What are the other Names for this Condition? (Also known as/Symptoms)

• Dent's Disease
• Low-Molecular-Weight Proteinuria with Hypercalciuria and Nephrocalcinosis
• X-Linked Recessive Hypercalciuric Hypophosphatemic Rickets

What is Dent Disease? (Definition/Background Information)

• Dent Disease is a rare genetic disorder that predominantly affects males with a general onset during childhood. It is caused by mutation(s) in two genes, namely the CLCN5 gene and the OCRL gene
• There are two variations of Dent Disease based on the causative genes of the condition. These include:
  • Type 1 Dent Disease: It is caused by CLCN5 mutation, and accounts for approximately 60% of the reported cases
  • Type 2 Dent Disease: It is observed in 15% of all cases, and is caused by mutation(s) in the OCRL gene
  • In about 25% of cases, the genetic cause is not known, and the risk factors remain indeterminate
• The CLCN5 and OCRL genes are involved in reabsorption of minerals and nutrients from the proximal tubules in the nephrons (the kidney’s basic functional unit). Gene mutations and aberrant gene products can cause reduced reabsorption of minerals and nutrients, which can lead to the symptoms of Dent Disease
• Dent Disease is an X-linked recessive disorder, and so having a mother who is a “carrier” of Dent Disease is a major risk factor for developing the condition. It is believed that many individuals with this condition may go undiagnosed, owing to symptoms being mild or overlapping with other kidney disorders
• The signs and symptoms generally affect the function of kidneys and may cause increased low-molecular weight protein, calcium, and amino acids to be passed through urine. Other symptoms can include the presence of kidney stones and chronic kidney disease. In individuals with Type 2 Dent Disease, the brain and eyes may be affected as well leading to intellectual impairment and cataracts
• Dent Disease is diagnosed through a physical examination, assessment of symptoms, evaluation of family history, urine tests, imaging tests of the abdomen, and kidney biopsy (if required)
• Progressive dysfunction of the kidneys, chronic kidney disease, and end-stage renal disease are some of the potential complications associated with Dent Disease
• Dent Disease is a genetic condition that cannot be cured. However, there are treatment options available to treat individual symptoms and delay kidney disease progression. These may include the use of thiazide and amiloride diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), growth hormone treatment for children with delayed growth, vitamin D supplementation, and dietary modifications
• The prognosis of Dent Disease is generally considered to be good. However, many affected males (over 50% of them) in their 30s-50s develop end-stage renal disease, which complicates the prognosis

Who gets Dent Disease? (Age and Sex Distribution)

• Dent Disease is a rare genetic disorder with an unknown prevalence. So far, approximately 250 affected families have been reported with the condition in the medical literature
  • Type 1 Dent Disease is reportedly more prevalent than Type 2 Dent Disease
  • Type 1 Dent Disease is likely underdiagnosed, because it may not be identified in those with mild signs and symptoms, and because its features overlap with those of other kidney disorders
• Typically, Dent Disease onset is during childhood and the symptoms progress with age
• The condition only affects males; generally, females are carriers and may have mild symptoms
• No particular race or ethnic group is at more risk than the others

What are the Risk Factors for Dent Disease? (Predisposing Factors)

• Dent Disease is an X-linked disorder; and so, being born to a mother who is a carrier of the disorder is a major risk factor for the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Dent Disease? (Etiology)

Mutations in two genes, the CLCN5 and OCRL genes, which are located on the female sex chromosome (X chromosome), can cause Dent Disease.

• CLCN5 codes for the protein electrogenic Cl-/H+ exchanger ClC-5, a chloride channel transporter belonging to the CLC family of transporters. The OCRL gene codes for phosphatidylinositol bisphosphate (PIP2) 5-phosphatase, which is an enzyme
• Normally, the two proteins regulate reabsorption of nutrients, minerals, and water into blood from the liquid waste that subsequently becomes urine. The two genes are responsible for the reabsorption in the proximal tubules, which, along with the glomerulus, forms a nephrons (the functional unit of a kidney)
• When the genes are mutated, reabsorption of minerals and nutrients is disrupted in the proximal tubules, leading to characteristic kidney malfunctions observed in individuals with this disorder
• Dent Disease is classified as type 1 or type 2 Dent Disease
  • The type 1 disease is caused by mutation(s) in the CLCN5 gene, and is the reason for the disorder in about 60% of reported cases
  • The type 2 disease is caused by mutation(s) in the OCRL gene. Although this gene is expressed ubiquitously in the human body (including in the brain and the eyes), mutations in this gene appear to predominantly affect the kidneys. Approximately, 15% of all cases of Dent Disease have the OCRL mutation
  • The exact genetic cause of Dent Disease is not known in the rest of the cases (25%, or in about 1 in 4 individuals)
• The 2 forms of Dent Disease are inherited in an X-linked fashion (X-linked recessive disorder). Typically, the mother is the “carrier” of the defective gene and does not develop the condition
• For a female to get Dent Disease, a mutated gene should be present in both the X chromosomes. This would mean that her father should be diagnosed with Dent Disease and her mother should be a carrier of the condition. The incidence of such a scenario is very low

X-linked recessive: X-linked recessive conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on a sex chromosome (X or Y chromosome). All X-linked recessive traits are fully evident in males, because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that they will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that they inherit two mutated copies of the gene, they will inherit the condition.

