Nephrol Dial Transplant (2003) 18: 1923–1925 DOI: 10.1093/ndt/gfg294

Case Report

End-stage renal failure in Lowe syndrome

Leila Tricot1, Yasmina Yahiaoui1, Luis Teixeira1, Leila Benabdallah1, Eugene Rothschild1, Jean-Pierre Juquel2, Veronique Satre3, Jean-Pierre Gru¨ nfeld1 and Dominique Chauveau1 Downloaded from https://academic.oup.com/ndt/article/18/9/1923/1842037 by guest on 29 September 2021 1Service de Ne´ phrologie, Hoˆpital Necker, Paris, 2Service de Ne´ phrologie, AURA, Paris and 3De´ partement de Biologie et Pathologie de la Cellule, Hoˆpital de la Tronche, Grenoble, France

Keywords: chronic renal failure; Fanconi syndrome; Case oculocerebrorenal syndrome Lowe syndrome was diagnosed at age 9 in the proband because ofpersistent proteinuria. Congenital bilateral cataracts were noted and operated on. However, visual Introduction acuity remained poor (1/20 bilaterally). Growth delay and mental retardation had been recognized in the first Oculocerebrorenal (OCRL) syndrome was first recog- year of life. On examination, facial appearance nized in 1952 by Lowe (OMIM # 309 000). It is char- included prominent forehead with deep set eyes and acterized by X-linked inheritance, congenital cataracts, horizontal nystagmus. Except for mental retardation mental retardation and renal Fanconi syndrome [1]. (IQ 48) and agitation, the neurological examination Additional features at presentation may also include was normal. There were no rickets. Mild renal failure growth retardation, rickets and areflexia and other eye was found: creatinine clearance was measured as anomalies such as glaucoma and search nystagmus. 45 ml/min/1.73 m2. Biochemical blood tests disclosed: In 1995, the molecular basis to the protean a normal glucose and protides concentration, 85 g/l; manifestations of Lowe syndrome was provided by kalaemia, 5.7 mmol/l; chloride, 107 mmol/l; calcium, mapping the OCRL1 gene to chromosome Xq24–26; it 2.42 mmol/l; phosphate, 1.34 mmol/l; pH 7.20; bicar- contains 23 exons with two main domains: one for bonate, 20 mmol/l. Diffuse hyperamino-aciduria and phosphatase activity and a homologous domain to Rho tubular-type proteinuria (3–6 g/l) were found. Proximal GAP, a small G protein ATPase. The protein is a tubular acidosis (type II) was documented with a phosphatidylinositol 4,5 biphosphate 5-phosphatase decreased bicarbonate reabsorption threshold. There [PtdIns(4,5)P2-5ase] localized in the Golgi complex. It is was no glucosuria. A renal biopsy was performed which thought to be involved in cellular differentiation and showed 10 sclerosed glomeruli out of50. The other migration [2]. The small GTPase Rho is known to glomeruli were normal or had a thickened Bowman’s regulate various cell functions involving cytosqueletal capsule. Some proximal tubules were normal while control. others were atrophic and surrounded by patchy The proximal tubule dysfunction is the hallmark of interstitial fibrosis. Some arterioles appeared slightly OCRL, presenting in early childhood as a Fanconi thickened. Treatment consisted ofalkalinization by syndrome, with no glucosuria. A non-homogeneous sodium bicarbonate (3.5 g/day) that corrected acidosis pattern ofthe decline ofglomerular filtration has been and growth. reported with a rapid deterioration in some but not all Left eye enucleation for glaucoma was performed at teenagers. Relying on a cross-sectional study, end-stage age 29. Blood pressure was normal. Renal failure renal disease (ESRD) was predicted to occur in the progressed slowly (mean yearly decline –0.8 ml/min). fourth decade [3]. However, no report documented the At age 35, he had moderate chronic renal insufficiency course ofrenal disease on long-term follow-up. Here, (serum creatinine, 250 mmol/l; estimated creatinine we report the characteristics ofrenal involvement, clearance, 30 ml/min according to the Cockcroft and including renal replacement therapy in a 49-year-old Gault formula). Renal ultrasound showed two small male with OCRL. kidneys (7 cm in size), with dedifferentiation and one cyst bilaterally but no nephrocalcinosis. Bone X-rays disclosed demineralization associated to hypocalcae- Correspondence and offprint requests to: Leila Tricot, Necker Hospital, mia (2.08 mmol/l) and hyperparathyroidism (PTH1–84, 149 rue de Se` vres, 75015 Paris, France. Email: [email protected] 323 pg/ml). 25-OH vitamin D3 therapy was started.

