NORD gratefully acknowledges José M Millán, PhD, Biomedical Research Institute IIS- La Fe & CIBERER, and Carmen Ayuso, MD, PhD, Biomedical Research Institute Fundacion Jimenez Diaz (IIS-FJD, UAM) & CIBERER, Madrid, Spain, for assistance in the preparation of this report.
Senior Løken syndrome (SLS) is a rare disorder that results in nephronophthsis and Leber congenital amaurosis. Nephronophthisis is the progressive wasting of the filtering unit of the kidney; it is characterized by cysts that develop in the kidneys during infancy or early childhood. Individuals will also develop symptoms of early-onset retinal dystrophy, a progressive retina disease that damages vision, within the first few years of life. Eventually the individual may experience renal failure and vision loss.
SLS is inherited as an autosomal recessive genetic trait. Currently, ten genes have been linked to the disorder.
Senior Løken syndrome is a rare inherited disorder characterized by progressive kidney and eye problems.
The onset of nephronophthisis usually occurs within the first year of life or early childhood; it is characterized by fluid-filled cysts that form in the kidneys and progressively worsen. The cysts can damage the kidneys and cause increased urine production (polyuria), weakness and fatigue, and excessive thirst (polydipsia). The kidney problems are present at birth in some families, but for other families symptoms will develop very gradually before becoming apparent.
Renal ultrasound scans may help in the diagnosis showing kidneys of normal size, with increased echogenicity and corticomedullary cysts. As the disease progresses, kidneys become atrophic and the cysts become more prominent. Progressive failure of kidney function occurs as a result of degeneration or loss of function of the small collecting tubes (tubules) in the kidney. This can cause chronic interstitial nephritis and uremia.
Chronic interstitial nephritis is a kidney syndrome in which the spaces between the tissue of the kidney (interstitial) become inflamed and structural changes occur. Eventually the patient may have symptoms such as nausea, vomiting, weight loss, fatigue, anemia and ultimately kidney failure.
Uremia is a condition that is characterized by a gradual increase of urea and other by-products of protein breakdown in the blood, causing a severe toxic condition. Normally, these by-products of protein breakdown would be passed in the urine.
Early-onset retinal dystrophies
Early-onset retinal dystrophies are a group disorders characterized by the progressive atrophy of the retina, which is a tissue at the back of the eye that detects color and light. The most severe form is the Leber congenital amaurosis (LCA). LCA causes vision problems such as sensitivity to light (photophobia), involuntary movements (nystagmus), and severe farsightedness (hyperopia). A decrease in visual responsiveness at birth is the first sign of this disorder with roving eye movements being apparent in the first few years of life.
In some patients with Senior Løken syndrome the progressive atrophy of the retina of the eye may take a course similar to retinitis pigmentosa. This condition typically becomes apparent later in life with the earliest symptom being difficulty seeing in dimly lit places (night blindness). This is slowly followed by tunnel vision. The rate of progression can vary.
Other symptoms have been noted in particular families such as diabetes insipidus, neurosensory hearing loss, muscular incoordination caused by disease of the cerebellum in the brain (cerebellar ataxia), abnormal formation of fibrous tissue in the liver (hepatic fibrosis) and skeletal abnormalities.
Senior Løken syndrome is inherited as an autosomal recessive trait (OMIM #266900). Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Senior Løken syndrome is currently known to be caused by mutations in at least 10 genes: NPHP1, INVS /NPHP2, NPHP3, NPHP4, IQCB1/NPHP5, CEP290/NPHP6, SDCCAG8/NPHP10, WDR19/NPHP13, CEP164, and TRAF3IP1.
The proteins created by these genes play a large role in cell structures called cilia. Cilia are microscopic hair-like structures that stick out from the surface of a cell and are responsible for transmitting information between cells. Cilia are essential for sensory input, since retinal photoreceptors have a cilium connecting outer and inner segments of the cell and there are also cilia in the inner hearing, but are also important for the structure and function of the cells in the kidneys.
Mutations in one of the above referred genes can lead to problems with the function of cilia, causing disruption of important signaling within cells. Therefore, the damaged cilia are responsible for Senior Løken syndrome, which is considered as a “ciliopathy “, a heterogeneous group of genetic disorders that occur due to primary ciliary dysfunction, affecting many parts of the body, including the kidney, eye, liver and brain. However, it is still unclear how they specifically lead to Leber congenital amaurosis and nephronophthisis. Other ciliopathies are Bardet Biedl syndrome, Joubert syndrome, Laurence Moon syndrome, McKusick Kaufman syndrome and Biemond syndrome, among others.
Senior Løken syndrome is a very rare disorder affects males and females in equal numbers. It is estimated that the prevalence is 1/1 million people worldwide. There have been over one hundred and fifty cases of this disorder reported in the medical literature.
Senior Løken syndrome can be diagnosed through genetic testing and clinical examinations. A complete kidney and ophthalmologic evaluations should be performed, as well as the recommendation of hepatic and neurological exams. Genetic diagnosis will require the mutation screening of the 10 genes; given that the most common mutation is the deletion of NPHP1 gene the genetic testing should include a method able to detect deletions in that gene.
Children affected with Senior Løken syndrome should be monitored regularly by a pediatric nephrologist. The child’s weight and height, kidney function, urinary concentration and blood pressure should be monitored. An early diagnosis of nephronophthisis can be managed and delay the progression of kidney failure; however once end-stage kidney disease develops patients will require dialysis or a kidney transplant.
There is no treatment to prevent the progression of vision loss.
Patients with medullary cystic disease need careful management of uremia when it occurs. Diet must be carefully monitored. An increase of calories in the diet should be coupled with a reduction in the total content of dietary protein. Sufficient carbohydrates and fats should be consumed to provide energy and prevent the body from metabolizing its own proteins.
When the retinal atrophy in Senior Løken syndrome resembles retinitis pigmentosa, the patient may benefit from various visual aids. The aids may be 1) optical aids, such as Corning and NOIR glasses, the Fresnel Prising telescopes, microscopes and night vision aids; 2)non-optical aids, such as the Wide Angle Mobility Light, paper guides, large print typewriters and adjustable stands; and 3) electronic aids such as Apollo Laser and Visualtek closed-circuit TV, reading machines and talking computers.
Genetic counseling may be of benefit for patients and their families.
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