When to investigate for purine and pyrimidine disorders. Introduction and review of clinical and laboratory indications

Abstract

When to suspect and thus investigate for inborn errors of purine and pyrimidine metabolism is a dilemma for even the most observant investigator. Often parents of affected children, or a history involving siblings, can provide valuable clues. The recognition of new purine and pyrimidine disorders requires skill and serendipity. But even identifying known disorders can prove difficult, since they cover a broad spectrum of illnesses, can have more than one symptom, or lead to early death. This problem is compounded by the fact that they are relatively recently described and therefore often little known, either in the clinic or laboratory. The considerable heterogeneity in clinical expression within families as well as between families means that asymptomatic homozygotes may not be recognized or can present at any time from early childhood through adolescence up to their eighth decade. Consequently, all siblings should be screened. These disorders should be suspected in any case of unexplained anaemia, failure to thrive, susceptibility to recurrent infection, or neurological deficits with no current diagnosis, including autism, cerebral palsy, delayed development, deafness, epilepsy, self-mutilation, muscle weakness, the inability to walk or talk, and-unusual in children and adolescents-gout, sometimes with renal disease. Some disorders present with radiolucent kidney stones, in acute or chronic renal failure, alone or with any of the above, or as an intolerance/sensitivity to therapy (e.g. 5-fluorouracil in malignancies or azathioprine immunosuppression in organ transplantation), often with life-threatening consequences. Several parameters need to be evaluated to ensure correct diagnosis. Pitfalls which can mask diagnosis using only a single test are renal failure, blood transfusion, diet or drugs.

Metabolomic signature associated with reproduction-regulated aging in Caenorhabditis elegans

“…Previous studies have reported that many diseases such as Alzheimer's disease, immunodeficiency and growth retardation are related to disorders of purine and pyrimidine metabolism [44, 45]. Consistent with our results, the downregulation of purine and pyrimidine metabolism in aging mice was previously indicated in a transcriptional analysis [46].…”

A Novel Nucleotide Found in Human Erythrocytes, 4-Pyridone-3-carboxamide-1-β-d-ribonucleoside Triphosphate

“…An optimal nucleotide pattern is essential for normal cell function, and disturbances lead to serious clinical consequences covering the full spectrum of human disease (1). Changes in the nucleotide pattern are crucial to various phases of the cell cycle or differentiation, and pharmacological alterations of the nucleotide profile are components of anticancer, anti-inflammatory, immunosuppressive, antiviral, and anti-ischemic therapies (2)(3)(4).…”

Inborn errors of purine and pyrimidine metabolism

“…It reaches 6.7, 4.4 and 4.0 in Great Britain, the Czech Republic and the Netherlands, respectively, whereas in 12 of 18 participating countries, it is 1.0 or less. Of these patients, 70% have been identified in three countries where adequate laboratory facilities are available (Simmonds et al 1997).…”

“…Signs and symptoms vary widely among inborn errors of purine and pyrimidine metabolism and may be nonspecific. The broad spectrum of presentation underlines the importance of these Fhousekeeping_ enzymes for providing the vital building blocks for DNA, RNA and ATP, as well as the pyrimidine sugars essential to phospholipid and glycolipid synthesis (Simmonds et al 1997). Any system can be affected-immunological, haematological, neurological, musculoskeletal, and (because of the extreme insolubility of purine bases) renal as well (Sanderson et al 2004;Simmonds 1994;Simmonds and Van Gennip 2003;Van Kuilenburg et al 2004a).…”

“…It has to be stressed out that correct diagnosis from uric acid concentrations in blood and urine requires the establishment of local control ranges for healthy adult males and females as well as children, and careful attention to diet and sample handling (Simmonds et al 1997). Additionally, owing to higher uric acid clearance, children may have normal plasma uric acid levels despite purine overproduction.…”