Purine Salvage Deficiencies

Overview

Definition

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.

Epidemiology

• 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

Etiology

• 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

Pathophysiology

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.

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

Diagnosis

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

Management

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.