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Dent disease

Dent disease

Dent disease is a rare genetic chronic kidney disorder that occurs almost exclusively in males. In affected individuals, kidney problems result from damage to structures called proximal tubules, that is characterized by spillage of small proteins in the urine, increased levels of calcium in the urine, kidney calcifications (nephrocalcinosis), recurrent episodes of kidney stones (nephrolithiasis) and chronic kidney disease 1. Signs and symptoms of Dent disease appear in early childhood and worsen over time, but some individuals may be undiagnosed well into adulthood. The exact incidence and prevalence of Dent disease is unknown. Dent disease is likely underdiagnosed because it may not be identified in people with mild signs and symptoms, and because its features overlap with those of other kidney disorders. Dent disease is fully expressed in males only. Dent disease type 1 has been reported in approximately 250 families 2. Dent disease type 2 has been reported in approximately 25 individuals 2.

Researchers have described two forms of Dent disease, which are distinguished by their genetic cause and pattern of signs and symptoms 1. Dent disease type 1 is caused by mutations in the CLCN5 gene. Dent disease type 2 is caused by mutations in the OCRL1 gene. Both of these genes are located on the X chromosome. These mutations may be inherited or occur randomly with no previous family history of the disorder (spontaneously or de novo mutation). Both subtypes of Dent disease type 1 and Dent disease type 2 are characterized by the features described above, but Dent disease type 2 can also be associated with abnormalities unrelated to kidney function. Dent disease type 2 additional signs and symptoms include mild intellectual disability, weak muscle tone (hypotonia), and clouding of the lens of the eyes (cataract) that is described as subclinical because it does not impair vision. Some researchers consider Dent disease type 2 to be a mild variant of a similar disorder called Lowe syndrome. Dent disease is a rare condition, with about 250 affected families reported. Dent disease type 1 is more common than Dent disease type 2.

Dent disease is fully expressed only in males, although some females who carry the gene may develop mild manifestations such as spillage of small proteins in the urine, increased levels of calcium in the urine, or rarely kidney stones.

The most frequent sign of Dent disease is the presence of an abnormally large amount of proteins in the urine (tubular proteinuria). Other common signs of the disorder include excess calcium in the urine (hypercalciuria), calcium deposits in the kidneys (nephrocalcinosis), and kidney stones (nephrolithiasis). Kidney stones can cause abdominal pain and blood in the urine (hematuria). In some cases, Dent disease will progressively worsen causing severe kidney disease; in other cases affected individuals only experience mild or moderate disease into old age. Kidney disease can progressively worsen until the kidneys stop functioning (end-stage renal failure or ESRD), although this usually does not occur until 30 to 50 years of age or later and will not occur at all in some individuals. In most affected males, progressive kidney problems lead to end-stage renal disease (ESRD) in early to mid-adulthood. End-stage renal disease (ESRD) is a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively.

Some people with Dent disease develop rickets, a bone disorder that results when the levels of vitamin D and certain minerals (including calcium) in the blood become too low. Rickets can be associated with weakening and softening of the bones, bone pain, bowed legs, and difficulty walking.

No standard guidelines have been established for the treatment of Dent disease. The main goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD).

Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease. However, frequent side effects included hypokalemia, volume depletion, and cramping. Careful dosing and close monitoring for these side effects are necessary.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been used in children with proteinuria to prevent or delay further loss of kidney function. However, their effectiveness has not been clear.

Although a high citrate diet has been used in the treatment of Dent disease (aiming to slow progression of chronic kidney disease), no human trials have proven its effectiveness.

If males with Dent disease progress to end-stage renal disease (kidney failure), renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Because Dent disease features are largely localized in the kidney, the disease will not recur 3.

