Adenine Phosphoribosyltransferase Deficiency: An Under-Recognized Cause of Urolithiasis and Renal Failure

Early diagnosis of monogenic forms of urolithiasis is important to prevent associated renal injury and other treatable disease manifestations, but is often delayed due to lack of knowledge of these rare disorders. Adenine phosphoribosyltransferase (APRT) deficiency is an under-recognized autosomal recessive disorder causing 2,8 dihydroxyadenine (2,8-DHA) urolithiasis and crystalline nephropathy secondary to intratubular 2,8-DHA crystalline precipitation. Patients often present with kidney stones but may also present with renal failure in the absence of stones or nephrocalcinosis. The disease can be efficiently treated by inhibitors of xanthine dehydrogenease (XDH), which makes early diagnosis and treatment essential to prevent recurrence of urolithiasis and nephropathy. Here, we reviewed 67 patients from 56 families with complete APRT deficiency identified at Necker Universitary Hospital, Paris, France, between 1978 and 2014. The initial clinical presentation was urolithiasis in all symptomatic pediatric patients. In adult patients, recurrent nephrolithiasis was a much more common presentation (73%) than crystalline nephropathy (27%). Unfortunately, APRT deficiency was often misdiagnosed and irreversible loss of renal function occurred in 20% of cases. APRT gene sequencing was performed in 54 patients (81%) in 46 families: 25 pediatric patients in 22 families and 29 adult patients in 26 families. 98 mutated alleles were found out of 108 analyzed (91%). Twenty seven different mutations were identified. A single T insertion at the intron 4 splice donor site (c.400+2dup) leading to a truncated protein, accounted for 36 percent of mutated alleles for pediatric and adult cases. This review summarizes the genetic data of a large cohort of pediatric and adult patients along with the issues for diagnosis and management of APRT deficiency and highlights the underdiagnosis associated with the potential severity of APRT deficiency. Early diagnosis is essential for treatment initiation and prevention of renal complications.