Chapter

Disorders of Purine and Pyrimidine Metabolism

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Abstract

During the past year, a number of developments have increased substantially our understanding of the coordinated relationship of human purine and pyrimidine metabolism and the role of specific aberrations of metabolism in this area in causation of human disease. However, in order to understand and appreciate the significance of these developments, background information is required. Since the subject has not previously been reviewed in this series, the considerable material relating clinical and biochemical correlations needs to be presented. A comprehensive description with specific citations of all major contributions of even the recent years is not possible within the space limitations of this chapter. Therefore, the information will be summarized largely by referencing more comprehensive reviews and more recent reports, rather than crediting, in all cases, the original citations of the various observations.

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... Other causes to consider in the absence of clinical or laboratory evidence of malignancies are dehydration, lactic acidosis, starvation, diuretic therapies, or renal diseases. 8,9 Typically, when I see elevated uric acid, I am concerned about a malignant process. I obtain lactate dehydrogenase, erythrocyte sedimentation rate, and further evaluations based on clinical scenarios. ...
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A 17-year-old girl presented with facial swelling and shortness of breath to an outside emergency department. She was treated for an allergic reaction with steroids and antihistamines, and discharged from the hospital. Subsequently, she was referred as an outpatient to pediatric nephrology for recurrent edema and proteinuria. Initial laboratory workup by nephrology was significant for a normal complete blood count and reassuring electrolyte panel. Pertinent laboratories were a creatinine of 0.5 mg/dL (0.4-1.1 mg/dL) and an albumin 2.3 g/dL (3.5-5.0 g/dL). The urine protein-to-creatinine ratio was >7 (<0.2). A renal ultrasound showed symmetrically sized kidneys with normal echotexture. The patient's renal biopsy results were consistent with minimal change disease. Based on the biopsy results, prednisone was started. Due to a poor response to prednisone, an alternate immunomodulator therapy was selected. Her subsequent complete blood counts showed a downward trend of all cell lines and an elevated serum uric acid. Concurrently, she reported worsening fatigue, low back pain, nausea, vomiting, night sweats, and pruritus. More details of her case and the outcome are presented.
... This seems not to be the case in erythrocytes which lacks a metabolic system of protein synthesis. However, erythrocytes transfer adenosine from the liver to periphery (Seegmiller, 1978), and elevated ATP level in erythrocytes can be a consequence of increasing the adenosine turnover necessary for put-me supply into regenerating epidermis. The question of interest is constancy of the EC in erythrocytes. ...
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Chapter
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In recent years, a growing interest has prompted increasing numbers of research publications and scientific conferences on the subject of urolithiasis. The aims of this symposium were three: a) to review and inte­ grate recent progress in major subject areas, b) to discuss current research developments and c) to stimulate interchange between investigators in Europe and in America. In a series of morning lectures, invited, recognized experts presented comprehensive reviews of major fields of urolithiasis research such as the physical chemistry of crystal formation, the metabolism of stone forming substances, and modes of therapy. A special emphasis was given to general renal physiology and the renal excretion of Ca++, Pi, Mg, oxalate and urate. Despite its obvious importance, renal function has been relatively neglected in uro­ lithiasis research. New research results were presented by the mechanism of after­ noon poster sessions. This procedure permitted informal lengthy discussions between those participants especially interested and the responsible investigator himself. In addition, informal group discussions were organized during the evenings on an ad hoc basis. In this volume, both the review lectures and brief summaries of the poster presentations have been collected. Interchange between European and American investigators was achieved by the direct participation of a large delegation from North America. This large attendance was made possible by the generous support of the National Institute for Arthritis, Metabolism and Digestive Disease U.S. N.I.H.