Dent disease causes

Dent disease can result from mutations in the CLCN5 gene or OCRL1 gene. Mutations in the CLCN5 gene cause Dent disease type 1, which accounts for about 60 percent of all cases of Dent disease. Mutations in the OCRL1 gene cause Dent disease type 2, which accounts for about 15 percent of all cases. In the remaining 25 percent of cases, the genetic cause of Dent disease is unknown, suggesting that additional subtypes of Dent disease caused by mutations in as yet unidentified genes most likely exist. Investigators have determined that the CLCN5 gene is located on the short arm arm (p) of chromosome X (Xp11.23-11p22). The OCRL1 gene is located on the long arm (q) of chromosome X (Xq25-q26). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xp11.23-p11.22” refers to bands 11.23-11.22 on the short arm of chromosome X. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The proteins produced from the CLCN5 and OCRL1 genes play critical roles in normal kidney function, particularly the function of the proximal tubules. These structures help to reabsorb nutrients, water, and other materials that have been filtered from the bloodstream. The kidneys reabsorb needed materials into the blood and excrete everything else into the urine. Studies suggest that mutations in the CLCN5 or OCRL1 gene disrupt the reabsorption function of the proximal tubules, which leads to the progressive kidney problems found in people with Dent disease.

Because the OCRL1 gene is active (expressed) throughout the body, it is unclear why Dent disease type 2 primarily affects the kidneys and, to a lesser extent, the brain, eyes, and other tissues.

Dent disease inheritance pattern

Dent disease is inherited in an X-linked recessive pattern. The CLCN5 and OCRL1 genes are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of a gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. If a father has Dent disease and the mother is not a carrier, all sons will be unaffected, and all daughters will be carriers.

In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene but usually does not experience signs and symptoms of the disorder. However, some females who carry a mutation in the CLCN5 or OCRL1 gene have mild features of Dent disease, including proteinuria and hypercalciuria. Severe kidney problems, including end-stage renal disease (ESRD), are rare in female carriers.

In most cases, male children inherit Dent disease from a carrier mother who has no symptoms or extremely mild symptoms of the disorder. When a mother is a known carrier of the CLCN5 or the OCRL1 mutation, there is a 50% chance of passing that mutation on to her children. Males who inherited a mutation will have Dent disease; females who inherited the mutation will be carriers. In extremely rare cases, the mutation that causes Dent disease occurs randomly for no apparent reason (de novo mutation). Affected males will not pass the disorder onto sons (who inherit the Y chromosome from fathers), but will pass the mutation on to all their daughters (who will become carriers).

Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some cases, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, they may not develop any symptoms or only have mild symptoms of the disorder. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females may develop various symptoms associated with Dent disease, but this has only occurred in extremely rare cases.

Figure 1. Dent disease X-linked recessive inheritance pattern

Dent disease X-linked recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Dent disease symptoms

The specific symptoms and severity of Dent disease can vary dramatically, even among individuals within the same family. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorders prevent physicians from developing a complete picture of associated symptoms and prognosis.

Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

Common signs of Dent disease include:

  • a large amount of protein in the urine (proteinuria)
  • excess calcium in the urine (hypercalciuria)
  • calcium deposits in the kidneys (nephrocalcinosis)
  • kidney stones which may cause abdominal pain and blood in the urine (hematuria)

Common symptoms associated with Dent disease include elevated levels of proteins and calcium in the urine (proteinuria and hypercalciuria). The type of proteinuria seen in Dent disease is known as low-molecular-weight proteinuria, which is a characteristic finding of the disorder and not always detected in routine medical testing. Hypercalciuria and low molecular weight proteinuria may be the only symptoms that develop in some people.

Affected individuals may also develop calcium deposits or calcifications in the kidney tissue (nephrocalcinosis) and/or experience recurrent episodes of kidney stone formation. Kidney stones can cause various symptoms including blood in the urine (hematuria), painful urination (dysuria), the urge to urinate often, abdominal pain (renal colic), blockage of the urinary tract, and repeated urinary tract infections. Eventually, the disorder can progress to cause chronic kidney disease with a progressive decline in kidney function. Symptoms associated with advanced chronic kidney disease include loss of appetite, unintended weight loss, fatigue, and anemia. In some cases, usually between the ages of 30-50, affected individuals can develop end-stage renal failure and require dialysis or kidney transplantation.

Some individuals with Dent disease may also develop bone disease such as softening of the bones (osteomalacia) and hypophosphatemic rickets, a condition caused by impaired transport of phosphate and altered vitamin D metabolism in the kidneys. In children, rickets is characterized by bowing deformity of the legs, as well as, growth plate abnormalities and progressive softening of the bones as occurs in osteomalacia. In adults, the growth plate is not present so that osteomalacia is the evident bone problem. In children, growth rates may be slower than normal, frequently resulting in mild short stature. Children may also experience bone pain and difficulty walking. Because of bone abnormalities, affected individuals may have an increased risk of fractures.

