Dent-2 Disease: A Mild Variant of Lowe Syndrome

doi:10.1016/j.jpeds.2009.01.049

The Journal of Pediatrics

Volume 155, Issue 1, July 2009, Pages 94-99

https://doi.org/10.1016/j.jpeds.2009.01.049 Get rights and content

Objective

To compare the renal and extra-renal phenotypes of patients classified as having Dent disease, Dent-2 disease, or Lowe syndrome.

Study design

Chart review of data from 93 patients with identified voltage-gated chloride channel and chloride/proton antiporter 5 gene and oculo-cerebro-renal syndrome of Lowe gene mutations observed by the authors, complemented with published data.

Results

There was a wide overlap of renal symptoms. Nephrocalcinosis was more prevalent in Dent-1 disease, and renal tubular acidosis, aminoaciduria, and renal failure was more prevalent in patients with Lowe syndrome. Patients with Lowe syndrome were shorter than patients with Dent-1 disease, and patients with Dent-2 disease showed an intermediate phenotype. Three patients with Dent-2 disease had mild peripheral cataract, and 9 patients were noted to have some degree of mental retardation.

Conclusion

There is a phenotypic continuum within patients with Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of oculo-cerebro-renal syndrome of Lowe gene function.

Section snippets

Methods

Clinical and laboratory data were gathered with chart review on 93 patients observed by the authors. Fifty-four patients were CLCN5 positive, 26 patients had classical Lowe syndrome with documented OCRL1 mutations, and 13 patients had ORCL1 mutations with a Dent-2 phenotype. Selected data on 34 of the patients with Dent-1, 23 of the patients with Lowe, and 8 of the patients with Dent-2 have been published previously by the authors,2, 5, 7, 11 but not a comprehensive review of the renal and

Renal Phenotype

The renal phenotype in the 3 patient groups is presented in the Table. LMWP was a constant feature in all 3 groups, and there was a wide overlap in most of the other symptoms of the proximal tubulopathy. Nephrocalcinosis was observed more frequently in patients with Dent-1 disease than those with Dent-2 disease and Lowe syndrome; aminoaciduria, renal tubular acidosis, and renal failure was observed more frequently in patients with Lowe syndrome than patients with Dent-1 and Dent-2 disease.

Mean

Discussion

We found a large overlap in renal phenotype in patients classified as having Dent-1 and Dent-2 disease and also in patients with Lowe syndrome. Although nephrocalcinosis was more prevalent in patients positive for CLCN5 than in patients with Dent-2 and Lowe, renal tubular acidosis was the only tubular abnormality characteristic of Lowe syndrome. Although investigations in our own patients revealed a striking absence of glycosuria in patients with Lowe syndrome,⁷ Cho et al recently reported 2

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A 16-year-old male presented with a several month history of nyctalopia and peripheral vision deficits. Central visual acuity, anterior and posterior segment examinations, and macular optical coherence tomography were unremarkable. Electroretinogram (ERG) testing revealed a rod-cone dystrophic pattern, with further workup demonstrating serum vitamin A deficiency (VAD). Laboratory evaluation revealed renal dysfunction and proteinuria with a significantly elevated urinary retinol-binding protein (RBP). Kidney biopsy showed glomerular and tubular disease.
Genetic screening for inherited renal disease was performed identifying a hemizygous pathogenic variant c.2152C>T (p.Arg718*) in the Chloride Voltage-Gated Channel 5 (CLCN5) gene, confirming the diagnosis of X-linked Dent Disease. Following vitamin A supplementation, our patient reported resolution of nyctalopia and reversal of abnormal ERG findings were demonstrated.
To our knowledge, this is the first case in the literature describing Dent disease solely presenting with ophthalmic symptoms of nyctalopia and abnormal electroretinogram findings that later reversed with vitamin A repletion. This case stresses the importance for clinicians to consider renal tubular disorders in the differential for VAD.
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  Cataract with other ophthalmic abnormalities: lens opacities combined with other eye phenotypes such as anterior segment dysgenesis, microphthalmia, ectopia lentis or aniridia. Mutations in several genes including some key transcription factors (e.g. FOXE3, PITX3, MAF, PAX6) are detected in a subset of these cases. Persistent fetal vasculature, an important cause of unilateral cataract, can be included in this category although it is only very rarely found to be associated with Mendelian mutations.
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  Cataract associated with multisystemic disorders: lens opacities combined with various metabolic and syndromic disorders; these can be inherited as X-linked (e.g. oculo facio cardio dental syndrome), autosomal recessive (e.g. Warburg Micro syndrome) or autosomal dominant (e.g. Stickler syndrome) traits.
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Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the kidney, the chloride channel Cl^-/H⁺ exchanger ClC-5 encoded by the CLCN5 gene is actively involved in preventing protein loss. This action becomes evident in patients suffering from the rare proximal tubulopathy Dent disease because they carry a defective ClC-5 due to CLCN5 mutations. In fact, proteinuria is the distinctive clinical sign of Dent disease, and mainly involves the loss of low-molecular-weight proteins. The identification of CLCN5 disease-causing mutations has greatly improved our understanding of ClC-5 function and of the ClC-5-related physiological processes in the kidney.
This review outlines current knowledge regarding the CLCN5 gene and its protein product, providing an update on ClC-5 function in tubular and glomerular cells, and focusing on its relationship with proteinuria and Dent disease.
Atypical phenotypes and novel OCRL variations in southern Chinese patients with Lowe syndrome
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: The authors declare no conflicts of interest.

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Original ArticleDent-2 Disease: A Mild Variant of Lowe Syndrome

Objective

Study design

Results

Conclusion

Section snippets

Methods

Renal Phenotype

Discussion

Kidney Int

Am J Hum Genet

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Adv Pediatr

Ophthalmology

Novel OCRL1 mutations in patients with the phenotype of Dent disease

Am J Kidney Dis

OCRL1 mutations in patients with Dent disease phenotype in Japan

Pediatr Nephrol

Renal manifestations of Dent disease and Lowe syndrome

Pediatr Nephrol

Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function

N Engl J Med

Renal phenotype in Lowe syndrome: a selective proximal tubular dysfunction

Clin J Am Soc Nephrol

Fanconi or not Fanconi? Lowe syndrome revisited

Clin J Am Soc Nephrol

Four additional CLCN5 exons encode a widely expressed novel long CLC-5 isoform but fail to explain Dent's phenotype in patients without mutations in the short variant

Kidney Blood Press Res

Structure and function of the Lowe syndrome protein OCRL1

Traffic

Hypercalciuria in patients with CLCN5 mutations

Pediatr Nephrol

A familial syndrome due to Arg648Stop mutation in the X-linked renal chloride channel gene

Pediatr Nephrol

Dent's disease: identification of a novel mutation in the renal chloride channel CLCN5

Clin Nephrol

Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease

Nephrol Dial Transplant

Phenotype and genotype of Dent's disease in three Korean boys

Pediatr Nephrol

Original Article
Dent-2 Disease: A Mild Variant of Lowe Syndrome