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Chapter
The deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a very rare hereditary disorder causing excessive purine production (1). When the enzyme deficiency is virtually complete it causes the pediatric neurological LeschNyhan syndrome (LNS); when partial, it causes severe gout and uric acid lithiasis. In most purine overproducers, including the HGPRT deficient patients, the pathology caused by the excessive amounts of uric acid is avoided successfully by the treatment with the xanthine oxidase inhibitor allopurinol, which effectively reduces uric acid levels. In overproducers with normal HGPRT activity, allopurinol administration is associated also with a significant deceleration of purine synthesis, manifest in a marked reduction in the amount of total purines excreted. In HGPRT deficiency this effect does not occur and the amount of the excreted oxypurines, replacing the uric acid, is markedly increased, rendering such patients to be at risk for xanthine stone formation. Xanthine lithiasis was indeed documented in allopurinol-treated children with the complete enzyme deficiency (2-4). The following is the first case of xanthine stones formation in an allopurinol-treated gouty patient with partial HGPRT deficiency (5).
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Chapter
In 1972, Giblett and co-workers1 and Dissing and Knudsen2 reported the coexistence of adenosine deaminase (ADA) deficiency and severe combined immunodeficiency disease (SCID). The discovery of an association between deficiency of an enzyme and an immunodeficiency represents a major conceptual landmark in that we now recognize that at least some immunodeficiency diseases, ‘experiments of nature’ as Dr Robert A. Good so elegantly called them, may indeed be inborn errors of metabolism’ whose major consequences are manifest in the function of the immune system3. Therefore, if some immunodeficiencies are indeed metabolic diseases, the diagnostic and therapeutic approaches to these disorders must be similar to our approach to metabolic diseases, namely biochemical and pharmacological. Rational approaches to therapy presupposes an understanding of the biochemical basis of the immune dysfunction. This paper describes some of our investigations into the adenosine deaminasedeficient form of severe combined immunodeficiency disease, as well as our experience with enzyme replacement therapy for this disorder and some recent studies with pharmacological agents upon adenosine deaminase-deficient lymphocytes.
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The inborn errors of metabolism have played a special role in the development of human genetics as a scientific discipline. The study of these disorders, each of them individually uncommon, has pointed out the ways in which molecular expression of gene action takes place in man. It has given us new understanding of mechanisms of human variation. It has pioneered in the field of prenatal diagnosis and has permitted new approaches to questions of population genetics by permitting the detection of recessive genes in heterozygotes. Each of these aspects of modern biochemical genetics is exemplified by the inborn errors of purine metabolism, an area in which there have been exciting new developments.
Article
Administration of allopurinol or its major metabolic oxidation product, oxipurinol, to man consistently results in inhibition not only of uric acid synthesis but also of pyrimidine synthesis. Molecular correlates of the latter inhibition produced by oxipurinol have been studied in permanent human lymphoblast lines in tissue culture, which appear to be satisfactory models for the study of this drug effect. Incubation of intact lymphoblasts with oxipurinol resulted within 90 min in significant inhibition of incorporation of [14C]orotic acid but not [3H]uridine into cold acid precipitable counts. This inhibition of pyrimidine synthesis was correlated with the generation of an orotidylic acid decarboxylase inhibitor which, in cell free extracts, required 5 phosphoribosyl 1 pyrophosphate and oxipurinol for its formation and could be generated in extracts of cells deficient in hypoxanthine guanine phosphoribosyltransferase. Stabilization of both orotidylic acid decarboxylase and orotate phosphoribosyltransferase also resulted from incubation of lymphoblasts with oxipurinol. Production of the stabilized activities appeared to coincide temporally, in substrate requirements, and in reversibility with the generation of the inhibitor of orotidylic acid decarboxylase activity, suggesting a common molecular basis for these effects. In addition oxipurinol treatment resulted in an alteration in the quaternary structure of the bifunctional enzyme complex containing both activities, with an increase in molecular weight from 41,000 to 108,000 as estimated by gel filtration studies. In the higher molecular weight material both increased stability and inhibition of orotidylic acid decarboxylase were demonstrated. These findings are in accord with the suggestion that ribonucleotides of oxipurinol result in inhibition of pyrimidine synthesis through alterations in the activity, stability, and quaternary structure of the enzyme complex. A concentration dependent increase in the specific activities of orotidylic acid decarboxylase and orotate phosphoribosyltransferase has been demonstrated in both lymphoblasts and fibroblasts incubated with oxipurinol. In lymphoblasts this increase in enzyme activity occurred within 2 to 3 hr and was not prevented by treatment of the cells with cycloheximide. Stabilization of the enzymes during extraction from the cell or direct activation of the enzyme activities appear to be more likely explanations for the increased enzyme activities than induction of new enzyme synthesis of inhibition of normal enzyme catabolism. No differences were found between normal and hypoxanthine guanine phosphoribosyltransferase deficient lymphoblast (or fibroblast) lines in activities of either orotate phosphoribosyltransferase or orotidylic acid decarboxylase.
