Case Scenario 1:
A 50-year-old man presents to the clinic with severe pain, redness, and swelling of the big toe that started suddenly at night. On examination, the joint is tender and warm. Laboratory findings show elevated serum uric acid levels.
a) State the probable diagnosis. What is its biochemical basis?
b) Explain the metabolic pathway of uric acid formation.
c) How do defects in purine metabolism lead to hyperuricemia and gout?
Answer:
a) Probable Diagnosis is Gout and its biochemical basis:
- Gout is a disorder of purine metabolism characterized by deposition of monosodium urate crystals in joints and tissues, leading to inflammation (arthritis).
- It occurs due to hyperuricemia (↑ serum uric acid > 7 mg/dL), which may result from:
- Overproduction of uric acid (increased purine degradation).
- Decreased excretion of uric acid by kidneys.
- b) Metabolic pathway of uric acid formation:
Purine nucleotide degradation pathway:
- Purine nucleotides (AMP, GMP) → dephosphorylated to nucleosides (adenosine, guanosine).
- Adenosine → inosine → hypoxanthine → xanthine → uric acid (by xanthine oxidase).
- Guanosine → guanine → xanthine → uric acid.
- Uric acid is normally excreted in urine.
- c) Defects in purine metabolism leading to gout:
| Mechanism | Examples |
| Overproduction of uric acid | Increased PRPP synthetase activity → ↑ purine synthesis. |
| HGPRT deficiency (Lesch-Nyhan syndrome) → impaired salvage, ↑ degradation. | |
| High cell turnover (leukemia, psoriasis) → ↑ purine breakdown. | |
| Decreased excretion of uric acid | Renal insufficiency, use of diuretics, alcohol consumption. |
Case Scenario 2:
A 2-year-old boy is brought to the pediatrician with delayed milestones, involuntary movements, and repeated episodes of biting his lips and fingers. On examination, he has signs of self-mutilation and hyperuricemia is detected on laboratory tests. He is diagnosed with Lesch-Nyhan syndrome.
a) What is Lesch-Nyhan syndrome and what is its biochemical defect?
b) Describe the normal purine salvage pathway and explain how its defect leads to the features of Lesch-Nyhan syndrome.
c) What are the clinical manifestations of this disorder and their biochemical basis?
Answer
- a) Lesch-Nyhan syndrome and its biochemical defect:
- Lesch-Nyhan syndrome is a rare X-linked recessive disorder of purine metabolism.
- It is caused by a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), an enzyme of the purine salvage pathway.
- The defect leads to overproduction of uric acid and neurological symptoms.
- b) Normal purine salvage pathway & consequences of HGPRT deficiency:
Normal salvage pathway:
- Hypoxanthine + PRPP → IMP (by HGPRT).
- Guanine + PRPP → GMP (by HGPRT).
- This pathway conserves purines and reduces de novo synthesis.
In HGPRT deficiency:
- Hypoxanthine & guanine cannot be salvaged → degraded to uric acid → hyperuricemia.
- Accumulated PRPP & decreased IMP/GMP → stimulates de novo purine synthesis, worsening uric acid overproduction.
- Neurological abnormalities are thought to result from impaired purine metabolism in the brain.
- c) Clinical manifestations & biochemical basis:
| Manifestation | Biochemical Basis |
| Hyperuricemia & gout | Increased degradation of purines to uric acid. |
| Self-mutilation (biting lips & fingers) | Neurological dysfunction due to purine imbalance in CNS. |
| Neurological symptoms | Intellectual disability, choreoathetosis, spasticity —defective purine recycling. |
Case Scenario 3:
A 4-year-old girl presents with megaloblastic anemia, failure to thrive, and a history of worsening anemia despite treatment with vitamin B12, folic acid, and pyridoxine. She has a low RBC count (2.55 million/cmm) and hemoglobin of 6 g/dL. Examination of her urine reveals a large amount of orotic acid crystals (~1500 mg/day).
- a) What is the most probable diagnosis in this child?
b) What is the biochemical defect and which enzyme is deficient?
c) Explain the pathway of pyrimidine synthesis and the step that is blocked in this disorder.
Answer
- a) Diagnosis: The most probable diagnosis is orotic aciduria, a rare inherited disorder of pyrimidine metabolism.
- Characterized by:
- Megaloblastic anemia not responding to B12/folate.
- Growth retardation & failure to thrive.
- Excessive orotic acid excretion in urine with crystalluria.
- b) Biochemical defect and deficient enzyme:
The defect is in de novo pyrimidine synthesis pathway, specifically:
- Deficiency of uridine monophosphate synthase (UMPS), which has two enzymatic activities:
- Orotate phosphoribosyltransferase (OPRT): converts orotate + PRPP → orotidine monophosphate (OMP).
- OMP decarboxylase: converts OMP → uridine monophosphate (UMP).
- This block leads to accumulation of orotic acid, which is excreted in urine.
- c) Pyrimidine synthesis pathway & block:
| Step in pathway | Enzyme | Effect of defect |
| Carbamoyl phosphate + aspartate → orotic acid | (normal pathway) | Normal up to orotic acid. |
| Orotic acid + PRPP → OMP | Orotate phosphoribosyltransferase | Blocked in orotic aciduria. |
| OMP → UMP | OMP decarboxylase | Also blocked in orotic aciduria. |
- As a result, UMP and subsequent pyrimidines (CMP, TMP) are deficient → impaired DNA synthesis → megaloblastic anemia.
- UMP deficiency removes feedback inhibition, increasing orotic acid production.