Purine Salvage Deficiencies

The purine salvage pathway involves production of purine nucleotides from intermediates formed during degradation of RNA and DNA. The salvaged nucleosides can be reconverted back into nucleotides. These salvage pathways are crucial in some tissues cannot undergo de novo synthesis of purine nucleotides. Deficiencies in these pathways can give rise to conditions such as Lesch-Nyhan syndrome and adenine phosphoribosyltransferase (APRT) deficiency. Lesch-Nyhan syndrome presents with neurologic deficits and self-mutilation in the 1st year of life and APRT deficiency presents with renal dysfunction. There is no cure for either disease, and treatment is supportive. The prognosis is poor for patients with Lesch-Nyhan syndrome; patients die within the 1st 2 decades of life but APRT deficiency can result in end-stage renal disease if left untreated.

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Purines are used for cellular energy and may be recycled through a salvage pathway that is susceptible to enzyme deficiencies that cause Lesch-Nyhan syndrome and adenine phosphoribosyltransferase (APRT) deficiency.


  • Lesch-Nyhan syndrome: 
    • Incidence: 1 in 380,000 live births 
    • Males are affected (X-linked disorder).
    • Females are heterozygous carriers.
  • APRT deficiency: 
    • Incidence: 1 in 15,000–100,000 live births
    • Japanese and Icelandic patients are more susceptible to disease.
    • Equal prevalence in males and females


  • Lesch-Nyhan syndrome: 
    • Due to hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency
    • Caused by mutation of HPRT1 gene
    • Rare
    • X-linked recessive inheritance
  • APRT deficiency:
    • Caused by a mutation in APRT, leading to excessive production and renal excretion of 2,8-dihydroxyadenine (DHA)
    • Autosomal recessive inheritance
Phosphoribosyl pyrophosphate chemical structure

Chemical structure of phosphoribosyl pyrophosphate:
This pentose phosphate plays an important role in transferring phosphoribose groups to accommodate different reactions. Increased levels of this chemical are seen with Lesch-Nyhan syndrome.

Image: “Skeletal formula of phosphoribosyl pyrophosphate (PRPP).” by Fvasconcellos. License: Public Domain


Lesch-Nyhan syndrome

  • HPRT deficiency
  • Results in failure of salvage pathway for hypoxanthine and guanine; purines degraded to uric acid
  • Decreased inositol monophosphate and guanosyl monophosphate results in an increase in conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) to 5-phosphoribosylamine:
    • Exacerbates uric acid overproduction
    • Hyperuricemia predisposes to gout and further complications.
Inositol structure

General structure of inositol:
Less inositol monophosphate is produced in Lesch-Nyhan syndrome as more uric acid is produced, resulting in hyperuricemia.

Image: “Inositol” by Edgar181. License: Public Domain

Adenine phosphoribosyltransferase deficiency

  • Deficiency in the APRT enzyme that hinders salvaging of adenine
  • Accumulation of adenine results in its oxidation into DHA → precipitates in the urinary tract 
  • Can cause nephrolithiasis and renal failure

Clinical Presentation

Lesch-Nyhan syndrome

  • Presents within the 1st year of life: xanthine in the urine (orange sandy precipitate) often 1st sign
  • Neurologic dysfunction: 
    • Cognitive dysfunctions
    • Intellectual disability
    • Spastic cerebral palsy
    • Hypotonia
    • Involuntary movements
  • Psychiatric problems:
    • Behavioral dysfunctions
    • Self-mutilating behavior
  • Hyperuricemia:
    • Urolithiasis
    • Nephropathy
    • Gouty arthritis
    • Tophi
  • Hematologic: macrocytic anemia

Adenine phosphoribosyltransferase deficiency

  • There is no typical age for clinical onset.
  • Renal dysfunction:
    • Uric acid nephropathy
    • Renal colic
    • Frequent infections
    • Renal failure


Lesch-Nyhan syndrome

  • Laboratory tests show hyperuricemia.
  • Urine studies show an elevation in the urate:creatinine concentration.
  • Genetic testing is diagnostic.

Adenine phosphoribosyltransferase deficiency

  • Diagnosis is made by identification of DHA in urine.
  • Other components of workup:
    • Physical examination of the eyes for patients with ophthalmologic symptoms
    • Laboratory studies of serum creatinine, urine studies
    • Imaging of the kidney with CT or ultrasonography to evaluate for kidney stones


Lesch-Nyhan syndrome

  • There is no cure for this disorder.
  • Treatments are aimed at reducing symptoms:
    • Allopurinol for hyperuricemia
    • Baclofen or benzodiazepines for spasticity
    • Behavioral and physical intervention for self-injurious behavior
  • Prognosis is poor, and patients most often die within the 1st 2 decades of life.

Adenine phosphoribosyltransferase deficiency

  • Treatment involves:
    • Purine restriction
    • High fluid intake
    • Avoidance of urine alkalinization
    • Allopurinol
    • Renal transplantation for end-stage renal disease
  • Prognosis is better than for Lesch-Nyhan syndrome if treatment controls renal disease. However, there is a risk of end-stage renal disease in patients who do not receive appropriate treatment.

Clinical Relevance

  • Urolithiasis: formation of stones in kidney, bladder, and/or urethra. The most common type of stone is a calcium oxalate stone. Patients often present with colicky flank pain radiating to the groin and hematuria. Patients are diagnosed using non–contrast-enhanced CT of the abdomen and pelvis. Management depends on the size of the stone. Small stones will pass spontaneously with conservative management (hydration, analgesics); large stones require intervention with extracorporeal shock wave lithotripsy or percutaneous nephrolithotomy. Complications include hydronephrosis and pyelonephritis.
  • Gout: medical condition caused by elevated uric acid levels and monosodium urate deposition in the tissue. The most common presentation is monoarticular acute arthritis. Most often, the first metatarsophalangeal joint is affected. Other organs, such as the kidneys can be affected. Diagnosis is confirmed with identification of urate crystals from a joint aspiration. Treatment for acute flares may include NSAIDs, colchicine, or glucocorticoids.
  • Tophi: deposit of monosodium urate crystals in hyperuricemic conditions. Tophi are most commonly seen in patients with gout and develop over time, usually appearing many years after a patient is noted to have hyperuricemia. Tophi can form throughout the body in locations such as joints, cartilage, and bones. These formations may lead to poor mobility and can cause bone destruction.


  1. NIH Genetic and Rare Diseases Information Center. (2019). Adenine phosphoribosyltransferase deficiency. GARD. Retrieved May 16, 2021, from https://rarediseases.info.nih.gov/diseases/546/adenine-phosphoribosyltransferase-deficiency
  2. Puig, J.G., Torres Jimenez, R. (2010). Lesch-Nyhan syndrome. Orphanet. Retrieved May 16, 2021, from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=510
  3. Jinnah, H.A. (2000). HPRT1 disorders. GeneReviews. Retrieved May 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK1149/
  4. Edvardsson, V.O., Sahota, A., Palsson, R. (2012). Adenine phosphoribosyltransferase deficiency. GeneReviews. Retrieved May 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK100238

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