Article
A patient in whom avascular necrosis of one femoral head and, later, clinical gout developed underwent hip surgery which revealed that the femoral head and surrounding synovial membrane were covered with monosodium urate crystals. Although cases of hyperuricemia and gout in nontraumatic avascular necrosis of the femoral head have been reported, examination of biopsy specimens from such patients has been rare. Careful studies will be necessary to determine the incidence and importance of urate crystal deposition in such patients.
Article
In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide.Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily. Whereas the serum uric acid level rose moderately in the hydrochlorothiazide-treated patients, it fell strikingly to less than half of the pretreatment level in patients treated with ticrynafen. Body weight decreased slightly in both groups, as did serum potassium levels. Blood urea nitrogen and serum creatinine levels rose slightly in both groups. The magnitude of these changes was not significantly different between the two groups. Use of ticrynafen was well tolerated.Ticrynafen appears to be a useful new antihypertensive agent because of its unique combination of diuretic, antihypertensive, and hypouricemic effects.(JAMA 237:652-657, 1977)
Article
BONE metastases are common in bronchogenic carcinoma, but the occurrence of metastases to small bones of the hands and feet is relatively rare.1 It is particularly unusual for such metastases to be responsible for the presenting complaint of a patient with lung cancer. We recently encountered two patients with squamous cell carcinoma of the lung; one had symptoms referrable to such peripheral bone metastases, and one had symptoms simulating gout.Report of Cases Case 1. — A 52-year-old man was admitted to the hospital with a two-month history of painful swelling of his right ring finger. For several weeks he had experienced intermittent fever and chills. He had experienced a chronic cough and dyspnea during exertion for a number of years. He had smoked three packs of cigarettes per day for 35 years and had traveled extensively, including a visit to parts of southwestern United States within the past
Article
Arterial disease is respected as an inevitable as well as the most serious complication of gout. Barring accident or other common hazards, the patient afflicted with gout will die directly or indirectly of changes in his circulatory apparatus. Formerly, gouty lesions were ascribed to arterial changes; this opinion is no longer held. Hyperuricemia is not believed to be the cause of the vascular changes. Instead, the underlying, unknown cause of the other manifestations of gout is thought to induce the arteriosclerosis.Discovery of urate in the arteries or in the heart adds specificity to the cardiovascular changes. Urate crystals in blood vessels or in the heart were reported by the earliest writers. The authenticity of these reports has been doubted, notably by Minkowski. Deposition of urates in the vessel walls and in the heart valves is regarded not as the cause of the tissue changes but rather as an accompaniment
Article
A female patient, at the moment 2½ years old, with a purine nucleoside phosphorylase (PNP) deficiency showed a gradual decrease of T cell immunity during the first year of life whereas B cell immunity developed normally (1) Later on in life some disturbance of B cell immunity also developed as could be concluded from the appearance of homogeneous immunoglobulins in the serum from the decrease in the synthesis of specific antibodies. Earlier studies (1, 2) have shown that an inherited PNP deficiency existed in two older sisters of the patient, both suffered from the same immunodeficiency and have died. The oldest sister has been treated with several thymus transplants, resulting in a partial and transient restoration of T cell function. However the most obvious therapeutic approach of these patients would be correction of the consequences of the metabolic defect. Therefore, the patient under study was treated by oral substitution with uridine and purines and afterwards with several transfusions of irradiated red cells and plasma. The former treatment was rather unsuccessfull, the latter resulted in a remarkable change in the metabolic state of the patient and some improvement of in vicro immune functions. In contrast to findings of Polmar et al. (3) in a ADA deficient patient, complete immunological restoration could not be Achieved by this treatment until now.
