Defects in metabolism of purines and pyrimidines




Ned Tijdschr Klin Chem 1999; 24: 171-175


Defects in metabolism of purines and pyrimidines


Defects in the metabolism of purines and pyrimidines are not well-known in the general hospital. For this reason relatively few patients suffering from these diseases are being diagnosed. However, at present 27 different defects of purine- and pyrimidine metabolism have already been documented. Clinically, these defects are not easily recognised, at least for the larger part, because of non-specific symptoms. Therefore, the assistance of a clinical chemistry laboratory specialized in inborn errors is indispensable to discover most of these defects. This review describes the various biochemical and clinical aspects of the defects of purine and pyrimidine metabolism and provides a guide for their detection, diagnosis and treatment.


Definition and frequency

Defects of purine and pyrimidine metabolism are characterized by abnormal concentrations of purines, pyrimidines and/or their metabolites in cells or body fluids due to a decreased or an increased activity of an enzyme involved in this metabolism. Symptomatology in these defects is highly variable from very severe to relatively mild and may present at any age. Until now about 835 patients have been diagnosed in a population of 435 x 106 in 18 European countries. Of these patients 70% have been detected in only 3 countries where adequate laboratory facilities are available (1). Moreover, the finding of more than 50 patients with one of the relatively newly discovered pyrimidine degradation defects in a relatively short period of 15 years suggests that at least some of these defects are not very rare (2).


Etiology and pathogenesis

Purines and pyrimidines are the building blocks of DNA and RNA, the basic elements of the cell programming machinery. In addition they fulfill a variety of functions in the metabolism of the cell of which the most important are regulation of cell metabolism and function, energy conservation and transport, formation of coenzymes and of active intermediates of phospholipid and carbohydrate metabolism. Therefore, in case a defect exists, any system can be affected. To date 27 defects of purine and pyrimidine metabolism have been documented. They are listed in Tables 1 and 2.





In purine metabolism uric acid is the end product of biosynthesis 'de novo', salvage and degradation and therefore measurement of uric acid in plasma and urine will lead to an indication for several purine defects but certainly not all defects (table 1). Pyrimidine metabolism does not have such an end product. Moreover, as in many inborn errors of metabolism clinical symptomatology is aspecific and highly variable (Table 3). Therefore, screening methods covering a broad spectrum of purine and pyrimidine metabolites will provide the best possibility of detecting most of the known defects or even new defects. Such methods are already operative in many centres around the world for amino acids, organic acids, mucopolysaccharides and oligosaccharides. However, unfortunately only a limited number of centres screen for purines and pyrimidines, although appropriate methods are also available for this area of the metabolism. These methods are summarized in Table 4. Urine is the preferential material for screening of abnormal purine and pyrimidine metabolism as in this body fluid all waste products accumulate. In case urine is not available, plasma or CSF can be used. For tissuespecific abnormalities like the deficiencies of myo-AMDP, eryAMDP, eryITPA, cancer cell MTAP or ery-UMPH-1, and the superactivities of cancer cell IMPDH and fibroblast PU-5’N (see tables 1 and 2), the relevant tissues have to be investigated. Confirmation of the diagnosis has to be carried out by enzyme analysis and/or mutation analysis.



