Dent disease (X-linked recessive nephrolithiasis)
- Steven J Scheinman, MD
Steven J Scheinman, MD
- President and Dean
- The Commonwealth Medical College
- John C Lieske, MD
John C Lieske, MD
- Professor of Medicine
- Mayo Clinic Division of Nephrology and Hypertension
Dent disease is an X-linked recessive disorder of the proximal tubules that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, renal failure, and rickets [1,2]. In most cases, it is due to mutations that inactivate a voltage-gated chloride transporter named CLC-5. In others, it is associated with mutations in the OCRL1 gene, which is also mutated in the oculocerebrorenal syndrome of Lowe. Further genetic heterogeneity is assumed to exist since there are patients with the distinctive phenotype of Dent disease without mutations in either of these genes . (See 'Molecular genetics' below.)
The following topic review will present the genetics, clinical manifestations, and treatment of Dent disease.
Although different features of Dent disease predominated among early reports [4-7], an accurate description of the phenotype was offered in the report entitled, "Dent's disease: a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure, and a marked male predominance" .
"Dent disease" is accepted as the encompassing name of this disease, based upon this limited renal phenotype that includes a partial Fanconi syndrome. The disease is distinguished clinically from the Lowe syndrome by the absence of cataracts, mental developmental delay, and renal tubular acidosis .
In 60 percent of cases, Dent disease is due to mutations that inactivate a voltage-gated chloride transporter, CLC-5, which is expressed in the kidney and is encoded by a gene at Xp11.22 . In another 15 percent of cases, it is associated with mutations in the OCRL1 gene, which is also mutated in the oculocerebrorenal syndrome of Lowe. Further genetic heterogeneity is assumed to exist since there are patients with the distinctive phenotype of Dent disease who do not have mutations in either of these genes .
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- Silva IV, Cebotaru V, Wang H, et al. The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover. J Bone Miner Res 2003; 18:615.
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- Fervenza FC. A patient with nephrotic-range proteinuria and focal global glomerulosclerosis. Clin J Am Soc Nephrol 2013; 8:1979.
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- Scheinman SJ, Cox JP, Lloyd SE, et al. Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int 2000; 57:232.
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- MOLECULAR GENETICS
- CLCN5 gene (Dent disease 1)
- OCRL1 gene (Dent disease 2)
- OCRL1 gene and the Lowe oculocerebrorenal syndrome
- Mechanisms of proteinuria
- Mechanisms of hypercalciuria and hyperphosphaturia
- CLINICAL MANIFESTATIONS
- Common clinical presentation
- Proximal tubular reabsorptive failure and proteinuria
- Hypercalciuria, nephrocalcinosis, and kidney stones
- Chronic kidney disease
- - Renal pathology
- Rickets or osteomalacia
- Other abnormalities
- Lowe syndrome
- EVALUATION AND DIAGNOSIS
- Role of genetic testing
- DIFFERENTIAL DIAGNOSIS
- Reduction in calcium excretion
- Other therapies
- SUMMARY AND RECOMMENDATIONS