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Purine Nucleotide Synthesis 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 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 nucleotide synthesis 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

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).

Phosphoribosylpyrophosphate synthetase superactivity

This X-linked, recessive disorder causes purine overproduction. Excess purine is degraded, resulting in hyperuricemia and gout and neurologic and developmental abnormalities.

Diagnosis of phosphoribosylpyrophosphate synthetase superactivity is by enzyme studies on RBCs and cultured skin fibroblasts.

Phosphoribosylpyrophosphate synthetase superactivity treatment is with allopurinol and a low-purine diet.

Adenylosuccinase deficiency

This autosomal recessive disorder causes profound intellectual disability, autistic behavior, and seizures.

Diagnosis of adenylosuccinase deficiency is by identifying elevated levels of succinylaminoimidazole carboxamide riboside and succinyladenosine in CSF and urine.

There is no effective treatment for adenylosuccinase deficiency.

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