Article
Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.
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Radiological and morphological findings in advanced arthritis urica and pyrophosphate arthropathy are well known. In contrast, the early changes of synovial membrane in these disturbances of metabolism pose diagnostic problems. With the assistance of various cytological techniques and polarizing microscopical as well as electron microscopical investigation it was examined to what extent needle biopsies can be helpful in the differential diagnosis of gout and pseudogout.
Article
Four cases of the Lesch Nyhan syndrome found in the Tokyo area were given L 5 hydroxytryptophan orally. L 5 hydroxy tryptophan relieved self mutilation effectively without causing any side effects. However this substance did not alleviate choreoathetoid movement. Self destructive behavior may be caused by an imbalance of cerebral amines, especially of serotonin.
Article
Adenosine deaminase (ADA) deficiency is associated with a form of severe combined immunodeficiency disease (SCID). Enzyme replacement therapy has restored immunologic competence in some ADA-SCID patients (Polmar et al. N Engl J Med 295:1337, 1976). Their lymphocytes, however, remain ADA deficient. Enzyme therapy also reduces the high levels of deoxyATP (dATP) present in these patients prior to therapy. The effects of adenosine and deoxyadenosine upon proliferation of ADA deficient lymphocytes were studied using 3H-leucine incorporation as a measure of cell proliferation. Studies were carried out upon lymphocytes from one ADA-SCID patient and three normal individuals whose lymphocytes were made ADA deficient with the ADA inhibitor EHNA.
Article
Patients with combined immunodeficiency (CID) and adenosine deaminase (ADA) deficiency may have low or absent ADA activity in various tissues. Hirschhorn et al. have shown that the activity in patient fibroblasts is a mutant form of ADA (PNAS 73: 213, 1976). Others have suggested that the deficiency reflects an inhibition of ADA (Trotta et al., PNAS 73: 104, 1976). We have isolated and in part characterized properties of the residual ADA from spleen of one patient. Radioimmunoassay for ADA protein in erythrocytes and spleen extracts of the patient showed no cross-reacting protein. Chromatography of ADA-CID spleen extracts produced a fraction with adenosine deaminating activity which could not be adsorbed on affinity or anti-ADA columns. The deaminating activity could not be inhibited with erythro-9-(2-hydroxyl-3-nonyl) adenosine. The pH optimum activity curve and Km differed from normal spleen ADA. A similar fraction, representing about 1% of the total ADA activity, was isolated from normal spleen extracts. We conclude that the adenosine deaminating activity observed in patients with ADA-CID is not ADA. The activity may be due to an enzyme whose principal substrate may be another metabolite. The presence of this non-ADA deaminating activity in normal spleen suggests that the observed activity in ADA-CID tissue is not due to a mutant form of ADA and that the inhibited enzyme activity reported by Trotta et al. may be due to an amplification of this non-ADA deaminating enzyme.
