23 Inborn Errors of Purine 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. 246 Inborn Errors of Purineand Pyrimidine Metabolism

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- HPRT1 308000 ciency 23.4 PRPS Phosphoribosylpyrophosphate synthetase PRPS1 311850 superactivity 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 603041 encephalopathy (MNGIE) 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 25–150 µmol/h per ml a After several months Treatment 247

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 a Once 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. 248 Inborn Errors of Purineand Pyrimidine Metabolism

Stonesalreadyformedmaybetreatedbylithotripsy.

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. Treatment 249

I 23.5 Adenine phosphoribosyltransferase deficiency

No. Symbol Medication Dosage Target

23.5 APRT Allopurinol Child: Urine 2,8 DHA vir- 10 mg/kg per day 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. 250 Inborn Errors of Purineand Pyrimidine Metabolism

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. Oraladministrationofadenine10 mg/kgperdaywithallopurinol5–10 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 Divided Monitor Target per day times/day 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. Treatment 251

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 Target per day 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 23.15 β-Ureidopropionase deficiency No specific treatment is available. 252 References

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 arebeingtreatedwithautologouscordbloodorbonemarrowCD34+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.

References

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