Dent Disease -CEW

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====== 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.

===== Main Features =====

  * **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 =====

  * 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.

===== Other Findings =====

  * **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.

===== Etiology =====

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.

===== References =====
  - Devuyst O, Thakker RV. Dent's disease. //Orphanet J Rare Dis.// 2010;5:28. [[https://doi.org/10.1186/1750-1172-5-28]]
  - 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]]
  - 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/]]
  - 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]]
  - 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]]
  - 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]]
  - MedlinePlus. Dent disease. National Library of Medicine. [[https://medlineplus.gov/genetics/condition/dent-disease/]]

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