *Avoidance of ascorbic acid* - **Ascorbic acid** (vitamin C) is generally not contraindicated in PKU and does not impact phenylalanine metabolism. - This intervention is not relevant to the management of PKU. *Vitamin D supplementation* - While vitamin D supplementation might be necessary for general health, especially in children with restricted diets, it is not the primary treatment for **phenylketonuria (PKU)**. - It does not directly address the elevated phenylalanine levels. *High-protein diet* - A **high-protein diet** would exacerbate the condition, as proteins are a major source of phenylalanine. - This would lead to even higher phenylalanine levels and worsen the symptoms of PKU.
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