ENZYME · DISORDER
DEFECT · BUILDUP
FEATURES
CLUE · TREATMENT
Hypoxanthine → IMP, guanine → GMP using PRPP
When absent, bases go to uric acid and PRPP rises (more de novo synthesis)
Partial deficiency (Kelley-Seegmiller) → gout only
Lesch-Nyhan syndrome
X-linked recessive
Absent HGPRT → hyperuricemia
Boy with self-mutilation (lips, fingers), dystonia, intellectual disability, gout, orange "sand" in diaper (urate crystals), kidney stones
Allopurinol / febuxostat for uric acid (not neuro features)
Adenosine deaminase deficiency
autosomal recessive
ADA converts adenosine → inosine; without it dATP accumulates → inhibits ribonucleotide reductase → lymphocyte toxicity
SCID: absent T, B and NK function; recurrent infections, failure to thrive, absent thymic shadow
Gene therapy, enzyme replacement, stem-cell transplant
Purine nucleoside phosphorylase deficiency
dGTP accumulates → T-cell toxicity
T-cell immunodeficiency with neurologic signs, low uric acid
Contrast ADA (T and B)
Orotic aciduria
autosomal recessive
UMP synthase defect → orotic acid can't become UMP
Megaloblastic anemia unresponsive to B12 or folate, failure to thrive, orotic acid in urine, no hyperammonemia
Uridine (or uridine triacetate) bypasses the block
OTC deficiency (contrast)
Carbamoyl phosphate spills into pyrimidine pathway → orotic acid
↑ Orotic acid with hyperammonemia, no megaloblastic anemia
See 9.01
Hypoxanthine → xanthine → uric acid
Blocked by allopurinol, febuxostat
Allopurinol ↑ toxicity of 6-MP and azathioprine (also metabolized by XO)
↑ cell turnover (tumor lysis, myeloproliferative), Lesch-Nyhan, PRPP synthetase overactivity, von Gierke
Hyperuricemia → monosodium urate crystals
Rasburicase converts uric acid → allantoin in tumor lysis
Gout — underexcretion
most cases
Renal: thiazides, loop diuretics, low-dose aspirin, alcohol, cyclosporine, lead, CKD, lactate/ketones compete
Hyperuricemia
Probenecid ↑ excretion
Acidic urine favors uric acid precipitation
Radiolucent stones
Alkalinize urine (potassium citrate)