End-stage renal failure in Lowe syndrome

Leila Tricot1, Yasmina Yahiaoui1, Luis Teixeira1, Leila Benabdallah1, Eugene Rothschild1, Jean-Pierre Juquel2, Veronique Satre3, Jean-Pierre Grünfeld1 and Dominique Chauveau1

1 Service de Néphrologie, Hôpital Necker, Paris, 2 Service de Néphrologie, AURA, Paris and 3 Département de Biologie et Pathologie de la Cellule, Hôpital de la Tronche, Grenoble, France

Correspondence and offprint requests to: Leila Tricot, Necker Hospital, 149 rue de Sèvres, 75015 Paris, France. Email: tricot{at}necker.fr

Keywords: chronic renal failure; Fanconi syndrome; oculocerebrorenal syndrome



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Oculocerebrorenal (OCRL) syndrome was first recognized in 1952 by Lowe (OMIM # 309 000). It is characterized by X-linked inheritance, congenital cataracts, mental retardation and renal Fanconi syndrome [1]. Additional features at presentation may also include growth retardation, rickets and areflexia and other eye anomalies such as glaucoma and search nystagmus.

In 1995, the molecular basis to the protean manifestations of Lowe syndrome was provided by mapping the OCRL1 gene to chromosome Xq24–26; it contains 23 exons with two main domains: one for phosphatase activity and a homologous domain to Rho GAP, a small G protein ATPase. The protein is a phosphatidylinositol 4,5 biphosphate 5-phosphatase [PtdIns(4,5)P2-5ase] localized in the Golgi complex. It is thought to be involved in cellular differentiation and migration [2]. The small GTPase Rho is known to regulate various cell functions involving cytosqueletal control.

The proximal tubule dysfunction is the hallmark of OCRL, presenting in early childhood as a Fanconi syndrome, with no glucosuria. A non-homogeneous pattern of the decline of glomerular filtration has been reported with a rapid deterioration in some but not all teenagers. Relying on a cross-sectional study, end-stage renal disease (ESRD) was predicted to occur in the fourth decade [3]. However, no report documented the course of renal disease on long-term follow-up. Here, we report the characteristics of renal involvement, including renal replacement therapy in a 49-year-old male with OCRL.



   Case
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 Introduction
 Case
 Discussion
 References
 
Lowe syndrome was diagnosed at age 9 in the proband because of persistent proteinuria. Congenital bilateral cataracts were noted and operated on. However, visual acuity remained poor (1/20 bilaterally). Growth delay and mental retardation had been recognized in the first year of life. On examination, facial appearance included prominent forehead with deep set eyes and horizontal nystagmus. Except for mental retardation (IQ 48) and agitation, the neurological examination was normal. There were no rickets. Mild renal failure was found: creatinine clearance was measured as 45 ml/min/1.73 m2. Biochemical blood tests disclosed: a normal glucose and protides concentration, 85 g/l; kalaemia, 5.7 mmol/l; chloride, 107 mmol/l; calcium, 2.42 mmol/l; phosphate, 1.34 mmol/l; pH 7.20; bicarbonate, 20 mmol/l. Diffuse hyperamino-aciduria and tubular-type proteinuria (3–6 g/l) were found. Proximal tubular acidosis (type II) was documented with a decreased bicarbonate reabsorption threshold. There was no glucosuria. A renal biopsy was performed which showed 10 sclerosed glomeruli out of 50. The other glomeruli were normal or had a thickened Bowman’s capsule. Some proximal tubules were normal while others were atrophic and surrounded by patchy interstitial fibrosis. Some arterioles appeared slightly thickened. Treatment consisted of alkalinization by sodium bicarbonate (3.5 g/day) that corrected acidosis and growth.

Left eye enucleation for glaucoma was performed at age 29. Blood pressure was normal. Renal failure progressed slowly (mean yearly decline –0.8 ml/min). At age 35, he had moderate chronic renal insufficiency (serum creatinine, 250 µmol/l; estimated creatinine clearance, 30 ml/min according to the Cockcroft and Gault formula). Renal ultrasound showed two small kidneys (7 cm in size), with dedifferentiation and one cyst bilaterally but no nephrocalcinosis. Bone X-rays disclosed demineralization associated to hypocalcaemia (2.08 mmol/l) and hyperparathyroidism (PTH1–84, 323 pg/ml). 25-OH vitamin D3 therapy was started. At age 48, a corneal graft was performed. Post-operatively, the patient was given acyclovir for ocular herpes infection for 10 days. Renal function deteriorated rapidly thereafter until referral for ESRD at 49 years of age. His weight was 65 kg for a final size of 1.70 m. Blood pressure was 150/80 mmHg on antihypertensive therapy. Initially, the patient was mentally unstable and had many stereotypical behaviours. He became quieter when more familiar with the medical staff.

From 35 to 49 years of age, he had lived in a specialized centre for the disabled. Although his family remained very supportive, the parents repeatedly declined any form of renal replacement therapy. At the time of ESRD, they changed their mind. Since the patient could not make his own decision, and regular treatment required specific learning of both the family and the staff at the centre, the decision-making process involved all these partners. Finally, continuous ambulatory peritoneal dialysis was considered the best technique because of tantrums. The treatment was started and has been maintained uneventfully, alternatively at his institution or at home every weekend for 5 months. Additional evaluation towards placement on the waiting list for kidney transplantation is currently underway.

