Rareshare would like to acknowledge Dr. Lada Beara Lasic, Assistant Professor of Medicine, Division of Nephrology, NYU Medical school and Dr. John Lieke, Professor of Medicine, Mayo Clinic, for reviewing this content.

Dent disease is extremely rare, with a prevalence estimated to be between 1 in 400,000 and 1 in 1,000,000. At least 250 affected families have been reported to date. Dent disease Type 1 is more common than Type 2. Rare disease prevalence and incidence rates are difficult to accurately determine because of frequent misdiagnosis, or because people often go undiagnosed or unreported.

Mutations in the CLCN5 gene can give rise to Dent disease 1, and the OCRL gene causes Dent disease 2. Both genes are important for the normal function of the proximal tubules, the kidney structure where the filtration and reabsorption of water and minerals takes place. Disrupting these genes will disrupt the normal function of the kidney and give rise to symptoms of this disease.

Mutations in the CLCN5 gene which account for approximately 60-65% of Dent's disease cases and are classified as Dent disease type 1 (DD1). The CLCN5 gene encodes the ClC-5 protein, a kidney-specific chloride/proton antiporter (Cl-/H+ exchanger) primarily located in the proximal renal tubules. This protein plays a crucial role in the acidification of early endosomes in proximal tubular cells, which is essential for the reabsorption of low-molecular-weight proteins from the urine.

Mutations in the OCRL1 gene account for approximately 10-15% of Dent's disease cases and are classified as Dent disease type 2 (DD2). The OCRL1 gene encodes an enzyme called phosphatidylinositol bisphosphate (PIP2) 5-phosphatase. This enzyme plays a role in intracellular transport and the regulation of phosphatidylinositol 4,5-bisphosphate levels, which are important for molecular trafficking in proximal tubules of the kidney. Mutations in OCRL1 are also associated with Lowe Syndrome, and some researchers consider DD2 a milder variant of this condition. DD2 may present with extra-renal manifestations like mild intellectual disability, cataracts, and hypotonia.

Dent disease is inherited in an X-linked recessive pattern. Both genes associated with this condition are located on the X chromosome, which is one of the two sex chromosomes. Females have two X chromosomes and males have one X and one Y chromosome. The altered gene is passed on from a mother to her son. Women with an altered CLCN5 or OCRL gene usually do not show any symptoms of the disorder, most likely due to their second X chromosome (with an unaltered form of the gene) compensating for the altered gene on the other X chromosome. Sometimes, female carriers can develop mild disease manifestations. In males (who have only one X chromosome), one altered copy of either of these genes in each cell is enough to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons, since fathers pass on a Y chromosome (and not an X chromosome) to their sons. Affected males will pass on the altered gene to all of their daughters, who will thus be carriers for the disorder.

In approximately 20-30% of cases, no mutations are found in either CLCN5 or OCRL1, suggesting the involvement of other, yet unidentified genes. 

The specific disease manifestations vary greatly from person to person, even among affected individuals within the same family.

The most common manifestations are proteinuria (elevated levels of proteins in the urine, especially of low molecular weight or small proteins) and hypercalciuria (elevated levels of calcium in the urine).

Some individuals can also develop deposits of calcium in the kidney (nephrocalcinosis), and more rarely kidney stones. People with kidney stones can experience painful urination, abdominal pain, a block of the urinary tract and recurrent urinary tract infections. Affected patients may also develop low levels of potassium, phosphate, rickets and decreased growth. Many affected patients will develop a progressive loss of kidney function and may need kidney replacement therapies like kidney transplantation or dialysis.

People with Dent disease type 2, in addition to these symptoms, can also experience mild intellectual disability, elevated muscle enzymes and cataracts without vision problems.

A diagnosis of Dent disease can be strongly suggested by finding elevated low molecular weight proteins in the urine (usually over 5-fold the normal range) together with other typical findings. Commonly measured low molecular weight proteins include β2-microglobulin, α1-microglobulinand/or retinol binding protein (RBP). Additional findings consistent with Dent disease include: excessive calcium in the urine (hypercalciuria; generally indicated by greater than 4mg/kg of calcium in a 24 hour urine collection), the presence of kidney stones, the deposition of calcium in the kidneys (nephrocalcinosis), the presence of red blood cells in the urine (hematuria), abnormally low phosphate levels in the blood (hypophosphatemia), impaired kidney function (chronic kidney disease) and a history of Dent disease in the family that follows an X-linked pattern. The diagnosis may be confirmed by a genetic test.

Urine tests can be done to detect the presence of low molecular weight proteins and calcium. Blood tests may reveal low potassium and low phosphate levels. A genetic test may help confirm the diagnosis. The genetic tests examine the chromosomes to detect changes in the 2 genes known to cause Dent disease (CLCN5 and OCRL1).

There is no specific treatment for this condition. Symptoms are treated as they present themselves. Thiazides diuretics can be used to reduce the levels of calcium in the urine and prevent the formation of kidney stones. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) can be used to diminish the amount of proteins in the urine and try to prevent kidney damage, although this approach may not work well in Dent disease. Sometimes patients are given potassium citrate for prevention of kidney stones.

However, the efficacy of these treatments is unclear and they can cause side effects. Potassium and phosphate supplements are used to correct low potassium or phosphate levels.

If the condition progresses to end-stage kidney disease, dialysis or a kidney transplant might be needed.

People with Dent disease have a good vital prognosis. End stage kidney disease has been reported to occur in 30% to 80% of males between 30 and 50 years old. However, Dent patients do well with kidney transplantation, and the disease cannot recur in a transplanted kidney.

Dent’s disease severity differs on a case by case basis. Individuals with Dent’s disease may experience mild symptoms such as low molecular weight proteins and calcium in their urine without other symptoms of discomfort. Others may experience kidney stones, chronic kidney disease, and even kidney failure. Some cases of Dent’s disease can worsen over a person’s lifetime, leading to kidney problems and kidney failure between the ages of 30 to 50. Still others can continue a relatively symptom-free life managing their symptoms and taking care to prevent kidney degeneration.

The Rare Kidney Stone Consortium at the Mayo Clinic has established a registry of individuals with rare or otherwise unidentified kidney problems. Registering as a part of this list provides doctors and researchers with more information to find linkages and conduct more research on rare diseases. For more information, e-mail rarekidneystones@mayo.edu

1. https://rarediseases.org/rare-diseases/dent-disease/.
2. https://ghr.nlm.nih.gov/condition/dent-disease.
3. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-28.
4. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=1652.
5. The European Rare Kidney Disease Reference Network: https://www.erknet.org/patients/your-kidney-disease/dents-disease/disease-information.