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A rare autosomal recessive oculo-renal ciliopathy characterized by the association of nephronophthisis (NPHP), a chronic kidney disease, with retinal dystrophy.
ORPHA:3156Classification level: Disorder
- Nephronophthisis with retinal dystrophy
- Renal dysplasia-retinal aplasia syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Adolescent, Adult, Childhood, Infancy
- ICD-10: Q61.5
- OMIM: 266900 606995 606996 609254 610189 613615 614845 616307 616629
- UMLS: C0403553
- MeSH: C537580
- GARD: 322
- MedDRA: -
The worldwide prevalence is estimated at around 1/1,000,000.
The disease typically presents in the first two decades of life as a combination of nephronophthisis (NPH) with retinal degeneration. Depending on the genetic background either the visual disorder or chronic kidney disease determine the clinical picture. NPH typically presents with symptoms such as polyuria, polydipsia, secondary enuresis and anemia. Chronic kidney disease usually slowly progresses to end-stage kidney disease (ESKD). Ocular features include congenital or early-onset severe visual loss due to retinal dystrophy (Leber congenital amaurosis) or a milder phenotype determined by a slowly progressing tube-like restriction of visual fields and night blindness (tapeto-retinal degeneration). Funduscopy reveals various degrees of atrophic and pigmentary retinal alterations. In rare occasions, other additional clinical signs may be observed like liver fibrosis, obesity and neurologic disorders.
Senior-Loken syndrome (SLS) is a genetically heterogeneous ciliopathy. Mutations in 10 different genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, CEP164 and TRAF3IP1) have been described. These genes encode for proteins of the primary cilia playing key roles in the development and function of several cell types, including retinal photoreceptor and renal tubular epithelial cells. Epistatic interactions, oligogenic inheritance or modifying alleles have been also suggested to influence the expressivity of the different extrarenal phenotypes.
Complete renal (kidney function, urinary analysis and abdominal ultrasound) and ophthalmologic (funduscopy, visual acuity test, refraction defects, color vision test, ocular motility and electroretinogram) evaluations are recommended. Hepatic evaluation to exclude liver fibrosis (liver function and abdominal ultrasounds) and neurological examination for infant patients are also highly recommended. Genetic diagnosis of SLS requires the mutational screening of the implicated genes; deletion of the NPHP1 gene is the most common anomaly.
SLS presents genetic and clinical overlap with other ciliopathies, in particular with isolated NPH and Joubert syndrome related diseases (JSRD) such as Joubert syndrome with oculorenal defect, Bardet-Biedl syndrome (BBS) and Alström syndrome. Physical examination should consider the presence of the main clinical signs of JSRD (hypotonia, ataxia and breathing abnormalities in infants) and BBS (polydactyly and obesity). The phenotypic hallmark of JSRD is the presence of a 'molar tooth sign' (a midbrain-hindbrain malformation) on MRI. Other extrarenal signs to consider are nystagmus, psychomotor and learning delay, diabetes mellitus, deafness, hypogonadism, and/or scoliosis.
Prenatal diagnosis is feasible only when the genetic mutation has been previously identified in another member of the family.
Transmission of SLS is autosomal recessive and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of an affected individual are obligate carriers.
Management and treatment
Regular follow up by a pediatric nephrologist is recommended with the monitoring of growth, blood pressure, renal function (including urinary concentration and sodium excretion). In order to delay the progression of renal failure and minimize possible complications, early management of NPH is necessary. So far, there is no specific therapy correcting the genetic or functional defects in NPH. Thus, in the early stage of renal disease the main goal is the correction of water and electrolyte imbalances by replacing the ongoing loss of water and salt. Once end-stage renal disease is reached, dialysis and renal transplantation are the therapies of choice. Disease does not recur after kidney transplantation. No treatment is currently available to prevent the progression of visual loss.
Prognosis mostly depends on the progression of the disease in the two affected organs (kidney and eye).
- Summary information
- Polski (2011, pdf)