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Purine Salvage Disorders

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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 salvage disorders, purine metabolism disorders (see also Table) include

Purine Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

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

ADA

Biochemical profile: Mild hyperuricemia

Clinical features: Hemolytic anemia with anisopoikilocytosis and stomatocytosis

Treatment:Deoxycoformycin

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 ).

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 of Lesch-Nyhan syndrome 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 of adenine phosphoribosyltransferase deficiency 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 of adenine phosphoribosyltransferase deficiency 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.

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