Disorders of Purine and Pyrimidine Metabolism — MCQs
Which vitamin deficiency leads to megaloblastic anemia?
Which of the following statements about carbamoyl phosphate synthase is incorrect?
A 5-year-old presents with intellectual disability, self-mutilation, and hyperuricemia. What enzyme defect is most likely?
Hereditary orotic aciduria Type-I is due to deficiency of?
Inosinic acid is biological precursor of ?
Which molecule provides nitrogen-9 to the purine ring?
A 55-year-old patient with gout has high uric acid levels; which drug should be avoided?
Lesch–Nyhan syndrome is caused by deficiency of which enzyme?
A 6 year old male child presented with deterioration of renal functions. On examination, he is mentally retarded and has got athetosis. There are multiple healed wounds on his body. His mother reassures you that it was as a result of self inflicted injuries. USG showed bilateral renal calculi. Which of the following statements is FALSE regarding the above mentioned condition?
A 7 – year old boy presented with abdominal pain, vomiting, oliguria, and periorbital puffiness following chemotherapy. Investigations reveal hyperuricemia, raised creatinine levels, and hyperkalemia. What is the next best step in the management of this condition ?
Disorders of Purine and Pyrimidine Metabolism Indian Medical PG Practice Questions and MCQs
Question 1: Which vitamin deficiency leads to megaloblastic anemia?
- A. Riboflavin
- B. Folate (Correct Answer)
- C. Vitamin C
- D. Niacin
Explanation: ***Folate*** - **Folate** is essential for DNA synthesis; a deficiency impairs erythrocyte maturation, leading to the production of **large, immature red blood cells** (megaloblasts) [3]. - This vitamin deficiency also presents with symptoms like **fatigue, glossitis**, and neurologic manifestations are absent unlike vitamin B12 deficiency [1]. *Riboflavin* - **Riboflavin (Vitamin B2)** deficiency can cause **normocytic anemia**, but generally not megaloblastic anemia. - Its deficiency is mainly associated with **angular stomatitis, cheilosis**, and ocular symptoms. *Vitamin C* - **Vitamin C** deficiency (scurvy) is associated with impaired collagen synthesis, leading to **gingival bleeding, petechiae**, and poor wound healing. - While it can cause some anemia, it is typically **microcytic** due to impaired iron absorption if it affects iron metabolism, not megaloblastic [2]. *Niacin* - **Niacin (Vitamin B3)** deficiency causes **pellagra**, characterized by the "3 D's": **dermatitis, diarrhea, and dementia**. - It does not directly lead to megaloblastic anemia, as it is not involved in a critical step of DNA synthesis in the same way folate is.
Question 2: Which of the following statements about carbamoyl phosphate synthase is incorrect?
- A. Requires biotin as a cofactor (Correct Answer)
- B. Enzyme found in the cytosol
- C. Enzyme found in mitochondria
- D. Catalyzes a condensation reaction
Explanation: ***Requires biotin as a cofactor*** - This is the **incorrect** statement and therefore the correct answer to this question. - Carbamoyl phosphate synthase (both CPS I and CPS II) does **NOT require biotin** as a cofactor. - Biotin is a cofactor for **carboxylase enzymes** such as pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase. - Carbamoyl phosphate synthase requires **ATP** and **Mg²⁺** but not biotin. *Enzyme found in mitochondria* - This statement is **correct**. - **Carbamoyl phosphate synthase I (CPS I)** is located in the **mitochondrial matrix** and catalyzes the first step of the urea cycle. - CPS I uses free ammonia (NH₃) as the nitrogen source and is activated by N-acetylglutamate. *Enzyme found in the cytosol* - This statement is **correct**. - **Carbamoyl phosphate synthase II (CPS II)** is located in the **cytosol** and is involved in de novo pyrimidine biosynthesis. - CPS II uses the amide nitrogen of glutamine (not free ammonia) as the nitrogen source. *Catalyzes a condensation reaction* - This statement is **correct**. - Both CPS I and CPS II catalyze the condensation of CO₂ (as bicarbonate), ammonia/glutamine, and two molecules of ATP to form carbamoyl phosphate, 2 ADP, and inorganic phosphate. - This is a complex reaction involving phosphorylation and condensation steps.
Question 3: A 5-year-old presents with intellectual disability, self-mutilation, and hyperuricemia. What enzyme defect is most likely?
