Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Dent disease

Dent disease is an X-linked recessive disorder of proximal tubule function, that is cause by mutations in one of the genes CLCN5 and OCRL1, Dent 1 and Dent 2 respectively. The disease is characterized clinically by low molecular weight proteinuria, nephrocalcinosis/nephrolithiasis, hypercalciuria, and progressive renal failure.

Epidemiology

Dent disease is a rare disorder with only a few hundert cases published worldwide. However is can be surmised that many cases remain undetected because simply treated as recurrent nephrolithiasis.[Error: Macro 'ref' doesn't exist]

Clinical Findings

Low-molecular weight proteinuria is present in almost all patients with Dent disease. It is frequent in obligate female carriers even. Also female carriers may show a disposition to kidney stone formation. Based on these observations Hopes criteria were developed. The include (1) low-molecular-weight (LMW) proteinuria; (2) hypercalciuria; and (3) at least one of the following: nephrocalcinosis, kidney stones, renal insufficiency, hypophosphatemia, or hematuria.[Error: Macro 'ref' doesn't exist]

The symptom frequencies is male patients:
99% low-molecular-weight proteinuria (alpha1- and beta2-Microglobulin, Retinol binding protein)
95% hypercalciuria
75% nephrocalcinosis
50% nephrolithiasis
30-80% end-stage renal failure in the 3rd-5th decade
rickets (vitamin D metabolism)
night blindness (retinol binding)
hematuria (kidney stones)

Symptom frequencies in female patients:

  • 50-70% low-molecular-weight proteinuria (alpha1- and beta2-Microglobulin, Retinol binding protein)
  • 5% nephrolithiasis
  • 0,5% end-stage renal failure
  • hematuria (kidney stones)

Management

In therapy, thiazide diuretics can be tried as they reduce hypercalciuria.

Symptoms

Proteinuria
Proteinuria is an early symptom. It is the most consistent symptom and detected in obligate female carriers even. Typically at the beginning, it is a low-molecular-weight (tubular) proteinuria (LMWP) that pattern may change however with disease progression.
Hypercalciuria
Hypercalciuria in Dent disease is a typical and early symptom but detected only if explicitly searched for. It accompanied by low molecular weight proteinuria and hypophosphatemia. As an x-linked recessive disorder boys are affected.
Hyperphosphaturia
Hyperphosphaturia is sometimes difficult to measure. However, it is of cardinal importance to the development of nephrocalcinosis and hypophaspatemia related bone disease.
Nephrocalcinosis
Nephrocalcinosis develops based on impaired renal calcium and phosphate handling. The probability to detect it increases with age.
Proximal tubular damage syndrome
Along with pathognomonical signs as hypercalciuria, LMW proteinuria, and nephrocalcinosis infrequently other signs of proximal tybular damage (Fanconi) can be found.
Urolithiasis
Along with nephrocalcinosis kidney stones may develop. In some patients, the frequent stone formation is the only clinically apparent symptom.
Osteomalacia
The cause of rickets in male patients with Dent disease are disturbances in calcium-, phophate balance, and vitamin D metabolism.
Renal insufficiency
Up to 80% of male patients reach end-stage renal failure in their 30-50th decade. Cause is progressive nephrocalcinosis and complications of recurrent nephrolithiasis.

Systematic

Metabolic disturbances of proximal tubular function
Cystinosis
Dent disease
CLCN5
OCRL
Fanconi renotubular syndrome
Fanconi-Bickel syndrome
Fructose intolerance
Galactosemia
Glycogen storage disease 1
Hepatorenal tyrosinemia
Lowe disease
MELAS syndrome
Wilson disease

References:

1.

Hoopes RR et al. (2005) Dent Disease with mutations in OCRL1.

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2.

Santo Y et al. (2004) Examination of megalin in renal tubular epithelium from patients with Dent disease.

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3.

Ludwig M et al. (2004) Dent disease-like phenotype and the chloride channel ClC-4 (CLCN4) gene.

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4.

None (2004) Megalin and proximal renal tubular dysfunction in Dent disease.

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5.

Cobeñas CJ et al. (2004) A 3-year-old child with proteinuria and nephrocalcinosis. Suspicion of Dent disease.

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6.

None (2006) [Dent disease (idiopathic tubular proteinuria): Pathogenesis, pathophysiology, and therapy]

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7.

Ludwig M et al. (2006) Hypercalciuria in patients with CLCN5 mutations.

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8.

Devuyst O et al. (2010) Dent's disease.

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9.

OMIM.ORG article

Omim 300009 [^]
10.

Orphanet article

Orphanet ID 1652 [^]
11.

Wikipedia article

Wikipedia EN (Dent's_disease) [^]
Update: April 29, 2019