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Purines & Pyrimidine Analysis

Purine and pyrimidine metabolism is an intricate network of biochemical reactions catalysed by a myriad of enzymes. In theory, any genetically determined aberration in the activity or function of any of the enzymes in purine and pyrimidine metabolism can result in an inborn error of metabolism. However, an inborn error does not necessarily cause overt disease. At present 39 disorders in purine and pyrimidine metabolism have been described. These include inborn errors of metabolism, pharmacogenetic risk factors and oncological changes. Inborn errors of purine and pyrimidine metabolism are associated with a great diversity of clinical symptoms. Therefore, the diagnosis of these defects can be challenging. As a guideline, the clinical signs and symptoms requiring analysis of (urinary) purines and pyrimidines are listed in table 1. In general, a symptom from this list in isolation does not necessarily imply the need for analysis of purines and pyrimidines. Analysis of purines and pyrimidines is considered based on the whole clinical presentation and differential diagnosis. The defects that are encountered in the field of biochemical genetics are listed in tables 2 and 3. For all disorders listed in tables 1 and 2 confirmatory testing is available by means of enzyme activity measurements, molecular diagnostics or both.

  • Anaemia (megaloblastic, haemolytic)
  • Arthritis
  • Autism
  • Automutilation
  • Cachexia, feeding difficulties
  • Cerebral palsy
  • Developmental delay
  • Dysmorphic features
  • Encephalopathy
  • Epilepsy, seizures, fitting
  • Exercise intolerance
  • Gout
  • Haematuria
  • Hepatomegaly
  • Hyperactivity, short attention span
  • Hyperuricaemia
  • Hypo-/hypertonia
  • Immunodeficiency
  • Impaired hearing, deafness
  • Lactic acidosis
  • Lens dislocation
  • Lymphopaenia
  • Microcephaly
  • Mitochondrial DNA-depletion
  • Muscle weakness
  • Psychomotor retardation
  • Nephropathy
  • Nephro/urolithiasis
  • Optic atrophy
  • Renal failure (acute and chronic)
  • Scoliosis
  • Severe combined immunodeficiency
  • Spastic diplegia
  • Splenomegaly
  • T-cell immunodeficiency
  • Tetraparesis

High performance liquid chromatography (HPLC).

Urine: Traditionally 24-hour urine collection or overnight collection is preferred for diagnostic purposes. No preservatives are added to the sample.

The recommended procedure for 24-hour urine collection is a follows: during the collection period the urine aliquots are kept refrigerated (4°C) and after completion the urine is sent to the laboratory in a well-isolated package and stored in the refrigerator for max. one week at 4°C until analysis or stored frozen at -20°C when analysis is carried out after more than one week but within 2 months. For longer period store at -80 °c

Inborn errors of purine and pyrimidine metabolism with urinary biomarkers

Index metabolites in urine

Disorder OMIM Gene Increased excretion Decreased excretion
Phosphoribosyl pyrophosphate synthetase deficiency 301835 311850 PRPS1 orotic acid uric acid
Phosphoribosyl pyrophosphate synthetase superactivity 300661 311850 PRPS1 uric acid
Adenylosuccinate lyase deficiency 103050 608222 ADSL SAdo, SAICAR
AICAR transformylase/IMP cyclohydrolase deficiency 608688 ATIC AICAR
Hypoxanthine guaninine phosphoribosyl transferase deficiency 300322 300323 30800 HPRT hypoxanthine, xanthine, uric acid
Adenine phosphoribosyl transferase deficieny 102600 APRT 2,8-dihydroxyadenine
Adenosine deaminase deficiency 102700 608958 ADA (deoxy)adenosine
Purine nucleoside phosphorylase def. 613179 164050 PNP (deoxy)inosine, (deoxy)guanosine
Xanthine dehydrogenase def.Isolated 278300 607633 XDH hypoxanthine,xanthine Uric acid
Xanthine dehydrogenase def.combined with aldehyde oxydase deficiency 602841 AOX1 hypoxanthine,xanthine Uric acid
Xanthine dehydrogenase def.due to Molybdenum cofactor deficiency 252150 603707 603708 603930 MOCS1 MOCS2 GEPH hypoxanthine, xanthine S-sulfocysteine, sulfite, thiosulfate Uric acid, cystine
Orotate phosphoribosyl transferase deficiency (Uridine-5’-monophosphate synthase deficiency ) 258900 UMPS orotic acid
Thymidine phosphorylase deficiency 603041 131222 TYMP thymidine, deoxyuridine
Dihydropyirimidine dehydrogenase deficiency 274270 612779 DPYD DPYS uracil, thymine dihydrouracil, dihydrothymime
Dihydropyrimidinase deficieny 222748 DPYD DPYS uracil, thymine dihydrouracil, dihydrothymime
Beta-ureidopropionase deficiency 613161 606673 UPB1 N-carbamoyl-ß-alanine N-carbamoyl-ß-amino-isobutyric acid
ß-alanine-α-ketoglutarate aminotransferase deficiency 237400 ß-alanine
aminotransferase deficiency ß-aminoisobutyrate-pyruvate aminotransferase deficiency 210100 ß-aminoisobutyric acid
Uridine-5’-monophosphate hydrolase superactivity (pyrimidine specific 5’- nucleotidase superactivity) 266120 606224 UMPH1 Uric acid
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