Adenine phosphoribosyltransferase (APRT) deficiency is an underrecognized, autosomal recessive disorder of adenine metabolism, leading to 2,8-dihydroxyadeninuria that causes nephrolithiasis and kidney failure in a significant proportion of untreated patients. APRT deficiency has been found in all ethnic groups and 24 functionally significant human APRT mutations have been reported to date. Of more than 300 cases of APRT deficiency reported world-wide, more than 200 are from Japan, a substantial number of patients come from France and Iceland, and about 15 cases have been reported in the US. The estimated prevalence is 0.5 to 1 per 100,000 in the Caucasian population, 0.25 to 0.5 per 100,000 in the Japanese population and in Iceland the estimated point prevalence is 8.9/100,000. Likely explanation for the low prevalence in other countries includeJack of awareness of the disorder, inadequate evaluation of patients with kidney stones, and erroneous diagnosis of 2,8-dihydroxyadenine (2,8-DHA) stones as uric acid or xanthine stones as they are all radiolucent. The diagnosis of APRT deficiency is simple as the pathognomonic 2,8-DHA urinary crystals are readily detected by routine urine microscopy in almost all affected patients. Allopurinol is an effective and generally well-tolerated therapy that prevents recurrent stone disease and kidney failure. Our hypothesis is that the disease is significantly underdiagnosed in many countries, including in the US, and the establishment of a world-wide registry will facilitate the diagnosis and proper treatment of previously unidentified cases. The goals of this project are: (1) to collect clinical data into an International APRT Deficiency Registry in order to develop strategies for increasing the awareness and detection of APRT deficiency and thus improve clinical outcomes;(2) to determine the variables associated with stone recurrence and the efficacy of pharmacologic prevention;(3) to perform APRJ mutation analysis in all participating patients who have not had an APRT mutation identified previously, study genotype-phenotype correlations and assess the role of urinary metabolic risk factors on the formation of kidney stones;(4) to interface with patient organizations, health care professionals and researchers through our APRT Deficiency Website to further enhance the educational mission of this project and disseminate knowledge to the community;and (5) to develop a biobank for DNA and urine samples that can later be used for research, such as examination of the role of modifying genes.
The research team is well fit to carry out this research, given the vast experience of individual team members in all aspects of APRT deficiency, including the diagnosis and treatment, in addition to the large study population that they will bring to the Registry. We propose that this work will markedly reduce the suffering of affected patients and significantly reduce health care costs associated with APRT deficiency.
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