- A. Adenosine deaminase deficiency
- B. Xanthine oxidase deficiency
- C. Glucose-6-phosphatase deficiency
- D. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (Correct Answer)
Explanation: ***Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)*** - Deficiency of **HGPRT** an enzyme in the **purine salvage pathway** leads to **Lesch-Nyhan syndrome**, characterized by **hyperuricemia**, **self-mutilation**, **intellectual disability**, and **dystonia**. - The accumulation of **uric acid** due to defective salvage leads to the characteristic symptoms. *Adenosine deaminase deficiency* - This deficiency causes **severe combined immunodeficiency (SCID)** due to the accumulation of toxic metabolites in lymphocytes. - It does not typically present with **self-mutilation** or **hyperuricemia**. *Xanthine oxidase deficiency* - This deficiency leads to **xanthinuria**, characterized by **low uric acid levels** and an increased risk of **xanthine kidney stones**. - The clinical presentation does not include **intellectual disability** or **self-mutilation**. *Glucose-6-phosphatase deficiency* - This enzyme deficiency causes **Glycogen Storage Disease Type Ia (von Gierke disease)**, characterized by **hypoglycemia**, **lactic acidosis**, and **hepatomegaly**. - It is not associated with **self-mutilation** or the primary neurological/behavioral features seen in Lesch-Nyhan syndrome.
Question 4: Hereditary orotic aciduria Type-I is due to deficiency of?
- A. Orotate phosphoribosyl transferase
- B. UMP synthase (Correct Answer)
- C. Orotic acid decarboxylase
- D. All of the options
Explanation: ***UMP synthase*** - Hereditary orotic aciduria Type-I is caused by a deficiency of the **bifunctional enzyme UMP synthase** (also called UMP synthase complex). - UMP synthase catalyzes two sequential reactions in the *de novo* pyrimidine synthesis pathway: 1. **OPRT activity**: Converts orotate → orotidine 5'-monophosphate (OMP) 2. **ODC activity**: Converts OMP → uridine 5'-monophosphate (UMP) - This is the **most precise and complete answer** as it identifies the actual enzyme complex that is deficient. - **Clinical features**: Megaloblastic anemia, growth retardation, immunodeficiency; responds to oral uridine supplementation. *Orotate phosphoribosyl transferase* - This represents only **one of the two catalytic activities** of the UMP synthase enzyme (the first step). - While this activity is indeed deficient in Type-I orotic aciduria, naming only this activity is **incomplete** because the enzyme has two functions. - This would be a **partial answer** rather than the complete enzyme name. *Orotic acid decarboxylase* - This represents only **the second catalytic activity** of the UMP synthase enzyme (converts OMP to UMP). - Like OPRT, this activity is also deficient, but naming only this component is **incomplete**. - **Type II orotic aciduria** (extremely rare) involves isolated ODC deficiency without OPRT deficiency. *All of the options* - While technically both OPRT and ODC activities are affected in Type-I orotic aciduria, the **standard nomenclature** refers to the deficient enzyme as **"UMP synthase"** - the name of the complete bifunctional enzyme. - In medical terminology and examination context, we identify enzyme deficiencies by the **name of the enzyme complex**, not by listing all its individual catalytic activities. - Therefore, **"UMP synthase"** is the single most accurate and complete answer.
Question 5: Inosinic acid is biological precursor of ?
- A. Purines and thymine
- B. Orotic acid and uridylic acid
- C. Adenylic acid and guanylic acid (Correct Answer)
- D. Uracil and thymine
Explanation: ***Adenylic acid and guanylic acid*** - Inosinic acid (IMP) is a **key intermediate** in the **de novo purine synthesis pathway**. - It serves as the direct precursor for the synthesis of **adenylic acid (AMP)** and **guanylic acid (GMP)**, which are components of DNA and RNA. *Purines and thymine* - While inosinic acid is a precursor to purines, it is **not a precursor to thymine**. - Thymine is a **pyrimidine base** and is synthesized through a separate pathway. *Orotic acid and uridylic acid* - **Orotic acid** is an intermediate in **pyrimidine synthesis**, not purine synthesis. - **Uridylic acid (UMP)** is also a pyrimidine nucleotide, and its synthesis pathway involves orotic acid, not inosinic acid. *Uracil and thymine* - **Uracil** and **thymine** are pyrimidine bases, and their synthesis pathways are distinct from the purine synthesis pathway involving inosinic acid. - Inosinic acid is exclusively involved in the synthesis of **purine nucleotides**.
