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Purine Catabolism Disorders

By Lee M. Sanders, MD, MPH, Associate Professor of Pediatrics, Stanford University

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Purines are key components of cellular energy systems (eg, ATP, NAD), signaling (eg, GTP, cAMP, cGMP), and, along with pyrimidines, RNA and DNA production. Purines and pyrimidines may be synthesized de novo or recycled by a salvage pathway from normal catabolism. The end product of complete catabolism of purines is uric acid.

In addition to purine catabolism disorders, purine metabolism disorders (see also Table) include

Purine Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)


Ca pyrophosphate arthropathy (chondrocalcinosis-2; 118600)

Increased nucleoside triphosphate pyrophosphohydrolase

ANKH (5p15.2-p14.1)*

Biochemical profile: Ca pyrophosphate dihydrate crystals in joints

Clinical features: Recurrent episodes of monoarticular or multiarticular arthritis

Treatment: No clear treatment

  • Classic form

  • Variant form

Hypoxanthine-guanine phosphoribosyltransferase

HPRT (Xq26-q27.2)*

Biochemical profile:Hyperuricemia, hyperuricosuria

Clinical features: Orange sandy crystals in diapers, growth failure, uric acid nephropathy and arthropathy, motor delay, hypotonia, self-injurious behavior, spasticity, hyperreflexia, extrapyramidal signs with choreoathetosis, dysarthria, dysphagia, developmental disabilities, megaloblastic anemia

In variant form, no self-injurious behavior

Treatment: Supportive care, protective measures, allopurinol, benzodiazepines, certain experimental approaches

Increased activity of phosphoribosylpyrophosphate synthetase (311850)

Phosphoribosylpyrophosphate synthetase

PRPS1 (Xq22-q24)*

Biochemical profile:Hyperuricemia

Clinical features:Megaloblastic bone marrow, ataxia, hypotonia, hypertonia, psychomotor delay, polyneuropathy, cardiomyopathy, heart failure, uric acid nephropathy and arthropathy, diabetes mellitus, intracerebral calcification

Treatment: Allopurinol, anti-inflammatory drugs, colchicines, probenecid, sulfinpyrazone

Phosphoribosylpyrophosphate synthetase deficiency (311850)

Phosphoribosylpyrophosphate synthetase

PRPS1 (Xq22-q24)

PRPS2 (Xp22.3-p22.2)

Biochemical profile: Increased urinary orotate, hypouricemia

Clinical features:Developmental disabilities, seizures with hypsarrhythmia, megaloblastic bone marrow

Treatment: ACTH

Hereditary xanthinuria

Biochemical profile:Xanthinuria, hypouricemia, hypouricosuria

Clinical features: Xanthine stones, nephropathy, myopathy

Treatment: High fluid intake; low-purine diet

Type I (278300)

Xanthine dehydrogenase

XDH (2p23-p22)*

Type II (603592)

Xanthine dehydrogenase and aldehyde oxidase

Adenine phosphoribosyltransferase deficiency (102600)

Adenine phosphoribosyltransferase

APRT (16q24.3)*

Biochemical profile: Urinary 2,8-dihydroxyadenine

Clinical features:Urolithiasis, nephropathy, round yellow-brown urine crystals

Treatment: High fluid intake, low-purine diet, avoidance of dietary alkalis, renal transplantation

Type I

No enzyme activity

Type II

Residual enzyme activity

Adenosine deaminase

ADA (20q13.11)*

Biochemical profile: Elevated serum adenosine and 2-deoxyadenosine

Clinical features: Growth failure, skeletal changes, recurrent infections, severe combined immunodeficiency, B-cell lymphoma, hemolytic anemia, idiopathic thrombocytopenia, hepatosplenomegaly, mesangial sclerosis

Treatment: Supportive care, enzyme replacement, bone marrow or stem cell transplantation, experimental gene therapy

Increased adenosine deaminase (102730)

Adenosine deaminase


Biochemical profile: Mild hyperuricemia

Clinical features: Hemolytic anemia with anisopoikilocytosis and stomatocytosis


Purine nucleoside phosphorylase

NP (14q13.1)*

Biochemical profile:Hypouricemia; hypouricosuria; high serum inosine and guanine; high urinary inosine, 2-deoxyinosine, and 2-deodyguanosine