Some individuals with Dent disease have developed vitamin A deficiency, which can lead to impaired night vision and dry eyes (xerophthalmia). This can be corrected by vitamin A supplementation.

Dent disease type 2

Dent disease type 2 is characterized by the characteristic symptoms associated with Dent disease type 1. However, some affected individuals have developed additional symptoms including mild intellectual disability, hypotonia, and clouding of the lenses of the eyes (cataracts). Cataracts in Dent disease type 2 are classified as subclinical because they do not impair vision.

Dent disease type 2 is caused by mutations in the same gene that causes Lowe syndrome, a rare multisystem disorder. Lowe syndrome is characterized by the kidney abnormalities that occur in Dent disease, but also additional symptoms affecting the eyes, brain and other organ systems. Some researchers believe that Dent disease type 2 represents the mild end of a disease spectrum that includes Lowe syndrome at the severe end. (For more information on Lowe syndrome, see the Related Disorders section of this report).

Female carriers

Some females who inherited one of the mutations that cause Dent disease may develop mild manifestations of the disorder such as low-molecular-weight proteinuria and/or hypercalciuria. In the medical literature, only 10 females with a Dent disease gene mutation have been reported to have developed kidney stones and only one affected female has been reported whose disease progressed to end-stage renal failure, however she did not have genetic testing to confirm the disease.

Dent disease diagnosis

A diagnosis of Dent disease is suspected in people with the following 3 criteria, when there is no other known cause of proximal tubule dysfunction:

  1. Low molecular-weight proteinuria at least five times above the upper limit of normal (the pathognomonic finding of Dent disease) – no known cases of Dent disease have been missed using this screening
  2. Hypercalciuria (excessive calcium in the urine)
  3. At least one of the following:
    • nephrocalcinosis
    • kidney stones
    • hematuria (blood in the urine)
    • hypophosphatemia (low phosphorus in the blood)
    • chronic kidney disease
    • family history consistent with X-linked inheritance

A possible diagnosis of Dent disease is considered if low molecular-weight proteinuria and at least one other finding are present.

In 75% of males with the above criteria, genetic testing confirms the diagnosis by finding a mutation in the CLCN5 (Dent disease type 1) or OCRL (Dent disease type 2) gene. About 25% of people with a clinical diagnosis of Dent disease do not have a mutation in either of these genes, suggesting that other, yet unidentified genes may also cause the condition 3.

Dent disease treatment

The treatment of Dent disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists who assess and treat problems of the kidneys (nephrologists), specialists who assess and treat problems of the urinary tract (urologists), dieticians, and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment. Genetic counseling may be of benefit for affected individuals and their families.

There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of these diseases, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Dent disease.

Medications known as thiazides may be used to treat individuals with Dent disease to prevent the recurrence of kidney stones and to lower levels of calcium in the urine. However, these medications can potentially cause significant adverse side effects.

Additional medications known as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with elevated levels of proteins in their urine to prevent or delay a further decline in kidney function. The effectiveness of these medications in children with Dent disease is unclear.

Vitamin D to treat rickets, if used, may be done so cautiously because excess amounts of vitamin D can increase calcium levels in the urine. Growth failure in children may be treated with growth hormone supplementation. A high citrate diet or citrate supplements have also been used to treat some individuals with Dent disease, based on the observation that a high citrate diet slows progression of kidney disease in a mouse model of Dent disease, although the efficacy of citrate is unproven in humans.

If kidney function continues to decline, or in cases where an individual is first diagnosed with Dent disease after the development of end-stage renal disease, additional more aggressive treatment may be required including hemodialysis, peritoneal dialysis, and a kidney transplant.

Dent’s disease prognosis

Dent disease prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males 4.

References
  1. Dent disease. https://ghr.nlm.nih.gov/condition/dent-disease
  2. Dent disease. https://rarediseases.org/rare-diseases/dent-disease
  3. Lieske JC, Milliner DS, Beara-Lasic L, et al. Dent Disease. 2012 Aug 9 [Updated 2017 Dec 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK99494
  4. Devuyst, O., Thakker, R.V. Dent’s disease. Orphanet J Rare Dis 5, 28 (2010). https://doi.org/10.1186/1750-1172-5-28
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