The mutation responsible for OCRL syndrome in our patient was identified as a missense mutation in exon 21. It is localized in the Rho GAP domain of the gene but its precise function is still unknown. This mutation was not due to polymorphism in OCRL as it was not found in 20 normal subjects. The functional significance of this mutation was checked by measuring low functional activity of PtdIns(4,5)P2-5ase in skin fibroblasts of the patient. The familial screening also showed that the only sister and the two brothers of the patient had not inherited the mutation; the carrier mother was heterozygous for the mutation and has bilateral lens opacities, anomalies which are often found in heterozygous females.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
OCRL is a very rare genetic disease. While its crude prevalence is still unknown, estimates in the Western populations are 1–5 per million (according to the French Lowe Association). The disorder is recognized early in childhood.

A diagnosis of OCRL was made at age 9 years in our patient, relying on bilateral congenital cataracts, mental retardation, growth delay and the characteristic Fanconi syndrome without glucosuria. Interestingly, growth delay was reversed with alkalinization and the patient’s final height was normal. This sharply contrasts with the very low final height in four adult patients reported by Charnas et al. [3].

Although a prominent feature, Fanconi syndrome is not congenital in OCRL syndrome. Metabolic anomalies including acidosis, aminoaciduria and organic aciduria are fully manifest for a few years, and progressively disappear thereafter [4]. The course of proximal tubular dysfunction in our patient parallels these previous findings, with Fanconi syndrome at age 9, which disappeared later on. In our Division, a second OCRL patient receives follow-up. At 28 years of age, creatinine clearance is ~17 ml/min (C. Naret, personal communication). Three different phases in the course of renal decline in our patient may be outlined. First, creatinine clearance was already impaired at age 9 and slowly declined over the next 40 years. Finally, a sharp decline occurred during the final months before dialysis for which we cannot rule out acyclovir-related nephrotoxicity. ESRD was reached at age 49, ~13 years later than predicted by Charnas et al. [3] on the basis of their cross-sectional study in 23 patients ranging from 4 months to 31 years. There is no longitudinal study examining the course of renal decline in the long term in OCRL patients. The culprit mutation in our proband might be responsible for a milder renal phenotype as it lies in exon 21 outside of the functional phosphatase domain of ocrl1. Conversely, a striking divergence in severity of non-renal manifestations was outlined in two unrelated patients carrying the same mutation [5].

What are the mechanisms of renal decline in OCRL syndrome? In our patient, at first evaluation, a patchy tubulointerstitial nephropathy was found on biopsy at age 9. Although early proximal tubule anomalies are the hallmark of the disease [1], no explanation for their mechanism has been provided so far. Some authors also found thickening of all basement membranes of the kidney as well as an increase in glomerular cellularity. Nevertheless, neither laboratory nor histology findings suggest a key role for glomerular involvement in renal decline, both in our patient and in eight additional renal biopsies from OCRL children from the Enfants-Malades series (M.-C. Gubler, unpublished results). Presumably, focal tubulointerstitial lesions extend progressively, leading to glomerular obsolescence and ESRD. Interestingly, the pattern of renal decline in the OCRL syndrome sharply contrasts with that observed in cystinosis which is also characterized by early Fanconi syndrome but a much faster progression towards ESRD [3]. The early mechanism of progressive renal decline in OCRL cannot be fully understood until the function of the gene product within the Golgi complex is clarified.

Superimposed causes of renal failure in OCRL patients such as rhabdomyolysis and nephrocalcinosis were ruled out in our patient. Renal failure and acidosis are the major causes of reduced longevity in OCRL patients in the early literature with no detail on the precise cause of mortality [4]. With better management of metabolic derangements, longer survival might be expected. However, to our knowledge long-term follow-up and outcome of renal replacement therapy in adult OCRL patients have not been reported. Renal replacement therapy presents more difficulties in OCRL patients because of mental delay and poorly adapted behaviour. In many OCRL patients the necessary compliance with treatment may not be achievable as unpredictable behaviour may prevent successful dialysis. Decisions regarding initiation or withdrawal of dialysis in severely mentally retarded patients are difficult. The views of the family and staff in the institution where the patient lives on a daily basis must be sought. The General Medical Council in the UK has recently published guidelines on clinical decision-making in this complex area [6].

Kidney transplantation in recipients with mental retardation was reported to provide excellent patient and graft survival rates and a better quality of life in selected patients with Down syndrome [7]. The authors concluded that the presence of mental retardation should not be considered a contra-indication to a kidney transplant. In our patient, peritoneal dialysis was elected as the first-line treatment. Whether or not kidney transplantation is appropriate requires further evaluation.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Lowe CUTM, MacLachlan EA. Organic-aciduria, decreased renal amonia production, hydrophtalmos and mental retardation. Am J Dis Child 1952; 83: 164–184[ISI]
  2. Olivos-Glander IMJP, Nussbaum RL. The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am J Hum Genet 1995; 57: 817–823[Medline]
  3. Charnas LBI, Rader D, Hoeg J, Gahl W. Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med 1991; 324: 1318–1325[Abstract]
  4. Abbassi V, Lowe UC, Calcagno PL. Oculo-cerebro-renal syndrome. Am J Dis Child 1968; 115: 145–168[Medline]
  5. Leahey A-MCL, Nussbaum RL. Nonsense mutations in the OCRL-1 gene in patients with the oculocerebrorenal syndrome of Lowe. Hum Mol Genet 1993; 2: 461–463[Abstract]
  6. General Medical Council. Withholding and withdrawing life-prolonging treatments: good practice in decision-making. 2002. Available at http://www.gmc-uk.org
  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: 509–512[ISI][Medline]
Received for publication: 28.10.02
Accepted in revised form: 10. 4.03





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