Patiens with ADA or PNP deficiency can be treated with bone marrow transplantation which provides B and T cells with sufficient enzyme activities to prevent the accumulation of the toxic nucleosides and nucleotides. This will also lead to restoration of the activity of S-adenosyl-homocysteine hydrolase (SAHH) which is secondarily inhibited by these accumulating substances. Initial treatment is done by repeated transfusions with irradiated erythrocytes. In ADA deficient patients enzyme replacement therapy is also possible with PEG-ADA (bovine ADA coupled to polyethylene glycol) injected intramuscularly. Gene therapy has been tried in ADA deficient patients with only limited success, but it is expected that adequate gene therapy will become available for both diseases in the near future (16). Patients with a deficiency of XDH (xanthinuria type I), APRT, FJHN, HGPRT or HGPRTp (KS), or patients with a superactivity of PRPS should be treated with a.o. allopurinol in order to decrease the production of the poorly-soluble substances (xanthine, 2,8-dihydroxyadenine or uric acid) accumulating in these diseases. Additional measures like high fluid intake, alkalinisation of the urine by administration of bicarbonate or citrate (not successful in APRT deficiency) and a low-purine diet may be necessary in order to prevent cristallization. Patients with AMDA-1 deficiency should be advised to avoid heavy exercise in order to prevent rhabdomyolytic attacks and myoglobinuria. In some patients treatment with ribose seems to improve exercise tolerance (17). Patients with TPMT, PU-5’N (18), MCF, XDH-AO, UMPS, DPD or DHP deficiency or their relatives should be informed about the pharmacogenetic consequences of their defect. They should avoid drugs being a substrate or precursor of the substrate for the defective enzyme or receive a dosis adapted to the residual activity of that enzyme. Patients with UMPS deficiency can be treated with uridine which is converted to UMP by uridine kinase. Uridine supplementation results in hematologic remission and acceleration of growth but does not prevent suboptimal physical and mental development (19). Therapy for the other defects mentioned in Table 1 has not yet been established.


Inheritance and prevention

In most of the defects of purine and pyrimidine metabolism inheritance is autosomal recessive. Exceptions are PRPS superactivity and HGPRT deficiency which are X-linked, ADA deficiency being X-linked in 1/3 and autosomal recessive in 2/3 of the patients, and FJHN in which inheritance is autosomal dominant. Mutation analysis has been reported in nearly all defects, but the great number of different mutations and the occurrence of many new mutations does not allow carrier detection with 100% certainty. For these reasons also antenatal diagnosis by mutation analysis is difficult, unless mutant alleles can be detected by automated direct DNA sequencing of genomic DNA. Prenatal diagnosis by metabolite or enzyme analysis is available for most of the defects using chorionic villi, amniotic fluid or amniotic fluid cells, or fetal blood (20).





Conclusions and recommendations

As in many inborn errors of metabolism, the causal relationship between clinical symptoms and biochemical abnormalities in purine and pyrimidine disorders is not yet clear. Moreover, in most defects the symptomatology is highly aspecific and onset can occur at any age. Therefore, screening for defects of purine and pyrimidine metabolism is indicated in patients with one of the symptoms mentioned. The finding of more than 50 patients with pyrimidine degradation defects in a relatively short period suggests that these defects are not rare. Some defects can even in the heterozygous state lead to severe toxic reactions during treatment with purine or pyrimidine analogues (e.g. azathioprine in TPMT deficiency and 5-fluorouracil in partial and complete DPD deficiency). For some enzymes, defects have not yet been detected. Some of these defects can be expected to be lethal when complete, but in that case partial defects still have to be found. However, the successful recognition of the well-known defects and of new defects of purine and pyrimidine metabolism strongly depends on the availability of screening methods in diagnostic laboratories. It requires adequate knowledge of the field and close collaboration between clincians and biochemists



1. Simmonds HA, Duley JA, Fairbanks LD and Mc Bride MB.When to investigate for purine and pyrimidine disorders.Introduction and review of clinical and laboratory indications. J Inher Metab Dis 1997; 20: 214-226.

2. Van Gennip AH, Abeling NGGM, Vreken P and Van Kuilenburg ABP. Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects. J Inher Metab Dis 1997; 20: 203-213.

3. Van Gennip AH. Screening for inborn errors of purine and pyrimidine metabolism by bidimensional TLC and HPLC. In Zweig G, Sherma J, Krstulovic AM, eds. Handbook of Chromatography. CRC Press, Boca Raton, FL. 1987; Vol I, part A: 221-245.

4. Van Gennip AH, Abeling NGGM, De Korte D. Application of TLC and HPTLC for the detection of aberrant purine and pyrimidine metabolism in man. In Sherma J, Fried B, eds. Handbook of Thin-Layer Chromatography. Marcel Dekker, New York. Chromatographic Science Series 1990; 55: 863-906.

5. Wadman SK, De Bree PK, Van Gennip AH, Stoop JW, Zegers BJM, Staal GEJ, Siegenbeek van Heukelom LH. Urinary purines in a patient with a severely defective Tcell immunity and a purine nucleoside phosphorylase deficiency. Adv Exp Med Biol 1977; 76A: 471-476.