Clinical features: Growth failure, cellular immunodeficiency, recurrent infections, hepatosplenomegaly, cerebral vasculitis, spastic diplegia, tetraparesis, ataxia, tremors, hypotonia, hypertonia, developmental disabilities, autoimmune hemolytic anemia, idiopathic thrombocytopenia, lymphoma, lymphosarcoma

Treatment: Supportive care, stem cell transplantation

Myoadenylate deaminase deficiency (adenosine monophosphate deaminase I; 102770)

Myoadenylate deaminase

AMPD1 (1p21-p13)*

Biochemical profile: No specific change

Clinical features: Neonatal weakness and hypotonia; exercise-induced weakness or cramping; after exercise, decreased purine release and low increase in serum ammonia (relative to lactate)

Treatment: Ribose or xylitol

Adenylate kinase deficiency (103000)

Adenylate kinase

AK1 (9q34.1)*

Biochemical profile: No specific change

Clinical features: Hemolytic anemia

Treatment: Supportive care

Adenylosuccinate lyase deficiency (103050)

  • Type I (severe form)

  • Type II (mild form)

Adenylosuccinate lyase

ADSL (22Q13.1)*

Biochemical profile: Elevated succinyladenosine and succinylaminoimidazole carboxamide ribotides in body fluids

Clinical features: Autism, severe psychomotor delay, seizures, growth delay, muscle wasting

Treatment: Supportive care, adenine, and ribose

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database).

Myoadenylate deaminase deficiency (or muscle adenosine monophosphate deaminase deficiency)

The enzyme myoadenylate deaminase converts AMP to inosine and ammonia. Deficiency may be asymptomatic or it may cause exercise-induced myalgias or cramping; expression seems to be variable because, despite the high frequency of the mutant allele (10 to 14%), the frequency of the muscle phenotype is quite low in patients homozygous for the mutant allele. When symptomatic patients exercise, they do not accumulate ammonia or inosine monophosphate as do unaffected people; this is how the disorder is diagnosed.

Treatment of myoadenylate deaminase deficiency is exercise modulation as appropriate.

Adenosine deaminase deficiency

Adenosine deaminase converts adenosine and deoxyadenosine to inosine and deoxyinosine, which are further broken down and excreted. Enzyme deficiency (from 1 of > 60 known mutations) results in accumulation of adenosine, which is converted to its ribonucleotide and deoxyribonucleotide (dATP) forms by cellular kinases. The dATP increase results in inhibition of ribonucleotide reductase and underproduction of other deoxyribonucleotides. DNA replication is compromised as a result. Immune cells are especially sensitive to this defect; adenosine deaminase deficiency causes one form of severe combined immunodeficiency.

Diagnosis of adenosine deaminase deficiency is by low RBC and WBC enzyme activity.

Treatment of adenosine deaminase deficiency is by bone marrow or stem cell transplantation and enzyme replacement therapy. Somatic cell gene therapy is being evaluated as well.

Purine nucleoside phosphorylase deficiency

This rare, autosomal recessive deficiency is characterized by immunodeficiency with severe T-cell dysfunction and often neurologic symptoms. Manifestations are lymphopenia, thymic deficiency, recurrent infections, and hypouricemia. Many patients have developmental delay, ataxia, or spasticity.

Diagnosis of purine nucleoside phosphorylase deficiency is by low enzyme activity in RBCs.

Treatment is with bone marrow or stem cell transplantation.

Xanthine oxidase deficiency

Xanthine oxidase is the enzyme that catalyzes uric acid production from xanthine and hypoxanthine. Deficiency causes buildup of xanthine, which may precipitate in the urine, causing symptomatic stones with hematuria, urinary colic, and UTIs.

Diagnosis of xanthine oxidase deficiency is by low serum uric acid and high urine and plasma hypoxanthine and xanthine. Enzyme determination requires liver or intestinal mucosal biopsy and is rarely indicated.

Treatment of xanthine oxidase deficiency is high fluid intake to minimize likelihood of stone formation and allopurinol in some patients.

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