Partial Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency as the Unsuspected Cause of Renal Disease Spanning Three Generations: A Cautionary Tale

Abstract

ABSTRACT. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked defect of purine metabolism. Clinical manifestations are usually related to the degree of enzyme deficiency: complete HPRT deficiency (Lesch-Nyhan syndrome) presenting with severe neurologic or renal symptoms, or partial HPRT deficiency (Kelley-Seegmiller syndrome) manifesting as a gout-urolithiasis syndrome. A 3-generation kindred is described in which the recognition of partial HPRT deficiency in 2 adolescent male siblings presenting with uric acid lithiasis led to the diagnosis in 2 maternal uncles already in renal failure of unknown cause. This report highlights the importance of clinical awareness leading to early diagnosis, appropriate diagnostic methodology, and therapy of a treatable inherited disorder of purine metabolism for the prevention of renal failure. Pediatrics 2002;109(1). URL: http://www. pediatrics.org/cgi/content/full/109/1/e17; hypoxanthineguanine phosphoribosyltransferase deficiency, renal failure.ABBREVIATIONS. HPRT, hypoxanthine-guanine phosphoribosyltransferase; LND, Lesch-Nyhan disease.H ypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.3.8) is an ubiquitous, cytoplasmic, housekeeping enzyme with highest activity in the brain and testes. HPRT catalyzes the transfer of the phosphoribosyl moiety of PP-ribose-P to hypoxanthine and guanine, forming inosine monophosphate and guanosine monophosphate, respectively. Inability to recycle hypoxanthine and guanine produces a lack of feedback control of synthesis accompanied by rapid catabolism of these bases to uric acid (Fig 1). 1-3 HPRT deficiency (McKusick #308000) is an X-linked defect (Xq26-q27.2) of purine metabolism with considerable genetic and clinical heterogeneity, the biochemical hallmark being increased levels of uric acid in blood and urine. [1][2][3][4][5][6] Clinical manifestations are related to the degree of enzyme deficiency, complete HPRT deficiency (Lesch-Nyhan disease; LND) presenting with severe neurologic (compulsive self-injury biting, choreoathetosis), gout, and renal symptoms (kidney stones, renal failure). 1-4 Partial HPRT deficiency (Kelley-Seegmiller syndrome) has a broad spectrum of presentation ranging from gout and urolithiasis only, to intermediate forms characterized according to the severity of neurologic involvement. [1][2][3][4][5][6] Prognosis in terms of renal complications in the partial defect depends on early diagnosis. Prenatal diagnosis is possible in LND by direct enzyme assay in a chorionic villous sample, or by molecular analysis where the mutation is well-defined. [1][2][3][4] From the University A' ‡Pediatric Department, *Biochemistry Laboratory, University Second Internal Medicine Department, Hippocration General Hospital, Thessaloniki, Greece; and §Purine Research Unit, Guy's Hospital, London, United Kingdom. We describe a 3-generation kindred in which the diagnosis of partial HPRT deficiency in 2 adolescent male siblings presenting with urolithiasis led to the diagnosis in a maternal brother and...

Uric Acid and the Kidney: Urate Transport, Stone Disease and Progressive Renal Failure

“…Thus, in humans, the hypoxanthine guanine phosphoribosyl transeferase pathway exclusively handles purine catabolism. Complete disruption of this pathway causes the severely disabling and self-mutilating Lesch-Nyhan syndrome and partial disruption the milder Kelley-Seegmiller syndrome (with predominant uric acid lithiasis and nephropathy) [3]. The kidney plays an important role in uric acid metabolism: approximately two thirds of the daily turnover of urate is accounted for by urinary excretion and the remaining one third is excreted via the gut, biliary tract and in gastric and intestinal fluids (intestinal secretion and uricolysis by gut flora) [4].…”

“…Functional studies confirm that URAT1 exhibits properties consistent with those previously described for urate transport activity in human BBM vesicles. URAT1 exchanges OH -or HCO 3 -for urate, operating in parallel with the sodium-proton (Na + /H + ) exchanger, or monocarboxylates (e.g. lactate) or dicarboxylates in parallel with their Na + -coupled co-transport [14] (not shown in Fig.…”

Partial hypoxanthine-guanine phosphoribosyltransferase deficiency presenting as acute renal failure

“…After arriving at the diagnosis in this case, we were intrigued to find a recent publication in Pediatrics documenting a family in Thessalonika, Greece, with the same disorder of HPRT deficiency [11]. It transpires that the patient we report is a direct descendant of that family, with a sex-linked inheritance pattern.…”

Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency

“…Nephrocalcinosis ( 12), and acute polyarthritis were some of the manifestations attributable to uric acid precipitation occurring before allopurinol was prescribed. Renal failure or sepsis secondary to urinary tract infections has also been described as causes of death in patients with HPRT deficiency and uncontrolled hyperuricemia [33,34]. However, effectiveness of a drug therapy must consider adverse effects as well as efficacy.…”