6. Van den Berghe G, Vincent MF and Jaeken J. Inborn errors of the purine nucleotide cycle: Adenylosuccinase deficiency. J Inher Metab Dis 1997; 20: 193-202.

7. Van Gennip AH, Busch S, Elzinga L, Stroomer AEM, Van Cruchten A, Scholten EG and Abeling NGGM. Application of Simple Chromatographic Methods for the Diagnosis of Defects in Pyrimidine Degradation. Clin Chem 1993; 39/3: 380-385.

8. Berglund G, Greter J, Lindstedt S, Steen G, Waldenström J, Wass U. Urinary excretion of thymine and uracil in a two-year-old child with a malignant tumor of the brain. Clin Chem 1979; 25: 1325-1328.

9. Henderson MJ, Ward K, Simmonds HA, Duley JA, Davies PM. Dihydropyrimidinase deficiency presenting in infancy with severe developmental delay. J Inher Metab Dis 1993; 16: 574-576.

10. Duran M, Rovers P, De Bree PK, Schreuder CH, Beukenhorst H, Dorland L, Berger R. Dihydropyrimidinuria : a new inborn error of metabolism. J Inher Metab Dis 1991; 14: 367-370.

11. Wevers RA, Engelke U, Rotteveel JJ, Heerschap A, De Jong JGN, Abeling NGGM, Van Gennip AH et al. H-NMR spectroscopy of body fluids in patients with inborn errors of purine and pyrimidine metabolism. J Inher Metab Dis 1997; 20: 345-350.

12. Van Gennip AH, Abeling NGGM, Vreken P, Van Kuilenburg ABP. Genetic Metabolic Disease of Pyrimidine Metabolism: Implications for Diagnosis and Treatment. International Pediatrics 1997; 12: 28-33.

13. De Korte D, Systermans JM, Seip M, Van Doorn CC, Van Gennip AH, Roos D. Pyrimidine 5’-nucleotidase deficiency: inproved detection of carriers. Clin Chim Acta 1989; 184: 175-180.

14. Paglia DE, Valentine WN, Nakatani M, Rauth BJ. Selective accumulation of cytosol CDP-choline as an isolated erythrocyte defect in chronic haemolysis. Proc Natl Acad Sci 1983; 80: 3081-3085.

15. Sinkeler SPT, Binkhorst RA, Joosten EMG, Wevers RA, Coerwinkel M, and Oei TL. AMP-deaminase deficiency: study of the human skeletal muscle purine metabolism during ischaemic isometric exercise. Clin Sci 1987; 72: 475-482.

16. Hershfield MS, Arredondo-Vega FX and Santisteban I.Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency. J Inher Metab Dis 1997; 20: 179-185.

17. Gross M. Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency . J Inher Metab Dis 1997; 20: 186-192.

18. Kerstens PJSM, Stolk JN, Hilbrands LB, Van de Putte LBA, De Abreu RA, Boerbooms AMT. 5’-Nucleotidase and azathioprine-related bone marrow toxicity. The Lancet 1993; 342: 1245-1246.

19. Webster DR, Becroft DMO, Parker Suttle D. Hereditary Orotic Aciduria and Other Disorders of Pyrimidine Metabolism In: Scriver CR, Beaudet AL, Sly WS, Valle D eds. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York 1995; 7th ed. vol II: 1799-1837.

20. Scriver CR, Beaudet AL, Sly WS, Valle D eds. The metabolic and Molecular Basis of Inherited Disease. Various authors: Part 7, Purines and pyrimidines. McGraw-Hill, New York 1995; 7th ed. vol II: 1655-1940.



University of Amsterdam, Academic Medical Centre, Lab. Genetic Metabolic Diseases, Depts. Emma Children's Hospital and Clinical Chemistry, Amsterdam.

Correspondence to: Dr. A.H. van Gennip, University of Amsterdam, Academic Medical Centre, Meibergdreef 9 (room 224), 1105 AZ Amsterdam, The Netherlands

Received: 20.11.98


Ingekomen: 16.11.98