Purine/Pyrimidine Metabolism

Question 1

Lesh-Nyhan Syndrome (LNS)

Answer 1

Cause: Deficiency or defect in the Hypoxanthine/Guanine Phosphoribosyltransferase (HGPRT) enzyme (X-Linked)
Result: No GMP/AMP via salvage > no inhibition on de nono synthesis & inc PRPP >
Sx: Uric acid (gout & renal stones[urolithiasis]), orange crystals in baby’s urine, Behavioral defects: Self-mutilation (lip biting), Motor defects (inc tonicity), Cognitive defects (retardation)
Tx: No Tx for neurological defects

Question 2

Gout

Answer 2

Cause: Elevated levels of Uric Acid
Result: Caused by:
OVERPRODUCTION
Idiopathic, Enzyme deficiency > increase in purine synthesis or red excretionl (mut. PRPP Synthetase > no inhibition
•2dary build (drugs) (i.e. chemotherapy) or diseases (myeloproliferative disorders)
• HGPRT def (Lesch Nyhan)

UNDERSECRETION of uric acid
• common, Inherited, Renal disease, Lactic Acidosis, Thiazide diuretics
Sx: Uric acid in joints, inf arthritis, renal uric acid stones, tophi (mono-Na cyrstals)
Tx: anti inf drugs, inc uric exc, Allopurinol (red prod), less meat, less diary fat
Dx: High serum uric acid & needle-like monosodium urate crystals in joint fluid

Question 3

ADA Deficiency (SCID or Severe Combined Immunodeficiency)

Answer 3

Cause: def in AMP Deaminase
Result: no AMP > IMP > no uric acid. AMP > dATP > inhibits ribonucleotide reductase > no dNTPs.
Sx: dec T, B and NK cells, immunity suppressed > susceptible to infections
Tx: Bone marrow transplant or enzyme replacement therapy
Dx: Diagnosed in childhood

Question 4

Orotic Aciduria

Answer 4

Cause: Def UMP Synthase enzyme, either Orotate Phosphoribosyl Transferase OR OMP Decarboxylase
Result: Build up of Orotic Acid
Sx: Metabolic acidosis, lots orotic acid in urine, Abnormal growth, Megaloblastic anemia, Similar symptoms to Hyperammonaemia II (no high serum NH3)
Tx: Dietary Uridine (bypass the de novo pathway)
Keywords: Acquired form (cancer) treated with a pyrimidine analog. + rare genetic form

Question 5

Purine Nucleotide Phosphorylase Deficiency

Answer 5

Cause: no Hypoxanthine or Guanine from Inosine/Guanosine respectively
Result: •Patient is immunocompromised, T-cells are affected but NOT B-cells.