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Purine and Pyrimidine Metabolism Disorders

by Chin-To Fong, MD

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; catabolism of pyrimidines produces citric acid cycle intermediates. For a more complete listing of disorders of purine and pyrimidine metabolism, see Table Disorders of Purine and Pyrimidine Metabolism.

Disorders of Purine and Pyrimidine Metabolism

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Genes (Chromosomal Location)


Disorders of pyrimidine metabolism

Hereditary orotic aciduria

Biochemical profile: Elevated urinary orotate

Clinical features: Megaloblastic anemia, recurrent infections, cellular immunodeficiency, developmental disabilities

Treatment: Uridine, uridylic and cytidylic acid

Type I (258900)

UMP synthase (orotidine-5-pyrophosphorylase and decarboxylase)

UMPS (3q13)*

Type II (258920)


Dihydropyrimidine dehydrogenase deficiency (274270)

  • Inborn error form

  • Pharmacogenetic form

Dihydropyrimidine dehydrogenase

DPYD (1p22)*

Biochemical profile: Elevated urinary uracil, thymine, and 5-hydroxymethyluracil

Clinical features: In inborn error form, growth and developmental delay, seizures, spasticity, microcephaly

In pharmacogenetic form, adverse reactions to 5-flurouracil, including myelosuppression, neurotoxicity, GI and skin symptoms, death

Treatment: No specific treatment except for withdrawal of offending drug

Dihydropyrimidinuria (222748)


DPYS (8q22)*

Biochemical profile: Elevated urinary dihydrouracil and dihydrothymine

Clinical features: Variable; feeding problems, seizures, lethargy, somnolence, metabolic acidosis

Sometimes benign

Treatment: Not established

β-Ureido propionase deficiency (210100)

β-Ureido propionase (β-alanine synthase)

UPB1 (22q11.2)

Biochemical profile: Elevated urinary ureidopropionate and ureidobutyrate

Clinical features: Microcephaly, developmental delay, dystonia, scoliosis

Treatment: Not established

Pyrimidine 5nucleotidase deficiency (266120)

5-Monophosphate hydrolase

NT5C3 (7p15-p14)*

Biochemical profile: No specific profile

Clinical features: Hemolytic anemia, basophilic stippling

Treatment: Supportive care

Activation-induced cytidine deaminase deficiency (hyper IgM syndrome type II; 605257)

Activation-induced cytidine deaminase

AICDA (12p13)*

Biochemical profile: High IgM, low to absent IgG and IgA

Clinical features: Recurrent bacterial infections, defective Ig class switching

Treatment: Control of infections

Disorders of purine metabolism

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

Lesch-Nyhan syndrome (300322)

  • 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 deficiency (102700)

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

Treatment: Deoxycoformycin

Purine nucleoside phosphorylase deficiency (164050)

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 database at ).

Disorders of Purine Salvage

Lesch-Nyhan syndrome

This is a rare, X-linked, recessive disorder caused by deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT); degree of deficiency (and hence manifestations) vary with the specific mutation. HPRT deficiency results in failure of the salvage pathway for hypoxanthine and guanine. These purines are instead degraded to uric acid. Additionally, a decrease in inositol monophosphate and guanosyl monophosphate leads to an increase in conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) to 5-phosphoribosylamine, which further exacerbates uric acid overproduction. Hyperuricemia predisposes to gout and its complications. Patients also have a number of cognitive and behavioral dysfunctions, etiology of which is unclear; they do not seem related to uric acid.

The disease usually manifests between 3 mo and 12 mo of age with the appearance of orange sandy precipitate (xanthine) in the urine; it progresses to CNS involvement with intellectual disability, spastic cerebral palsy, involuntary movements, and self-mutilating behavior (particularly biting). Later, chronic hyperuricemia causes symptoms of gout (eg, urolithiasis, nephropathy, gouty arthritis, tophi).

Diagnosis is suggested by the combination of dystonia, intellectual disability, and self-mutilation. Serum uric acid levels are usually elevated, but confirmation by HPRT enzyme assay is usually done.

CNS dysfunction has no known treatment; management is supportive. Self-mutilation may require physical restraint, dental extraction, and sometimes drug therapy; a variety of drugs has been used. Hyperuricemia is treated with a low-purine diet (eg, avoiding organ meats, beans, sardines) and allopurinol, a xanthine oxidase inhibitor (the last enzyme in the purine catabolic pathway). Allopurinol prevents conversion of accumulated hypoxanthine to uric acid; because hypoxanthine is highly soluble, it is excreted.

Adenine phosphoribosyltransferase deficiency

This is a rare autosomal recessive disorder that results in the inability to salvage adenine for purine synthesis. Accumulated adenine is oxidized to 2,8-dihyroxyadenine, which precipitates in the urinary tract, causing problems similar to those of uric acid nephropathy (eg, renal colic, frequent infections, and, if diagnosed late, renal failure). Onset can occur at any age.

Diagnosis is by detecting elevated levels of 2,8-dihyroxyadenine, 8-hyroxyadenine, and adenine in urine and confirmed by enzyme assay; serum uric acid is normal.

Treatment is with dietary purine restriction, high fluid intake, and avoidance of urine alkalinization. Allopurinol can prevent oxidation of adenine; renal transplantation may be needed for end-stage renal disease.

Disorders of Purine Nucleotide Synthesis

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 is by enzyme studies on RBCs and cultured skin fibroblasts.

Treatment is with allopurinol and a low-purine diet.

Adenylosuccinase deficiency

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

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

There is no effective treatment.

Disorders of Purine Catabolism

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 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 (see Severe Combined Immunodeficiency (SCID)).

Diagnosis is by low RBC and WBC enzyme activity.

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

Disorders of Pyrimidine Metabolism

Uridine monophosphate synthase deficiency (hereditary orotic aciduria)

Uridine monophosphate is the enzyme that catalyzes orotate phosphoribosyltransferase and orotidine-5-monophosphate decarboxylase reactions. With deficiency, orotic acid accumulates, causing clinical manifestations of megaloblastic anemia, orotic crystalluria and nephropathy, cardiac malformations, strabismus, and recurrent infections.

Diagnosis is by enzyme assay in a variety of tissues.

Treatment is with oral uridine supplementation.

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