What are the Signs and Symptoms of Dent Disease?

The typical signs and symptoms of Dent Disease include:

• Low molecular weight proteinuria (abnormal amounts of protein in the urine)
• Nephrocalcinosis, or calcium deposits in the kidneys
• Hypercalciuria, or increased calcium in urine
• Nephrolithiasis (kidney stones)
• Hematuria (blood in urine)

Signs and symptoms not related to kidneys can also occur. This is generally observed in Type 2 Dent Disease and may include:

• Hypotonia or weak muscle tone
• Intellectial disability
• Cataract

Note: Some scientists believe that Type 2 Dent Disease is a variant of a disorder known as Lowe syndrome, which has comparable symptoms.

• Some affected individuals may also develop the following:
  • Osteomalacia, or softening of the bones, pain during joint movement, and increased risk of fractures
  • Hypophosphatemic rickets: Deformity in legs and slow growth rate in children, owing to problems with phosphate transport and vitamin D metabolism in the kidneys
  • Fanconi syndrome: Increased phosphate, amino acids, uric acid, potassium and sugar in the urine
• Some women who are carriers of the disorder may develop mild symptoms of proteinuria and/or hypercalciuria. Very few women have reported kidney stones. End-stage renal disease is rare in women

How is Dent Disease Diagnosed?

Dent Disease may be diagnosed through the following tests and examinations:

• A thorough physical examination
• An assessment of symptoms
• An evaluation of family medical history
• Urine analysis to check for the following:
  • Excess amounts of low-molecular weight proteins
  • Excess calcium
  • Blood
  • The presence of excess amino acids
• 24-hour urine collection test to check for accumulation of chemicals that form kidney stones
• Imaging studies (X-ray and CT scan) to check for kidney stones
• Biopsy of kidney tissue, when warranted
• Genetic testing for confirmation of the condition

Prenatal diagnosis through genetic testing is possible for Dent Disease. The presence of genetic mutation does not necessarily mean that the individual will have severe signs and symptoms. Genetic consulting is necessary for the expectant mothers in such cases.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Dent Disease?

Some potential complications of Dent Disease include:

• Progressive kidney malfunction leading to end-stage renal disease, with associated signs and symptoms such as:
  • Loss of appetite
  • Weight loss (unintended)
  • Anemia
  • Tiredness and weakness
• Chronic kidney disease
• End-stage renal disease

How is Dent Disease Treated?

The treatment options for Dent Disease are tailored towards addressing individual symptoms, which may include:

• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in children to slow down the decline in kidney function
• Growth hormone treatment for children with delayed development
• Vitamin D supplementation for rickets; these may cause increased calcium in urine
• A class of medicines known as thiazide diuretics, to reduce calcium excretion in urine and prevent kidney stones from occurring/recurring. It is known to have certain severe side effects
• Medicines, known as amilorides or amiloride diuretics, to facilitate reabsorption of calcium in the tubules
• A diet rich in citrus fruits (juices) may be helpful
• Dialysis for kidney failure
• Kidney transplantation in case of end-stage renal disease

How can Dent Disease be Prevented?

• Currently, there are no specific methods or guidelines to prevent Dent Disease, since it is a genetic condition
• If there is a family history of the condition, genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Dent disease
• Regular medical screening at periodic intervals with tests, and physical examinations are strongly recommended

What is the Prognosis of Dent Disease? (Outcomes/Resolutions)

• The prognosis is reported to be good for most individuals with Dent Disease. Individuals with milder signs and symptoms, have better outcomes than those with severe condition
• However, end-stage renal disease occurs between the ages of 30 and 50 years in about 50% of the men with the disorder. In such cases, the prognosis may be guarded

Additional and Relevant Useful Information for Dent Disease:

• Dent Disease was first reported in the medical literature in 1964 by Drs. Dent and Friedman, who described two unrelated boys with rickets. The disorder was eventually fully described by Dr. Oliver Wrong in 1990, who named the disease after his colleague and mentor Dr. Dent
• Generally, Dent Disease is now classified into type 1 and type 2 based upon the specific genetic mutation present. There are individuals who lack mutations in the 2 genes (non 1, non 2), but present similar signs and symptoms of Dent Disease. Studies to understand other possible mutations in such individuals is currently being carried out