Dent disease type 1 (ORPHA:93622)
A rare X-linked monogenic renal tubular disease, characterized by manifestations of complex proximal tubule dysfunction with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Extra-renal involvement is absent.
Epidemiology
Prevalence is unknown.
Clinical description
The disease is generally found in males only, who may have manifestations of the disease from early childhood. It is characterized by proximal tubule (PT) dysfunction and LMW proteinuria (100% of cases), associated with hypercalciuria (90-95%), nephrolithiasis (30-50%), nephrocalcinosis (40-50%), and progressive renal failure. PT dysfunction may be severe, resulting in complete Fanconi syndrome, i.e. aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, and impaired urinary acidification, and can be complicated by rickets or osteomalacia. If tested, nearly all patients have a urinary concentration defect. Patients may present symptoms related to renal stones (abdominal pain, hematuria), Fanconi syndrome (polyuria, poor growth, rickets), or chronic kidney failure. Patients are also frequently referred after fortuitous discovery of nephrocalcinosis, renal stones, proteinuria or other biological signs of PT dysfunction, or after family screening. Some patients present with LMW proteinuria associated with significant albuminuria and glomerulosclerosis, in the absence of nephrotic syndrome and with mild tubular involvement that may be overlooked. There is considerable inter- and intra-familial variability. Most females carriers have low-degree of LMW proteinuria and may develop mild kidney failure later in life.
Etiology
Dent disease type 1 is caused by inactivating mutations in the CLCN5 gene (Xp11.22) that encodes a 746 amino acid electrogenic Cl-/H+ exchanger (ClC-5). Close to 250 CLCN5 mutations have been reported. Of these 9% are de novo mutations. Approximately 40% of patients with a phenotype compatible with Dent disease do not have CLCN5 mutations. Of these, approximately half have mutations in the OCRL1 gene and are considered to have Dent disease type 2.
Diagnostic methods
The diagnosis is based on the presence of LMW proteinuria, which is associated in the majority of cases with hypercalciuria and other biological, radiological and clinical symptoms of the disease. Molecular genetics confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other causes of low molecular weight proteinuria and Fanconi syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is X-linked. Genetic counseling should be offered to at-risk couples informing them that there is a 50% risk of having an affected boy or a carrier girl at each pregnancy, if the mother carries the mutation.
Management and treatment
Care is supportive, focusing on the prevention of nephrolithiasis, maintaining appropriate hydration and treatment of chronic kidney disease, if present. Long-term treatment with a high citrate diet or supplementation might delay progression of renal disease, even in the absence of stone formation. Thiazide diuretics have been used to treat hypercalciuria, but can cause significant adverse effects; in addition, their benefit on kidney function has not been demonstrated, and they may aggravate hypovolemia and hypokalemia, if present. Similarly, treatment of rickets with vitamin D must be cautious since it may increase hypercalciuria and aggravate nephrocalcinosis.
Prognosis
Progression to end-stage renal failure occurs between the third and fifth decades of life in the majority of affected males. Frequency of kidney failure increases with age: approximately 35-40% in patients between 30-50 years, and 75% in between 50 and 60 years. The disease does not recur in the transplanted kidney.

                            Last update: 
                            August 2021


                            - Expert reviewer(s): 
                            Pr Gema ARICETA | ERKNet* - Pr Francesco EMMA | ERKNet*


                                * European Reference Network