Senior-Loken Syndromes

Clinical Characteristics
Ocular Features: 

The retinal disease associated with juvenile nephronophthisis has been variably diagnosed as retinitis pigmentosa, sector retinitis pigmentosa, Leber congenital amaurosis, and tapeto-retinal degeneration.  The retinal picture varies among members of the same pedigree and the various disorders.  Areas of bone-corpuscle pigment clumping may be seen sectorially in the periphery or throughout the fundus, and is associated with arteriolar narrowing.  The ERG usually suggests widespread receptor disease with decreased responses but often normal photopic and scotopic implicit times in some patients.  In other cases, blindness is evident in the first year of life and the fundus picture resembles Leber congenital amaurosis with a nonrecordable ERG and clinical nystagmus.  Retinal pigment changes in these cases may be absent or minimal although arteriolar narrowing is usually seen.  Visual fields are often severely constricted and vision can be limited to light perception.

Systemic Features: 

Renal disease may begin with symptoms of polydipsia and polyuria often in the first decade of life.  The kidneys are cystic and renal function becomes progressively impaired.  The polycystic disease is referred to as nephronophthisis for the kidneys often fail completely.  A few patients have had sensorineural deafness.  Liver dysfunction has been reported in some patients but it is uncertain if this is coincidental or a part of the SLNS disorder.

Genetics

This renal-retinal phenotype seems to have an autosomal recessive pattern of inheritance but is genetically and clinically heterogeneous.  Together these account for the majority of hereditary causes of end-stage renal disease in children and young adults.  At least 5 renal-retinal disorders have been identified with a great deal of phenotypic overlap requiring genotyping for distinction.  The common causative mechanism may be defects in the cilia of photoreceptors and renal epithelial cells.

SLNS1 (266900) is caused by mutations in the NPHP1 gene (2q12-13) encoding nephrocystin.  Some form of pigmentary retinopathy is frequently present although its age of presentation is highly variable.

(There is a NPHP2 disorder (602088) but no SLSN disease is associated with the NPHP2 gene [now called INVS] at 9q22-31 and encoding inversin).

SLSN3 (606995) has been mapped to 3q21-22, overlapping the NPHP3 locus.  This is a later onset, adolescent disease often presenting with anemia and renal failure occurring at a mean age of 19 years.  'Tapetoretinal degeneration' is part of the clinical picture.

SLSN4 (606996) is caused by mutations in the NPHP4 gene (encoding nephrocystin-3) and located at 1p36.  The onset of retinal disease may be later in onset than in other conditions.

SLSN5 (IQCB1)(606254) is caused by mutations in the NPHP5 gene (encoding nephrocystin-5) and located at 3q13.33-21.2.  Multiple mutations in this gene have been found and all patients have a pigmentary retinopathy.

SLSN6 (610189) results from mutations in the NPHP6 (CEP290) gene at 12q21.  Some patients have had a 'tapetoretinal degeneration'.

SLSN7 (613615) is caused by mutations in the SDCCAG8 gene at 1q44.  Some patients have retinal degeneration leading to blindness.

SLSN8 (616307) is caused by mutations in the WDR19 gene at 4p14.  Patients have severe reduction in vision and visual fields are severely restricted.  Bone spicule pigmentation can be seen in the periphery, the retinal vessels are attenuated, the ERG is undetectable, and there may be temporal pallor of the optic discs.

Hereditary disorders with isolated pigmentary retinopathy and cystic kidney disease also occur separately.

Treatment
Treatment Options: 

No treatment beyond renal transplantation is available.  Low vison aids can be helpful in some patients.

References
Article Title: 

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O'Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005 Mar;37(3):282-8.

PubMed ID: 
15723066

Senior-Loken syndrome: revisited

Warady BA, Cibis G, Alon U, Blowey D, Hellerstein S. Senior-Loken syndrome: revisited. Pediatrics. 1994 Jul;94(1):111-2.

PubMed ID: 
8008515

References

Ronquillo CC, Bernstein PS, Baehr W. Senior-Loken Syndrome: A syndromic form of retinal dystrophy associated with nephronophthisis. Vision Res. 2012 Jul 19. [Epub ahead of print]

PubMedID: 22819833

Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O'Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005 Mar;37(3):282-8.

PubMedID: 15723066

Olbrich H, Fliegauf M, Hoefele J, Kispert A, Otto E, Volz A, Wolf MT, Sasmaz G, Trauer U, Reinhardt R, Sudbrak R, Antignac C, Gretz N, Walz G, Schermer B, Benzing T, Hildebrandt F, Omran H. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet. 2003 Aug;34(4):455-9.

PubMedID: 12872122

Warady BA, Cibis G, Alon U, Blowey D, Hellerstein S. Senior-Loken syndrome: revisited. Pediatrics. 1994 Jul;94(1):111-2.

PubMedID: 8008515

Godel V, Iaina A, Nemet P, Lazar M. Sector retinitis pigmentosa in juvenile nephronophthisis. Br J Ophthalmol. 1980 Feb;64(2):124-6.

PubMedID: 7362813