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Complete Deficiency of Adenine Phosphoribosyltransferase

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Complete Deficiency of Adenine Phosphoribosyltransferase Arch Dis Child: first published as 10.1136/adc.54.1.25 on 1 January 1979. Downloaded from Archives of Disease in Childhood, 1979, 54, 25-31 Complete deficiency of adenine phosphoribosyltransferase A third case presenting as renal stones in a young child T. M. BARRATT, H. A. SIMMONDS, J. S. CAMERON, C. F. POTTER, G. A. ROSE, D. G. ARKELL, AND D. I. WILLIAMS Department of Medicine, Guy's Hospital, The Hospital for Sick Children, Great Ormond Street, and the Institute of Urology, St Philip's Hospital, London SUMMARY We report a third case of 2, 8-dihydroxyadenine stones in a child with a complete lack of the adenine salvage enzyme-adenine phosphoribosyltransferase (APRT). The propositus, a 20-month-old girl of consanguineous Arab parents, presented with multiple urinary tract infections and supposed 'uric acid' stones in the right renal pelvis and left ureter. Both parents and one brother were heterozygotes for the defect, in keeping with an autosomal recessive mode of inheritance. In contrast with the other purine salvage enzyme disorder of childhood with true uric acid stones (the Lesch-Nyhan syndrome), uric acid excretion was normal in all family members. As in our previous case, treatment with allopurinol, without alkali, has eliminated the urinary excretion of 2, 8-dihy- droxyadenine: the stones were removed surgically. 2, 8-Dihydroxyadenine should be considered in any child thought to have uric acid stones and tests made to distinguish the two compounds. Many urinary stones or crystals identified in children AMP IMP result from the overexcretion of normally minor http://adc.bmj.com/ urinary constituents, compounds of limited solubility whose overexcretion may be the direct consequence adenosine inosine of a block in an essential step in a metabolic pathway. Examples are found in hereditary oroticaciduria¢< l~~~~~~~NP3 (Smith et al., 1972), xanthinuria (Dent and Philpot, ADENINE hypoxanthine 1954), and the Lesch-Nyhan syndrome (Nyhan, I xo I 1973). In the Lesch-Nyhan syndrome, uric acid stones or gravel form because of gross overproduction of 8-HYDkOXYADENINE xanthine on October 4, 2021 by guest. Protected copyright. uric acid arising from a lack of the hypoxanthine jXo xoI salvage enzyme-hypoxanthine-guanine phosphori- 2, 8-DIHYDROXYADENINE uric acid bosyltransferase (HGPRT: EC 2.4.2.8) (Fig. 1). These also have bizarre neurological APRT = adenine phosphroibosyltransferase; HGPRT = hypoxan- children thine guanine phosphoribosyltransferase; NP = nucleoside complications and other clinical manifestations phosphorylase; XO = xanthine oxidase; AMP = adenosine (Nyhan, 1973). monophosphate (adenylate); IMP = inosine monophosphate (inosinate). Institute of Child Health, London Fig. 1 Metabolic pathways of purine degradation T. M. BARRATT, professor of nephrology andsalvage illustrating the origin of2, 8-dihydroxyadenine. Guy's Hospital, London In the adenine becomes available H. A. SIMMONDS, lecturer in medicine absence ofAPRT, for J. S. CAMERON, professor of renal medicine oxidation by xanthine oxidase to hydroxy- then C. F. POTTER, research assistant dihydroxyadenine, in a fashion analogous to the production Institute of Urology, London ofuric acidfrom hypoxanthine. In man, adenine cannot G. A. ROSE, consultant biochemist be converted to adenosine by nucleoside phosphorylase D. 1. WILLIAMS, consultant urologist as hypoxanthine may be converted to inosine, so this St Peter's Hospital, London route is not available for disposal of adenine. The only D. G. ARKELL, senior registrar alternative pathway is oxidation. 25 Arch Dis Child: first published as 10.1136/adc.54.1.25 on 1 January 1979. Downloaded from 26 Barratt, Simmonds, Cameron, Potter, Rose, Arkell, and Williams A complete lack of the other purine salvage showed a nonfunctioning left kidney, and a radio- enzyme-adenine phosphoribosyltransferase lucent calculus in the pelvis of the right kidney (APRT: EC 2.4.2.7)-was described in children of (Fig. 3). She was 81 cm in height, 10 0 kg in weight, two separate families, one in France (Cartier and and had red hair. Neither kidney was tender or Hamet, 1974; Debray et al., 1976) and the other from palpable, and neurological examination was normal. our own unit (Simmonds et al., 1976a, b; Van Acker However, urine culture showed a growth of >105 et al., 1977). Children with this deficiency also Klebsiella aerogenes/ml, with numerous leucocytes, present with urolithiasis, because of the excretion of red cells, and debris. Hb was 11 *6 g/dl, WBC 14 400 2, 8-dihydroxyadenine, an extremely insoluble /mm3 (14.4 x 109/l). Plasma electrolytes were analogue of uric acid (Fig. 1). The excretion of this normal, with blood urea 4.5 and 3*4 mmol/l (27 compound follows the accumulation of adenine in and 20 mg/100 ml). Plasma