Nephrol Dial Transplant 18(9) ß ERA–EDTA 2003; all rights reserved 1924 L. Tricot et al. At age 48, a corneal graft was performed. Post- progressively disappear thereafter [4]. The course of operatively, the patient was given acyclovir for ocular proximal tubular dysfunction in our patient parallels herpes infection for 10 days. Renal function deterio- these previous findings, with Fanconi syndrome at age rated rapidly thereafter until referral for ESRD at 49 9, which disappeared later on. In our Division, a second years ofage. His weight was 65 kg fora final size of OCRL patient receives follow-up. At 28 years of age, 1.70 m. Blood pressure was 150/80 mmHg on anti- creatinine clearance is 17 ml/min (C. Naret, personal hypertensive therapy. Initially, the patient was mentally communication). Three different phases in the course unstable and had many stereotypical behaviours. He ofrenal decline in our patient may be outlined. First, became quieter when more familiar with the medical creatinine clearance was already impaired at age 9 and staff. slowly declined over the next 40 years. Finally, a sharp From 35 to 49 years ofage, he had lived in a decline occurred during the final months before dialy- specialized centre for the disabled. Although his family sis for which we cannot rule out acyclovir-related remained very supportive, the parents repeatedly nephrotoxicity. ESRD was reached at age 49, 13 declined any form of renal replacement therapy. At years later than predicted by Charnas et al. [3] on the Downloaded from https://academic.oup.com/ndt/article/18/9/1923/1842037 by guest on 29 September 2021 the time ofESRD, they changed their mind. Since the basis oftheir cross-sectional study in 23 patients patient could not make his own decision, and regular ranging from 4 months to 31 years. There is no treatment required specific learning ofboth the family longitudinal study examining the course ofrenal and the staff at the centre, the decision-making process decline in the long term in OCRL patients. The culprit involved all these partners. Finally, continuous ambu- mutation in our proband might be responsible for a latory peritoneal dialysis was considered the best milder renal phenotype as it lies in exon 21 outside technique because oftantrums. The treatment was ofthe functionalphosphatase domain ofocrl1. started and has been maintained uneventfully, alter- Conversely, a striking divergence in severity ofnon- natively at his institution or at home every weekend for renal manifestations was outlined in two unrelated 5 months. Additional evaluation towards placement on patients carrying the same mutation [5]. the waiting list for kidney transplantation is currently What are the mechanisms ofrenal decline in OCRL underway. syndrome? In our patient, at first evaluation, a patchy The mutation responsible for OCRL syndrome in tubulointerstitial nephropathy was found on biopsy at our patient was identified as a missense mutation in age 9. Although early proximal tubule anomalies are exon 21. It is localized in the Rho GAP domain ofthe the hallmark ofthe disease [1], no explanation fortheir gene but its precise function is still unknown. This mechanism has been provided so far. Some authors mutation was not due to polymorphism in OCRL as it also found thickening of all basement membranes of was not found in 20 normal subjects. The functional the kidney as well as an increase in glomerular significance ofthis mutation was checked by measuring cellularity. Nevertheless, neither laboratory nor histol- low functional activity of PtdIns(4,5)P2-5ase in skin ogy findings suggest a key role for glomerular fibroblasts ofthe patient. The familialscreening also involvement in renal decline, both in our patient and showed that the only sister and the two brothers ofthe in eight additional renal biopsies from OCRL children patient had not inherited the mutation; the carrier from the Enfants-Malades series (M.