Adenine Phosphoribosyltransferase Deficiency - Clinical Characteristics, Diagnosis, and Treatment

Introduction

Adenine phosphoribosyltransferase deficiency is a rare metabolic disorder that causes excessive excretion of 2,3-dihydroxyadenine (DHA) in urine. 2,3-dihydroxyadenine has very low solubility, leading to urine precipitation in the form of kidney stones and crystals. It can cause complications such as urolithiasis and nephropathy secondary to crystal precipitation into renal parenchyma. Adenine phosphoribosyltransferase deficiency is an autosomal recessive inheritance.

What Is the Metabolic Mechanism of Adenine Phosphoribosyltransferase Deficiency?

The adenine phosphoribosyltransferase enzyme is a metabolic pathway for adenine resulting from polyamine biosynthesis and dietary sources. Adenine phosphoribosyltransferase catalyzes the formation of inorganic phosphate and 5-adenosine monophosphate. This helps detect adenine only at low levels in urine and blood. In individuals with deficiency, adenine gets converted to 8-hydroxyadenine, which, with the help of xanthine dehydrogenase, gets metabolized to 2,3-dihydroxyadenine. 2,3-dihydroxyadenine helps in both tubular secretion and filtration, because of which it has a high renal clearance. This results in increased accumulation of 2,3-dihydroxyadenine levels in urine in individuals with Adenine phosphoribosyltransferase deficiency. The insoluble nature of 2,3-dihydroxyadenine causes its accumulation in the urine, leading to crystal formation and kidney stones. The crystal of 2,3-dihydroxyadenine can precipitate in the renal parenchyma, causing crystalline nephropathy.

What Is Adenine Phosphoribosyltransferase Deficiency?

APRT deficiency results in the deposition of 2,8-DHA in the renal tissue and causes nephrolithiasis or the formation of kidney stones and renal dysfunction. People usually experience symptoms in childhood or early adulthood, including recurring formations of renal calculi, recurrent urinary system infections, hematuria, and flank pains. In some forms, the disease does not manifest symptoms until severe kidney damage has already taken its toll.

What Is the Etiology of Adenine Phosphoribosyltransferase Deficiency?

APRT deficiency is a rare inherited disorder manifesting an autosomal recessive pattern due to a mutation in the APRT gene, which is found at chromosome 16q24. APRT enzyme is involved in the salvage pathway of adenine, where it transforms the substance into adenosine monophosphate (AMP). Lack of this enzyme results in the build-up of adenine, which is then transformed to 2,8-dihydroxyadenine (2,8-DHA) by xanthine oxidase. 2,8-DHA has very low solubility and gets deposited in the kidneys in the form of crystals, leading to the development of nephrolithiasis and chronic kidney diseases.

What Is the Diagnosis of Adenine Phosphoribosyltransferase Deficiency?

The approach to diagnosis in individuals with adenine phosphoribosyltransferase deficiency is based on the following findings:

Clinical Findings:

• Chronic kidney disease.

• Renal colic disease.

• Kidney stone disease.

• Crystal nephropathy.

• Allograft dysfunction after kidney transplantation.

• Reddish-brown diaper stain in young children and infants.

Radiographic Findings:

• Increased echogenicity of the kidneys, which is detected by ultrasound.

• Radiolucent kidney stones.

Laboratory Findings:

• Kidney Stone Analysis: Ray crystallography and infrared or ultraviolet spectrometry help differentiate 2,3-dihydroxyadenine from uric and xanthine, which also form radiolucent stones. The major components of stones in an individual with adenine phosphoribosyltransferase deficiency are 2,3-dihydroxyadenine and other minor minerals.

• Urine Microscopy: 2,3-dihydroxyadenine crystals are red and brown and can be detected by urine microscopy when viewed in polarized light microscopy. The 2,3-dihydroxyadenine crystals appear small and medium-sized with a central Maltese cross pattern. The larger crystals cannot be detected because they are not impermeable to light. Individuals with advanced chronic kidney disease have reduced 2,3-dihydroxyadenine clearance in the kidney, making crystals difficult to detect. High urine pH in individuals with radiolucent stones can help in the diagnosis of adenine phosphoribosyltransferase deficiency.

• Pathologic Findings: The findings show diffuse tubulointerstitial 2,3-dihydroxyadenine crystal deposits along with inflammation and fibrosis. These findings can also be observed in an individual without kidney disease. Kidney biopsy may show 2,3-dihydroxyadenine crystal nephropathy and crystals in the tubular lumen.

What Are the Clinical Characteristics?

• Age: The signs and symptoms do not occur until adulthood in many cases but can affect an individual at any age. A study by Runolfsdottir et al. stated that individuals with adenine phosphoribosyltransferase deficiency ranged from six months to 72 years, and around 18 % of the individuals with adenine phosphoribosyltransferase deficiency were diagnosed before the age of eighteen. Routine microscopy, abdominal ultrasound, CT, and screening of affected individuals helped in the diagnosis of asymptomatic individuals.

