Dent Disease

Dent disease is a rare X-linked recessive renal tubulopathy that occurs almost exclusively in males, characterized by proximal tubular dysfunction. Two forms are recognized: Dent disease 1 (caused by CLCN5 mutations) and Dent disease 2 (caused by OCRL mutations). Signs and symptoms appear in early childhood and worsen over time.

• Low-molecular-weight proteinuria (LMWP): The most constant and earliest feature, present in virtually all affected males. Proteinuria may be in the nephrotic range.
• Hypercalciuria: Common in childhood (up to 73% of pediatric patients), but decreases with age and declining GFR (present in only ~19% of adults).
• Nephrocalcinosis: Calcium deposits in the kidneys; reported in ~66% of patients.
• Nephrolithiasis: Kidney stones occur in ~26% of patients, more prominent in adults; may cause hematuria and abdominal pain.
• Progressive chronic kidney disease (CKD): GFR declines at approximately 1.0–1.6 mL/min/1.73 m²/year. End-stage renal disease (ESRD) develops in 30–80% of affected males between ages 30 and 50 years.
• Hematuria
• Hypophosphatemia: Does not resolve with age.
• Proximal tubular dysfunction: Variable features of renal Fanconi syndrome including aminoaciduria, glucosuria, phosphaturia, kaliuresis, and uricosuria.
• Hypokalemia: Develops with age; present in approximately half of patients over 18 years.

Diagnosis requires all three of the following: (1) LMWP, (2) hypercalciuria, and (3) at least one of: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia, or renal insufficiency. Molecular genetic testing confirms the diagnosis.

• Eye findings are primarily associated with Dent disease 2 (OCRL mutations).
• Subclinical cataracts: Clouding of the lens that does not impair vision. This is the most characteristic ocular finding.
• Ocular findings are relatively uncommon in Dent disease 2 overall (~11% of patients with extrarenal symptoms).
• Dent disease 1 (CLCN5 mutations) is not associated with ocular abnormalities.
• Dent disease 2 is considered by some researchers to be a mild variant of [Lowe syndrome](https://www.openevidence.com/rare-disease/oculocerebrorenal-syndrome-of-lowe) (oculocerebrorenal syndrome), which features more severe congenital cataracts.

• Rickets or osteomalacia: Due to low vitamin D and mineral levels; responds to vitamin D supplementation and phosphorus repletion.
• Growth restriction and short stature: May be treated with human growth hormone without adversely affecting kidney function.
• Mild intellectual disability: Seen in some males with Dent disease 2 (OCRL mutations).
• Hypotonia (weak muscle tone): Associated with Dent disease 2.
• Elevated muscle enzymes: May be present in Dent disease 2.
• Female carriers: Due to random X-chromosome inactivation, some may manifest hypercalciuria and, rarely, renal calculi and moderate LMWP. Females rarely develop CKD.

Management is supportive:

• Thiazide diuretics may decrease urinary calcium excretion but are limited by side effects (hypokalemia, volume depletion).
• ACE inhibitors/ARBs have unclear effectiveness for Dent disease-associated proteinuria.
• Avoid renal toxins (NSAIDs, aminoglycosides, IV contrast agents).
• Monitor annually: urinary calcium, GFR, blood pressure, hematocrit, serum calcium and phosphorus.
• Renal replacement therapy (hemodialysis, peritoneal dialysis, or transplantation) for ESRD. The disease does not recur after transplantation.

Dent disease is an X-linked recessive disorder caused by mutations in one of two genes:

• Dent disease 1 (~60% of cases): Caused by mutations in the CLCN5 gene (chromosome Xp11.22), which encodes the electrogenic chloride/proton exchanger ClC-5. ClC-5 is predominantly expressed in the proximal tubule and controls acidification and recycling of endosomal compartments. Loss of ClC-5 function impairs megalin-mediated endocytic reabsorption of low-molecular-weight proteins.*
• Dent disease 2 (~15% of cases): Caused by mutations in the OCRL gene (chromosome Xq25), which encodes a phosphatidylinositol-4,5-bisphosphate 5-phosphatase (OCRL1). OCRL mutations are also responsible for Lowe syndrome; Dent disease 2 is considered a milder phenotypic variant. Both ClC-5 and OCRL1 participate in a common endocytic pathway in the proximal tubule.*
• Remaining ~25% of cases: The genetic cause is unknown, suggesting involvement of additional genes.*

There is considerable intra-familial variability in disease severity, and no clear genotype-phenotype correlation has been established, although mutations affecting the pore or CBS domains of ClC-5 may be associated with more frequent GFR decline.

1. Devuyst O, Thakker RV. Dent's disease. Orphanet J Rare Dis. 2010;5:28. https://doi.org/10.1186/1750-1172-5-28
2. Claverie-Martín F, Ramos-Trujillo E, García-Nieto V. Dent's disease: clinical features and molecular basis. Pediatr Nephrol. 2011;26(5):693-704. https://doi.org/10.1007/s00467-010-1657-0
3. Lieske JC, Milliner DS, Beara-Lasic L, et al. Dent Disease. In: Adam MP, et al., editors. GeneReviews. Seattle (WA): University of Washington; 2017. https://www.ncbi.nlm.nih.gov/books/NBK99494/
4. Burballa C, Cantero-Recasens G, Prikhodina L, et al. Clinical and genetic characteristics of Dent's disease type 1 in Europe. Nephrol Dial Transplant. 2023;38(5):1163-1175. https://doi.org/10.1093/ndt/gfac257
5. Blanchard A, Curis E, Guyon-Roger T, et al. Observations of a large Dent disease cohort. Kidney Int. 2016;90(2):441-452. https://doi.org/10.1016/j.kint.2016.04.022
6. Gianesello L, Arroyo J, Del Prete D, et al. Genotype phenotype correlation in Dent disease 2 and review of the literature. Genes. 2021;12(10):1597. https://doi.org/10.3390/genes12101597
7. MedlinePlus. Dent disease. National Library of Medicine. https://medlineplus.gov/genetics/condition/dent-disease/