creatinine was initially the absence of the salvage enzyme, APRT, and its 40 ,mol/l (0 45 mg/100 ml), but later was 100 oxidation by xanthine oxidase via the 8-hydroxy and 120 ,umol/l (1 13 and 1-36 mg/100 ml). Serum intermediate (Fig. 1) (Bendich et al., 1950). urate was 0 *24 mmol/l (4 mg/100 ml) by a nonspecific We report studies in a third family with a complete colorimetric method. The differential diagnosis of lack of the APRT enzyme. Stones of 2, 8-dihydroxy- uric acid, or 2, 8-dihydroxyadenine urolithiasis was adenine were present in the daughter. As in the two considered. previous cases, the stones were first mistaken for At the 1st operation (May 1977) cystoscopy and uric acid because 2, 8-dihydroxyadenine and uric ureteric catheterisation showed a block in the left acid are indistinguishable in chemical tests used ureter 2 cm from the bladder. This calculus was routinely for identifying uric acid stones (Simmonds removed by ureterolithotomy, and the stone in the et al., 1978). pelvis of the right kidney was removed later at the same operation. Both stones were friable and greyish Clinical data in colour. The urinary infection was treated with cephalexin 125 mg four times a day. The patient was born in August 1975, the 3rd child Examination of the stones by thermogravimetric of consanguineous Arab parents (Fig. 2). Birth was analysis (Rose and Woodfine, 1976) suggested uric normal and she was well until aged one year, when acid, but further examination by wet chemistry she began to suffer repeated attacks of abdominal (Westbury and Omenoger, 1970) and by other pain and fever. These were diagnosed as urinary tract specific techniques (see Methods) showed them to be infections and, in May 1977, she was referred, aged composed of almost pure 2, 8-dihydroxyadenine for investigation of lithiasis. An IVU (Simmonds et al., 1978). Studies of urinary purines 21 months, http://adc.bmj.com/ II Fig. 2 The family of the propositus. None on October 4, 2021 by guest. Protected copyright. of the other members III of the family has dihydroxyadenine stones, but only the lV immediate family was testedfor APRT activity (Table 2). Consanguinity is present, the father's grandparents and v and the mother's great-grandparents being the same. * complete APRT deficiency 0 deceased 4) Heterozygote O not yet tested \ propositus Arch Dis Child: first published as 10.1136/adc.54.1.25 on 1 January 1979. Downloaded from Complete deficiency of adenine phosphoribosyltransferase 27 Fig. 3 IVU taken in May 1977 whenpatient was aged 21 months. The left kidney does not function at all, and there is a large radiolucent stone (arrow) in thepelvis ofthe right kidney. and purine enzyme activities showed complete lack allopurinol dosage increased to 20 mg/kg per 24 h; of APRT (see Methods and Results). on this dose the urine became free of 2, 8-dihydroxy- The child was treated with allopurinol 10 mg/kg adenine. Because of the risk ofxanthine or oxipurinol per 24 h and she returned home. Three months later, calculi, this dosage was later reduced to 15 mg/kg per in August 1977, she returned for more extensive 24 h, and the child returned home on this treatment. examination. In the interval she had had several more During the period of investigation of the proposi- urinary tract infections, treated with cephalexin and tus, her father suffered from an episode of renal colic, nitrofurantoin. In two of these, Kl. aerogenes was but the stone passed was subsequently identified as again grown from the urine, and in the 3rd attack- pure calcium oxalate. Escherichia coli. Otherwise she was well and had http://adc.bmj.com/ grown 1 *6 kg, and 4 cm in height. Examination of renal function showed a glomerular filtration rate of 90 ml/min per 1 *73 m2, with only 13 % of renal func- tion from the left kidney, as judged by scanning with DMSA. Plasma creatinine was 50, 46, and 56 ,umol/l (0-56, 0-52, and 0.63 mg/lOOml) and blood urea 3 0, 4-1, and 6-0 mmol/l (18, 24, 36 mg/100 ml). on October 4, 2021 by guest. Protected copyright. Urine culture showed Klebsiella. TVU and micturating cystography showed a doubtful calculus in the right renal pelvis, and several stones in a grossly refluxing left ureter and pelvis (Fig. 4). At the 2nd operation the left renal parenchyma appeared reasonably well preserved, and the stones were removed from the left by ureter pyelolithotomy and ureterolithotomy. A stricture at the site of the previous removal of stone from the left ureter was repaired. At a 3rd operation (September 1977), retrograde catheterisation of the right urinary tract showed 2 stones in the pelvis of the right kidney Fig. 4 Micturating cystogram, August 1977, when similar to those removed previously: these were patient was aged 24 months. There is reflux ofcontrast extracted. medium into the left urinary tract, and several stones The Klebsiella infection was again treated with are present in the pelvis and ureter.
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