Question 6: Which molecule provides nitrogen-9 to the purine ring?
- A. Glycine (Correct Answer)
- B. Glutamine
- C. CO2
- D. Aspartate
Explanation: ***Glycine*** - Glycine provides the **amino nitrogen at position 9** (N-9) of the purine ring. - It also contributes **carbon atoms at positions 4 and 5** (C-4, C-5) and the **nitrogen at position 7** (N-7). - Glycine is incorporated as an intact molecule early in purine synthesis, forming the **glycinamide ribonucleotide** intermediate. *Glutamine* - The **amide nitrogen** of glutamine donates nitrogen atoms at **positions 3 only** (N-3), not position 9. - This donation occurs during the formation of **formylglycinamide ribonucleotide** (FGAR) from FGAM. - Glutamine contributes two amide nitrogen atoms during purine synthesis, but N-9 is not one of them. *Aspartate* - Aspartate contributes the **nitrogen atom at position 1** (N-1) of the purine ring. - It is incorporated into the intermediate **5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide** (SACAIR). - The nitrogen from aspartate remains after fumarate is released. *CO2* - Carbon dioxide (CO2) contributes the **carbon atom at position 6** (C-6) of the purine ring. - It provides a **carbon source** for ring formation, not nitrogen atoms. - CO2 is incorporated during the carboxylation step in the purine biosynthetic pathway.
Question 7: A 55-year-old patient with gout has high uric acid levels; which drug should be avoided?
- A. Probenecid
- B. Allopurinol
- C. Febuxostat
- D. Aspirin (Correct Answer)
Explanation: ***Aspirin*** - High doses of **aspirin** can increase serum uric acid levels, which is detrimental for a patient with gout desiring to lower uric acid. - While low-dose aspirin (<300 mg/day) might have a minor uricosuric effect, higher doses are **anti-uricosuric** and should generally be avoided in gout. *Probenecid* - **Probenecid** is a **uricosuric agent** that helps excrete uric acid via the kidneys, making it beneficial for patients who underexcrete uric acid. - It works by inhibiting the reabsorption of uric acid in the renal tubules, thereby lowering serum uric acid levels. *Allopurinol* - **Allopurinol** is a **xanthine oxidase inhibitor** that reduces the production of uric acid by blocking the enzyme responsible for its synthesis. - It is a cornerstone treatment for chronic gout to lower uric acid levels and prevent recurrent attacks. *Febuxostat* - **Febuxostat** is also a **xanthine oxidase inhibitor**, similar to allopurinol, used to reduce uric acid production. - It is often considered an alternative for patients who cannot tolerate allopurinol or who do not achieve target uric acid levels with allopurinol.
Question 8: Lesch–Nyhan syndrome is caused by deficiency of which enzyme?
- A. Orotate Phosphoribosyltransferase
- B. Uracil phosphoribosyltransferase
- C. Quinolinate Phosphoribosyltransferase
- D. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (Correct Answer)
Explanation: ***Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)*** - Lesch-Nyhan syndrome is an **X-linked recessive disorder** caused by a defect in the **purine salvage pathway**, specifically the enzyme **HGPRT**. - This deficiency leads to an accumulation of **uric acid** and causes severe neurological symptoms, intellectual disability, and self-mutilating behavior. *Orotate Phosphoribosyltransferase* - Deficiency in **orotate phosphoribosyltransferase**, along with **UMP synthase**, is associated with **hereditary orotic aciduria**. - This condition presents with megaloblastic anemia, growth retardation, and increased excretion of orotic acid, not the neurological symptoms of Lesch-Nyhan syndrome. *Uracil phosphoribosyltransferase* - This enzyme is involved in the **pyrimidine salvage pathway**, converting uracil to UMP. - While important for nucleotide metabolism, its deficiency is not directly linked to Lesch-Nyhan syndrome. *Quinolinate Phosphoribosyltransferase* - **Quinolinate phosphoribosyltransferase (QPRT)** is involved in the **de novo synthesis of NAD+** from quinolinate. - Deficiencies or dysregulation of this enzyme are not associated with Lesch-Nyhan syndrome.
