Search for a rare disease
Other search option(s)
Dent disease type 1
Dent disease type 1 is a type of Dent disease with predominantly renal manifestations.
ORPHA:93622Classification level: Subtype of disorder
Prevalence is unknown but fewer than 250 families have been reported.
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 low-molecular-weight (LMW) proteinuria (99% of cases), associated with hypercalciuria (95%), nephrolithiasis (50%), nephrocalcinosis (75%), and progressive renal failure. PT dysfunction may be more severe than in Fanconi syndrome, i.e. aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, and impaired urinary acidification, and is often complicated by rickets or osteomalacia. These patients may present with bone pain and difficulty in walking due to rickets, or symptoms of renal stones such as abdominal pain and hematuria. Occasionally, patients are referred as a result of the fortuitous discovery of biological manifestations of PT dysfunction, including LMW proteinuria, which is characterised by the excretion of proteins such as alpha-1 and beta-2 microglobulins, retinol-binding protein (RBP), Clara cell protein, and vitamin D-binding protein. The urinary loss of RBP might cause episodic night blindness in some patients. There is considerable inter- and intra-familial variability in the occurrence of nephrolithiasis. Females carriers can present with milder features with LMW proteinuria and hypercalciuria and rarely develop nephrolithiasis and renal failure.
Dent disease type 1 may be caused by inactivating mutations in the CLCN5 gene, which is located on chromosome Xp11.22 and encodes a 746 amino acid electrogenic Cl-/H+ exchanger (ClC-5). More than 140 CLCN5 mutations have been reported. Approximately 40% of patients do not have CLCN5 mutations, even though they are clinically indistinguishable from those that have CLCN5 mutations.
Diagnosis is based on the presence of LMW proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia, or renal insufficiency. Molecular genetics confirms the diagnosis.
Differential diagnosis includes the other causes of generalized proximal tubule dysfunction.
Antenatal diagnosis and pre-implantation genetic testing is not advised because there is no evidence of a genotype-phenotype correlation and because of the generally good vital prognosis.
The disease follows an X-linked recessive mode of inheritance.
Management and treatment
Care is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. Thiazide diuretics can be used to treat hypercalciuria although significant adverse effects, including hypovolemia and hypokalemia related to the primary tubulopathy, have been reported. Similarly, treatment of rickets with vitamin D must be cautious since it may increase hypercalciuria. Long-term control of hypercalciuria by a high citrate diet might delay progression of renal disease even in the absence of stone formation.
Progression to end-stage renal failure occurs between the 3rd and the 5th decades of life in 30-80% of affected males.