and Pyrimidine Metabolism
Albert H. van Gennip, Jörgen Bierau, William L. Nyhan
23.1 Introduction
Purines and pyrimidines are vital components of all living cells. Not only are purines and pyrimidines the precursors of DNA and RNA and not only do they provide energy in the form of adenosine triphosphate (ATP), they are also involved in the biosynthesis of phospholipids and glycolipids. Furthermore, purines and pyrimidines are involved in signal transduction pathways.
A total of 30 defects of enzymes involved in the metabolism of purines and pyrimidines have been described. Some of these enzyme defects are relatively benign or nondiseases. A total of 15 of these defects in the metabolism of purines and pyrimidines are known to cause human disease. One defect, dihy- dropyrimidine dehydrogenase deficiency, becomes important to recognize in patients treated for cancer with fluorinated pyrimidine analogs. Administra- tion of these drugs can then be catastrophic, as a consequence of the inability of the patient to degrade these compounds, which results in severe toxicity.
In thiopurine methyltransferase deficiency, there may be enhanced toxicity of mercaptopurines.
A major advance in the management of the hyperuricemic disorders was the discovery of allopurinol, which inhibits xanthine oxidase. Effective therapy has eliminated the consequences of overproduction of uric acid, including gouty arthritis, tophaceous deposits, urate calculi, and urate nephropathy.
23.2 Nomenclature
No. Disorder (symbol) Definitions/comment Gene symbol OMIM No.
23.1 ADA Adenosine deaminase deficiency ADA 102700
23.2 PNP Purine nucleoside phosphorylase deficiency NP 164050
23.3 HPRT Hypoxanthine phosphoribosyltransferase defi- ciency
HPRT1 308000
23.4 PRPS Phosphoribosylpyrophosphate synthetase superactivity
PRPS1 311850
23.5 APRT Adenine phosphoribosyltransferase deficiency APRT 102600
23.6a XDH Xanthine dehydrogenase/oxidase deficiency XDH 607633
23.6b XDH/SO Combined XDH/sulphite oxidase deficiency 23.6c XDH/AO Combined XDH/aldehyde oxidase deficiency
23.7 ADSL Adenylosuccinate lyase deficiency ADSL 608222
103050
23.8 MAD Myoadenylate deaminase deficiency AMPD1 102770
Adenosine monophosphate deaminase deficiency
23.9 TPMT Thiopurine methyltransefrase deficiency TPMT 187680
23.10 UMPS UMP synthetase deficiency UMP 258900
Oroticaciduria
23.11a UMPH1 UMP hydrolase deficiency UMPH1 266120
5-Nucleotidase deficiency NT5C3 606224
pyrimidine 5-nucleotidase deficiency P5N1 23.11b UMPHS UMP hydrolase superactivity
23.12 TP Thymidine phosphorylase deficiency ECGF1 131222
Mitochondrial Neurogastronintestinal encephalopathy (MNGIE)
603041
23.13 DPD Dihydropyrimidine dehydrogenase deficiency DPYD 274270
23.14 DHP Dihydropyrimidinase deficiency DPYS 222748
23.15 UP β-Ureidopropionase deficiency UPB1 606673
23.3 Treatment
I 23.1 Adenosine deaminase deficiency
No. Symbol Age Medication Initial dosage Maintenance Maintain plasma
dosagea ADA actively
23.1 ADA Any PEG-ADA 60 U/kg per week 30 U/kg per week 25–150µmol/h
per ml
aAfter several months
The treatment of choice of adenosine deaminase (ADA) deficiency is trans- plantation of bone marrow (BMT) from an human leukocyte antigen (HLA)- identical sib. In the absence of identical sib BMT with T-cell depletion or hematopoietic stem cells:
• Enzyme replacement with polyethylene glycol-modified bovine adenosine deaminase (PEG-ADA; Adagen, Enzon; intramuscular injections)
• Somatic gene therapy
Dangers/Pitfalls
Bone marrow transplant: graft-versus-host disease
Gene therapy: immunity to gene-transfer system; the effect of gene therapy is difficult to assess, because treatment with PEG-ADA was continued in the patients who received gene therapy
I 23.2 Purine nucleoside phosphorylase deficiency Bone marrow transplantation (BMT).