Question 9: A 6 year old male child presented with deterioration of renal functions. On examination, he is mentally retarded and has got athetosis. There are multiple healed wounds on his body. His mother reassures you that it was as a result of self inflicted injuries. USG showed bilateral renal calculi. Which of the following statements is FALSE regarding the above mentioned condition?
- A. Allopurinol may be used in treating the condition
- B. Kelley - Seegmiller syndrome is a milder variant of the condition
- C. Hyperuricemia is a characteristic feature of the condition
- D. It is an autosomal recessive condition (Correct Answer)
- E. HGPRT enzyme deficiency is the underlying biochemical defect
Explanation: ***It is an autosomal recessive condition*** - **Lesch-Nyhan syndrome** is an **X-linked recessive disorder**, meaning it primarily affects males and is inherited through the mother. - The gene responsible for **hypoxanthine-guanine phosphoribosyltransferase (HGPRT)** deficiency is located on the X chromosome. *Allopurinol may be used in treating the condition* - **Allopurinol** can be used to treat the **hyperuricemia** and prevent **renal calculi** and **gout** in patients with Lesch-Nyhan syndrome. - It works by inhibiting **xanthine oxidase**, thereby reducing uric acid production. *Kelley - Seegmiller syndrome is a milder variant of the condition* - **Kelley-Seegmiller syndrome** is indeed a milder variant of **Lesch-Nyhan syndrome**, characterized by partial rather than complete deficiency of **HGPRT** activity. - Patients with Kelley-Seegmiller syndrome typically present with **hyperuricemia** and **gout-like symptoms** but without the severe neurological manifestations such as **cognitive impairment** and **self-mutilation**. *Hyperuricemia is a characteristic feature of the condition* - **Hyperuricemia** is a hallmark feature of **Lesch-Nyhan syndrome** due to the deficiency of **HGPRT**, leading to overproduction and decreased salvage of purines. - This elevated uric acid level can cause **gouty arthritis** and **renal calculi**, contributing to renal dysfunction. *HGPRT enzyme deficiency is the underlying biochemical defect* - **Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)** deficiency is the fundamental enzyme defect in **Lesch-Nyhan syndrome**. - This enzyme is crucial for the **purine salvage pathway**, and its absence leads to overproduction of uric acid and accumulation of purine precursors that contribute to the neurological manifestations.
Question 10: A 7 – year old boy presented with abdominal pain, vomiting, oliguria, and periorbital puffiness following chemotherapy. Investigations reveal hyperuricemia, raised creatinine levels, and hyperkalemia. What is the next best step in the management of this condition ?
- A. Hydration (Correct Answer)
- B. Probenecid
- C. Allopurinol
- D. Rasburicase
Explanation: ***Hydration*** - This patient presents with **tumor lysis syndrome (TLS)**, characterized by rapid tumor cell breakdown releasing intracellular contents (uric acid, potassium, phosphate) following chemotherapy. - **Aggressive intravenous hydration** is the **first-line and most critical initial step** in TLS management, aiming to maintain urine output at 2-3 mL/kg/hour to prevent uric acid crystal precipitation in renal tubules. - Even with oliguria present, optimizing intravascular volume and renal perfusion is essential before other interventions can be effective - without adequate hydration, rasburicase-generated allantoin cannot be excreted. - **Hydration forms the foundation** upon which all other TLS therapies depend, making it the priority "next best step." *Probenecid* - **Probenecid** is a uricosuric agent that increases renal uric acid excretion by blocking tubular reabsorption. - It is **contraindicated in tumor lysis syndrome** as it increases uric acid concentration in renal tubules, potentially worsening uric acid nephropathy and crystal formation. *Allopurinol* - **Allopurinol** is a xanthine oxidase inhibitor that prevents new uric acid formation by blocking purine metabolism. - While valuable for **prophylaxis** in high-risk patients before chemotherapy, it **does not reduce existing hyperuricemia** in established TLS. - Less effective than rasburicase for treating active, symptomatic hyperuricemia. *Rasburicase* - **Rasburicase** is a recombinant urate oxidase that rapidly converts uric acid to allantoin (5-10 times more soluble). - Highly effective for **treating established hyperuricemia** in TLS and often used in severe cases. - However, as the "next best step," **hydration must be established first** to ensure adequate renal perfusion and allow excretion of metabolites - rasburicase is typically administered **after or concurrent with** hydration initiation. - In clinical practice, both are often started together, but hydration is the foundational intervention.
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