• Kidney Stone Disease: In most cases, the individual will have kidney stones at the time of diagnosis. Untreated cases show stone recurrence, abdominal pain, and lower urinary tract symptoms like dribbling, hesitancy, straining, and incomplete voiding.

• Chronic Kidney Disease: Is present in more than 50 % of cases secondary to 2,3-dihydroxyadenine crystal nephropathy. At the time of adenine phosphoribosyltransferase deficiency diagnosis, most individuals would have progressed to end-stage renal disease. However, it was noted that the deficiency was detected after a kidney transplant in many cases.

• End-Stage Renal Disease: Adequate pharmacological intervention and early diagnosis can prevent the progression of chronic kidney disease to end-stage renal disease. Cases that are treated with Allopurinol or Febuxostat have a good prognosis.

What Is the Prevalence of Adenine Phosphoribosyltransferase Deficiency?

Adenine phosphoribosyltransferase deficiency is a rare disease, and most of the cases recorded were from Japan. 1/27000 of the population of Japan had adenine phosphoribosyltransferase deficiency. There have also been cases from Iceland and France. In heterozygotes, the incidence is higher than 1.2 %. In the white population, the incidence was 0.4 % to 1.2 % based on the enzyme activity of healthy individuals. Homozygotic cases ranged between 1/50000 and 1/100000, which are mostly undiagnosed cases.

Differential Diagnosis:

Differential diagnosis of adenine phosphoribosyltransferase deficiency involves cases of radiolucent kidney stones:

• Uric acid nephrolithiasis (a renal complication of a metallic disorder).

• Xanthinuria (a condition in which there is excessive urinary excretion of xanthin).

What Are the Treatment Modalities for Adenine Phosphoribosyltransferase Deficiency?

For Prevention and Reduction of Kidney Stones:

• Reduction of Renal 2,3-Dihydroxyadenine Excretion: Allopurinol 5 to 10 mg/kg per day or in 2 divided doses. The dosage should not be routinely reduced and may be prescribed lifelong for individuals with advanced chronic kidney disease and a history of kidney transplantation. Febuxostat 80 mg per day is more efficacious than Allopurinol.

• Reduction of Urine 2,3-Dihydroxyadenine Saturation and Crystallization: Adequate fluid intake may be adjunctive to pharmacotherapy.

• 2,3-Dihydroxyadenine Kidney Stones: Surgical approach or extracorporeal shock wave lithotripsy.

• Chronic Kidney Disease: Management of hypertension and reduction of cardiovascular risk factors. Individuals with proteinuria are prescribed ACE inhibitors or angiotensin receptor blockers.

• End-Stage Renal Disease: Treatment options are dialysis and kidney transplant. Individuals have been prescribed Allopurinol or Febuxostat.

Pregnancy Management:

Studies conducted on the usage of Allopurinol and Febuxostat have shown fetal toxicity or maternal toxicity in animals. Hence, precautions must be taken before prescribing these drugs and should be done so only if the benefits outweigh the risks. The drugs should be prescribed to women with adenine phosphoribosyltransferase deficiency who have undergone a kidney transplant, have chronic kidney disease, or have reduced glomerular filtration rate. Post-transplantation immunosuppressive therapies have side effects on the developing fetus.

What Is the Prognosis of Adenine Phosphoribosyltransferase Deficiency?

The outcomes of the individuals with APRT deficiency depend on the frequency and severity of the renal complications. Such signs, if diagnosed early and managed, can go a long way in helping the situation and avoid a complete transition to chronic kidney disease. In case of neglected recurrent kidney stones and crystal nephropathy, the patient is at risk of developing kidney failure. If patients adhere to the treatment throughout their lifetime and have regular follow-ups, most patients will have normal kidney function and a good quality of life.

How Is Genetic Counseling Done for Adenine Phosphoribosyltransferase Deficiency?

Counseling is important, especially for families affected by APRT deficiency. Since it is an autosomal recessive disease, both parents pass on the defective gene to the child so that the child can be affected. This means that if both parents are carriers of the disorder, the likelihood of passing the same to the child is one in four, or 25 %, for each pregnancy. Carrier tests can also be done to determine who is a healthy and recessive gene carrier, which is useful in family planning. Pre-natal diagnostic methods and pre-implantation genetic diagnosis are the available measures that can be taken by such couples to have a child free from the disease. Patients should discuss the disease type and its pattern, as well as related risks with other relatives.

Conclusion

Adenine phosphoribosyltransferase deficiency is a rare metabolic disorder that causes excessive excretion of 2,3-dihydroxyadenine (DHA) in urine. In addition, 2,3-dihydroxyadenine has very low solubility, leading to precipitation in the urine in the form of kidney stones and crystals. Complications involve urolithiasis and nephropathy secondary to crystal precipitation into renal parenchyma. Early diagnosis and preventive care help restore renal function and reduce morbidity and mortality rates.