-C. Gubler, mother was heterozygous for the mutation and has unpublished results). Presumably, focal tubulointersti- bilateral lens opacities, anomalies which are often tial lesions extend progressively, leading to glomerular found in heterozygous females. obsolescence and ESRD. Interestingly, the pattern of renal decline in the OCRL syndrome sharply contrasts with that observed in cystinosis which is also Discussion characterized by early Fanconi syndrome but a much faster progression towards ESRD [3]. The early OCRL is a very rare genetic disease. While its crude mechanism ofprogressive renal decline in OCRL prevalence is still unknown, estimates in the Western cannot be fully understood until the function of the populations are 1–5 per million (according to the gene product within the Golgi complex is clarified. French Lowe Association). The disorder is recognized Superimposed causes ofrenal failure in OCRL early in childhood. patients such as rhabdomyolysis and nephrocalcinosis A diagnosis ofOCRL was made at age 9 years in our were ruled out in our patient. Renal failure and acidosis patient, relying on bilateral congenital cataracts, are the major causes ofreduced longevity in OCRL mental retardation, growth delay and the characteristic patients in the early literature with no detail on the Fanconi syndrome without glucosuria. Interestingly, precise cause ofmortality [4]. With better management growth delay was reversed with alkalinization and the ofmetabolic derangements, longer survival might be patient’s final height was normal. This sharply expected. However, to our knowledge long-term contrasts with the very low final height in four adult follow-up and outcome of renal replacement therapy patients reported by Charnas et al. [3]. in adult OCRL patients have not been reported. Renal Although a prominent feature, Fanconi syndrome is replacement therapy presents more difficulties in not congenital in OCRL syndrome. Metabolic anoma- OCRL patients because ofmental delay and poorly lies including acidosis, aminoaciduria and organic adapted behaviour. In many OCRL patients the aciduria are fully manifest for a few years, and necessary compliance with treatment may not be End-stage renal failure in Lowe syndrome 1925 achievable as unpredictable behaviour may prevent References successful dialysis. Decisions regarding initiation or withdrawal ofdialysis in severely mentally retarded 1. Lowe CUTM, MacLachlan EA. Organic-aciduria, decreased renal amonia production, hydrophtalmos and mental retarda- patients are difficult. The views of the family and tion. Am J Dis Child 1952; 83: 164–184 staff in the institution where the patient lives on a 2. Olivos-Glander IMJP, Nussbaum RL. The oculocerebrorenal daily basis must be sought. The General Medical syndrome gene product is a 105-kD protein localized to the Council in the UK has recently published guidelines Golgi complex. Am J Hum Genet 1995; 57: 817–823 on clinical decision-making in this complex area [6]. 3. Charnas LBI, Rader D, Hoeg J, Gahl W. Clinical and Kidney transplantation in recipients with mental laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. retardation was reported to provide excellent patient N Engl J Med 1991; 324: 1318–1325 and graft survival rates and a better quality of life in 4. Abbassi V, Lowe UC, Calcagno PL. Oculo-cerebro-renal selected patients with Down syndrome [7]. The authors syndrome. Am J Dis Child 1968; 115: 145–168 concluded that the presence ofmental retardation 5. Leahey A-MCL, Nussbaum RL. Nonsense mutations in the should not be considered a contra-indication to a OCRL-1 gene in patients with the oculocerebrorenal syndrome Downloaded from https://academic.oup.com/ndt/article/18/9/1923/1842037 by guest on 29 September 2021 kidney transplant. In our patient, peritoneal dialysis ofLowe. Hum Mol Genet 1993; 2: 461–463 was elected as the first-line treatment. Whether or not 6. General Medical Council. Withholding and withdrawing life- prolonging treatments: good practice in decision-making. 2002. kidney transplantation is appropriate requires further Available at http://www.gmc-uk.org evaluation. 7. Benedetti EAM, Dunn T, Walczak DA et al. Kidney transplantation in recipients with mental retardation: clinical results in a single-center experience. Am J Kidney Dis 1998; 31: Conflict of interest statement. None declared. 509–512

Received for publication: 28.10.02 Accepted in revised form: 10.4.03