Dangers/Pitfalls
BMT: beware of graft-versus-host disease.
I 23.3 Hypoxanthine phosphoribosyltransferase deficiency
No. Symbol Age Medication Dosage Monitor Targeta
23.3 HPRT Child Allopurinol 20 mg/kg per day Blood uric acid Blood uric acid
< 3 mg/dl
Adult Allopurinol 200–600 mg/kg
per day
aOnce target blood level is achieved, monitor urine oxypurines to maximize hypoxanthine and minimize xanthine and uric acid
Allopurinol is sufficient therapy for variants with partial deficiency of hypox- anthine phosphoribosyltransferase deficiency (HPRT). In patients with Lesch- Nyhan syndrome, allopurinol does nothing for the neurological and behavioral features of the disease. Most patients require some muscle relaxant, valium or baclophen, doses adjusted individually. Self-injurious behavior usually re- quires the removal of teeth. Physical restraint is usually required to prevent self-mutilation. This often requires physician advocacy and intervention when authorities consider restraint an infringement of liberties.
Stones already formed may be treated by lithotripsy.
Dangers/Pitfalls
Urinary tract calculi may be composed of urate or xanthine, so allopurinol will not always prevent their formation. They are radiolucent. Ultrasound is therefore the usual approach to diagnosis.
BMT or stem cell transplantation has been of no benefit in this disease, and there have been a number of deaths.
In general, surgical interventions such as for hip dislocation or gastric fundoplication have been disastrous in this disease.
Uricosuric agents such as probenecid are contraindicated; they may induce acute renal shut down.
In the presence of renal insufficiency, dosage of allopurinol may have to be reduced; monitoring of levels in the blood is useful.
I 23.4 Phosphoribosylpyrophosphate synthetase abnormality
No Symbol Age Medication Dosage Target
23.4 PRPPS Child Allopurinol 20 mg/kg per day Blood uric acid <3 mg/dl
Adult 200–600 mg/kg per day
It is not necessary to monitor urinary purines in this disease. In the presence of normal HPRT activity and inhibition of xanthine oxidase, the total purine to be excreted decreases.
Some kindred have associated deafness, which is often recognized late. Hear- ing aids facilitate normal development.
See disorder 23.3.
Dangers/Pitfalls
Uricosuric agents such as probenecid are contraindicated in any overpro- duction hyperuricemia.
See disorder 23.3.
I 23.5 Adenine phosphoribosyltransferase deficiency
No. Symbol Medication Dosage Target
23.5 APRT Allopurinol Child:
10 mg/kg per day Urine 2,8 DHA vir- tually 0
Adult:
200–300 mg/kg per day
2,8-Dihydroxyadenine (2,8-DHA) stones may be radiolucent.
In case of acute or chronic renal failure, the dosage of allopurinol needs to be lowered.
Lithotripsy.
Dangers/Pitfalls See disorder 23.3.
I 23.6a Xanthine dehydrogenase deficiency, isolated
No. Symbol Medication Dosage
23.6a XDH Allopurinol
Child 10–20 mg/kg per day
Adult 100–300 mg/day
I 23.6b Combined xanthine dehydrogenase/sulfite oxidase deficiency, molybdenum cofactor deficiency
In cofactor deficiency (xanthine dehydrogenase/sulfite oxidase deficiency, XDH/SO) the use of dextromethorphan (an N-methyl-d-aspartate receptor agonist) may be useful as an anticonvulsant.
I 23.6c XDH/AO combined xanthine dehydrogenase/aldehyde oxidase deficiency (see disorder 23.6a)
In any XDH, partial activity is required for any benefit from allopurinol. In the presence of HPRT, any hypoxanthine is recycled, and this may reduce total purine excretion, virtually all of which is xanthine.
In SO deficiency a low-methionine/-cystine diet may be of benefit. Therapy is facilitated by the use of Homimex.