Article
Es wird über eine äußerst seltene chronische Hyperurikämie bei einem 2œjährigen Kleinkind als Ausdruck einer familiärgichtischen Diathese berichtet; gleichzeitig bestehen zentralnervöse Symptome (statische und lokomotorische Ataxie, Dysarthrie) sowie Zeichen einer Niereninsuffizienz (Ausdruck vielleicht einer angeborenen Fehlbildung oder Nephronophthise). Es wird eine Koordination aller drei Symptomkomplexe vermutet und gezeigt, daß sich eine an das männliche Geschlecht gebundene familiäre Häufung derselben (in der mütterlichen Familie) nachweisen läßt. Summary The case is reported of chronic hyperuricaemia in a 2œ-year old boy; there also were central nervous system symptoms (static and locomotor ataxia, and dysarthria) and evidence of renal impairment. It is thought that the hyperuricaemia and the cerebral and renal involvement were related. On the maternal side there was a high incidence of sex-linked (to the male) gouty diathesis. Only one other case of childhood hyperuricaemia with familial gouty diathesis has apparently been reported in the medical literature. Resumen Diátesis familiar gotosa y síntomas cerebrales y renales en un niño pequeño Se informa sobre una hiperuricemia crónica, extraordinariamente rara, en un niño de 2 años y medio como expresión de una diátesis gotosa familiar. Simultáneamente existían síntomas nerviosos centrales (ataxia locomotriz y estática, disartría) así como signos de insuficiencia renal (expresión quizás de una malformación congénita o de una tisis nefronal). Se supone la coordinación de los tres complejos sintomáticos y se demuestra una mayor frecuencia familiar de los mismos ligada al masculino, en la familia de la madre.
Article
Adenine compounds can be measured in picomole amounts using liquid chromatography of the fluorescent 1, N-etheno derivatives. The limit of detection for the etheno derivatives in tissue extracts, however, is tissue-dependent due to interference by nucleotides and fluorescent components which are normally present. Prior to derivatization nucleotides were partially removed from extracts of lymphocytes and erythrocytes by treatment with Dowex AG1-X2 anion exchange resin. Samples were analyzed using either a Partisil PXS 10/25 SCX column eluted with 100 mM NH4H2PO4, pH 4.5, at a flow rate of 2 ml/min; or using two μBondapak/C18 reversed-phase columns eluted with 5 mM KH2PO,4:25% methanol (V/V) pH 7.5, at a flow rate of 1 ml/min. Adenosine was found to be 0.07 nmole/ml in normal adult human plasma. The urine of a child with severe combined immunodeficiency disease associated with absence of adenosine deaminase contained a normal amount of adenosine (5–6 nmole/ml), but contained a high level (∼60 nmole/ml) of deoxyadenosine. Deoxyadenosine was not detected (
Article
Skin fibroblast cultures were utilized to study the mode of inheritance of a mutant feedback-resistant phosphoribosylpyrophosphate synthetase in a gouty family with purine overproduction. Selective conditions were applied to allow the survival in culture of mutant cells only. Whereas in the male gouty propositus the cell culture was homogeneous for the mutant enzyme, in the cell culture from his nongouty mother two cell populations were demonstrated, one normal and the other mutant. The mosaicism in the mother is compatible with X-linkage of the enzyme. From this finding, together with the clinical and biochemical data available, it is concluded that in this family the enzyme mutation is transmitted in a X-linked recessive pattern.Copyright © 1977 S. Karger AG, Basel
Article
Recent observations of urate excretion by the kidney in genetic overproducers of urate have contributed to our understanding of the mechanisms of renal damage in gout. Some of these overproducers showed normal serum urate concentrations when their urine urate excretions were high, putting them at risk from uric acid crystalluria and calculi. Others developed acute renal failure which was completely reversed by an intense alkaline diuresis. Some overproducers developed varying degrees of renal insufficiency while others members of the same family with the same genetic mutation retained normal renal function. How can these observations be reconciled with existing knowledge of the gouty kidney?
Article
Nine patients who ultimately proved to have acute gouty arthritis did not have urate crystals demonstrable by compensated polarized light in the first joint fluid aspirated despite leukocyte counts as high as 100,000/mm3. In 6 cases crystals were found in fluid from the same joint 5 hours to 1 day later. Factors that might explain the difficulty in identifying crystals include aspiration of the wrong site because diffuse swelling obscured predominant involvement of a bursa or adjacent small joint, loculation within a joint, crystal dissolution leaving only tiny birefringent chunks, and inexpert or insufficient search. Some cases remain without any tentative explanation. The possibility of acute gouty arthritis should not be excluded if crystals are not demonstrable in the first search of joint fluid. Repeated searches for typical monosodium urate crystals may be required for diagnosis.
