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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 976
A rare genetic nephropathy secondary to a disorder of purine metabolism characterized by the formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy.
Prevalence is estimated at 1/50,000 to 1/100,000 in Caucasian, 1/27,000 in Japanese and > 1/15,000 in Icelandic populations. Adenine phosphoribosyltransferase deficiency (APRT) deficiency appears to equally affect children and adults, male or female. In Caucasian populations, heterozygous prevalence is estimated between 0.4% and 1.2%.
Clinical manifestations include symptoms usually associated with urolithiasis. Stones are typically radiolucent. Onset can be between infancy and the 4th decade of life, or sometimes even later. A small portion of patients remain asymptomatic. The disease can present not only as urolithiasis but also as crystalline nephropathy secondary to the precipitation of 2,8-DHA into renal parenchyma (DHA nephropathy). DHA nephropathy occurs most often in patients with repeated misdiagnosed episodes of urolithiasis and progressive worsening of renal function, but it may also present as acute renal failure. Rarely, DHA nephropathy may occur in patients who experienced only a few stone episodes. DHA nephropathy can evolve to end stage renal disease requiring dialysis and transplantation and can recur after transplantation causing rapid loss of graft function if left untreated.
APRT deficiency is an autosomal recessive (AR) disorder caused by mutations in the APRT gene (16q24) encoding the APRT enzyme catalyzing AMP synthesis from adenine and 5'-phosphoribosyl-1-pyrophosphate. Two types of APRT deficiencies have been described, according to APRT activity in vitro ; type I characterized by a total lack of APRT activity, found primarily in Caucasians, and type II, found only in Japan, characterized by a 10-25% APRT activity. This in vitro distinction has no known clinical significance.
Lack of awareness of APRT deficiency often causes a significant delay between the onset of symptoms and a proper diagnosis. Diagnosis is primarily based on identifying 2,8-DHA by examination of crystals or stones. Crystalluria examination can be used for diagnosis. In DHA nephropathy patients, crystals may also be identified in renal biopsy, although this invasive test is theoretically unnecessary. Crystals and stones should be analyzed by morphologic examination combined with infrared spectrometry and/or x-ray crystallography. Diagnosis can be confirmed by enzyme activity analysis in erythrocyte lysates. Genetic testing may be used for diagnosis but may be useful for familial screening.
Confusion frequently occurs between 2,8-DHA and uric acid stones, which are typically both radiolucent. Contrary to uric acid, 2,8-DHA stones do not respond to alkali therapy. Differential diagnosis also includes other radiolucent stones, such as cystine, xanthine and drugs.
Genetic counseling is possible but rarely indicated. However, given the AR transmission, siblings of the affected individual, even if they are asymptomatic, should be screened through DNA analysis or APRT activity.
Management and treatment
To prevent further 2,8-DHA formation, treatment consists of allopurinol daily (usually 10mg/kg per day in children and 300 mg per day in adults) together with a high fluid intake and low purine diet. In cases of acute or chronic renal failure, allopurinol doses should be reduced. Asymptomatic individuals should be treated by allopurinol to prevent renal complications. Febuxostat, another xanthine oxydase inhibitor, may be even more efficacious than allopurinol in reducing DHA excretion. It remains unknown how this translates into improved patient outcomes. Febuxostat should be recommended in allopurinol-intolerant patients and also in rare patients who do not respond well to allopurinol.
Early diagnosis is the key and prognosis depends on progression of this treatable disorder. Allopurinol therapy effectively prevents stone recurrence and can lead to an improvement or stabilization of renal function in most patients. Stone recurrence and renal complications are rare in patients who remain compliant with allopurinol therapy.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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