Treatment may be monitored by measuring levels of sulfocysteine or sulfate in the urine. Target levels have not been established.
Cysteamine may be helpful in absorbing excess sulfite in patients with SO deficiency. Thiamine should be supplemented to avoid deficiency.
I 23.7 Adenylosuccinate lyase deficiency
Oral supplementation of d-ribose at a dose of 10 mmol/kg per day has been reported to be beneficial.
Oral administration of adenine 10 mg/kg per day with allopurinol 5–10 mg/kg
per day.
Dangers/Pitfalls
Adenine is converted to 2,8-DHA by XDH, raising the risk of kidney stone formation. Allopurinol is an inhibitor of XDH and serves to prevent formation of 2,8-DHA.
I 23.8 Myoadenylate deaminase deficiency
No. Symbol Age Medication Dose/day
23.8 MAD Any d-Ribose < 200 mg/kg
Any Xylitol 15–20 g
I 23.9 Thiopurine methyltransferase deficiency
In patients treatd with mercaptopurines (MP), dosage of MP to be lowered dependent on residual thiopurine methyltransefrase (TPMT) activity.
I 23.10 Orotic aciduria – UMP synthase deficiency No. Symbol Age Medication Dose mg/kg
per day
Divided times/day
Monitor Target
reduction
23.10 UMPS Any Uridine 50–300 1–5 Hematology Urinary orotic
acid
Clear relationship between urinary orotate and uridine dosage has not been established. The major target is zero megaloblastosis and a normal complete blood count.
Susceptibility to infection may remain after hematological findings are nor- mal.
Uridine dosage may be limited by diarrhea.
Triacetyluridine has not been tried in this disease, but it should be more effective than uridine because of greater bioavailability following oral admin- istration.
I 23.11a UMP hydrolase deficiency (UMPH1); synonyms: 5’-nucleotidase deficiency, pyrimidine 5’-nucleotidase deficiency (NT5C3, P5N1)
Splenectomy has been reported to cure the life-long hemolytic anemia associ- ated with UMPH1 deficiency.
I 23.11b UMP hydrolase superactivity (UMPHS); synonyms: 5’-nucleotidase superactivity
No. Symbol Age Medication Dosage mg/kg per day
Target
23.11b UMPHS Any Uridine 1,000 Seizures,
infection
Treatment with uridine has led to cessation of seizures and reduced suscepti- bility to infection, as well as improvement in neurological findings.
Triacetyluridine is more effective than uridine in this disease. Dosages have not been published.
I 23.12 Thymidine phosphorylase deficiency No specific treatment is available.
I 23.13 Dihydropyrimidine dehydrogenase deficiency Anticonvulsant therapy should be used for seizures.
The use of 5-halogenated pyrimidines such as 5-fluorouracil should be avoided.
I 23.14 Dihydropyrimidinase deficiency See disorder 23.13.
I 23.15β-Ureidopropionase deficiency No specific treatment is available.
23.4 Alternative Therapies/Experimental Trials
I 23.1 Adenosine deaminase deficiency Gene (transfer) therapy.
A clinical trial is currently being conducted by the National Institutes of Health, Bethesda, Maryland, USA, in which patients suffering from severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency are being treated with autologous cord blood or bone marrow CD34+ cells transduced with a human ADA gene. (NIH protocol number 01-HG-0189.)
Carrier erythrocyte-entrapped ADA has been employed with ADA defi- ciency.
I 23.3 Hypoxanthine phosphoribosyltransferase deficiency
An adult patient with HPRT deficienicy has been treated with bilateral direct stereotactic stimulation of the globus pallidum and self-injurious behavior has been extinguished.
I 23.10 Orotic aciduria – UMP synthase deficiency
Allopurinol has been used in orotic aciduria, and it has been found to increase activity of OPRT and ODC, and in some patients to reduce orotic acid excretion.
In other patients it had no effect.
I 23.7 Adenylosuccinate lyase deficiency
d-Ribose has been employed in adenylosuccinate lyase deficiency.
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