Article
The development of automated techniques in the clinical laboratory, which routinely includes the measurement of uric acid, has raised important questions concerning the clinical significance of abnormal serum urate values. Although numerous studies have focused on the relevance of hyperuricemia, the significance of hypouricemia has been elucidated only recently. As late as 1969 Lawee noted that a serum urate value below 2.6 mg/100 ml was ignored by the attending physician in all but 1 of 44 patients. In the present article the author wishes to focus on the nature, frequency, and significance of hypouricemia. The following aspects are dealt with: decreased uric acid production; increased uric acid excretion, and mechanism unknown. (51 references).
Article
The American Rheumatism Association subcommittee on classification criteria for gout analyzed data from more than 700 patients with gout, pseudogout, rheumatoid arthritis, or septic arthritis. Criteria for classifying a patient as having gout were a) the presence of characteristic urate crystals in the joint fluid, and/or b) a tophus proved to contain urate crystals by chemical or polarized light microscopic means, and/or c) the presence of six of the twelve clinical, laboratory, and X-ray phenomena listed in Table 5.
Article
Nine independently derived clones of mutagenized rat hepatoma cells selected for resistance to 6-mercaptopurine (6-MP) or 6-thioguanine (6-ThioG) have been isolated. Each has severely reduced catalytic activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and seven of them possess significantly increased activities of phosphoribosylpyrophosphate (PRPP) synthetase. The degrees of elevations of PRPP synthetase activities do not correlate with the degrees of deficiencies of HPRT activities. The cells from one of these clones, 1020/12, possess 40% of the normal HPRT catalytic activity and overproduce purines. We have extensively examined the cells from this clone. Immunotitration studies of 1020/12 cells indicate that there is a mutation in the structural gene for HPRT. Although they possess increased specific catalytic activities of the enzyme, PRPP synthetase, the catalytic parameters, heat stability, and isoelectric pH of PRPP synthetase from 1020/12 cells are indistinguishable from those of the enzyme from wild-type cells. The cause of purine overproduction by 1020/12 cells appears to be the elevated PRPP synthetase activity, rather than a PRPP “sparing” effect stemming from reduced HPRT activity. Support for this idea is provided by the observation that the complete loss of HPRT activity in a clone derived from 1020/12 cells does not further enhance the levels of PRPP synthetase or purine overproduction. We propose that the elevated levels of PRPP synthetase activity in these HPRT deficient cells result from a mutational event in the structural gene for HPRT, and that this causes the disruption of a previously undescribed regulatory function of this gene on the expression of the PRPP synthetase gene.
Article
An adenosine kinaseless (AK−) mutant of the mouse fibroblast line 3T6 has been obtained in cell culture by evolution of resistance to 6-thio-methylpurine ribonucleoside and tubercidin. The mutant excretes purines (xanthine and hypoxanthine) into the culture medium. Human or mouse cells lacking hypoxanthine-guanine phosphoribosyl transferase (HPT−) excrete increased amounts of purines, but a human cell mutant lacking both HPT and AK excretes considerably more hypoxanthine. The difference in hypoxanthine excretion between the HPT− mutant and the HPT− AK− mutant originates from the adenosine normally reutilized through the activity of adenosine kinase. The activity of adenosine kinase is essential to retard the adenosine cycle and to prevent cellular loss of purines.
Article
Twenty-seven patients with thirty-six joints affected with acute gouty arthritis were treated with fenoprofen calcium for a duration not exceeding 8 days and with a variable dose not exceeding 3.2 g daily. The results indicate that fenoprofen calcium was an effective drug in these patients. Side effects were modest.