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Senior-Løken Syndrome: for professionals


Overview

PrevalenceEstimated 1 in 1,000,000
InheritanceAutosomal Recessive
Genes Involved (OMIM No.)NPHP1 (#606966), NPHP4 (#606966)
SymptomsPolyuria
Polydipsia
Photophobia
Nyctalopia
Visual field constriction
Ocular FeaturesRetinal degeneration
Optic disc pallor
Cataracts
Renal FeaturesProgressive renal failure
Nephronophthisis
Tubulointerstitial fibrosis
Cortical cysts
Key InvestigationsFundus examination OCTERGRenal Ultrasound
Genetic TestingIdentification of NPHP1 or NPHP4 mutations
ManagementOcular Regular ophthalmic follow-upTreatment of complications (e.g. Cataracts)
Renal Renal replacement therapy (dialysis, transplant)
Management of hypertension and electrolyte imbalance
PrognosisVariable, depending on severity of renal involvement
Therapies under ResearchGene identification

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Clinical phenotype

Senior-Løken Syndrome (SLS) is a rare genetic disorder characterised by a combination of renal disease, typically in the form of nephronophthisis, and retinal degeneration, leading to blindness.1

Presenting features

Ocular:

  • Onset of photophobia, nystagmus, and hypermetropia can occur in the first few years of life or later in childhood.2-4
  • Nyctalopia
  • Peripheral visual field defect
  • Rod-cone dystrophy and RPE degeneration noted at an early age.
  • Cataracts

Renal:

  • Polyuria and polydipsia5
  • Hypertension
  • Proteinuria
  • Nephronophthisis often presents earlier than ocular symptoms

Additional features:

  • Intellectual disability
  • Liver fibrosis
  • Skeletal abnormalities: rarely, skeletal abnormalities like polydactyly or syndactyly may be observed

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Genetics

SLS is a rare autosomal recessive disorder. SLS is genetically heterogeneous, involving several genes. Some of these genes can also be associated with non-syndromic retinal dystrophy.6-9

  1. NPHP4 (OMIM: #607215)
  2. SDCCAG8 (OMIM: #613524)
  3. NPHP1 (OMIM: #607100)
  4. TRAF3IP1 (OMIM: #607380)
  5. IQCB1 (OMIM: #609237)
  6. SLSN3 (OMIM: #606995)
  7. WDR19 (OMIM: #608151)
  8. CEP290 (OMIM: #610142)

These genes are involved in ciliary structure and function as well as signalling pathways. Pathogenic variations disrupt the normal ciliary processes and lead to nephronophthisis and retinal degeneration.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Fundus examination:
    • Bone spicule pigmentation of the retina indicating retinal degeneration. Vessel attenuation and optic disc pallor.10
  2. Electroretinography (ERG):
    • Dark and light adapted full field ERGs, pattern ERG, 30hz flicker. May demonstrate unrecordable rod and cone response suggestive of generalised retinal dystrophy.11
  3. Fundus autofluorescence (FAF):
    • To assess overall health of the retina.
  4. Visual field testing:
    • Reduced peripheral visual fields.
  5. Genetic testing:
    • Retinal disease gene panel and consider renal disease panel (in conjunction with renal team).

Systemic

  1. Nephrologist referral:
    • Investigation of renal dysfunction. Renal assessments may include renal function tests, urinalysis, renal ultrasound, renal biopsy.12

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Diagnosis

A definitive diagnosis relies on genetic testing, identifying pathogenic variants in known SLS-related genes. Clinical and imaging findings support the genetic results.

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Differential diagnosis

Distinguishing SLS from other syndromic and non-syndromic causes of nephronophthisis and retinal degeneration is vital. Conditions like Bardet-Biedl syndrome and Alström syndrome share overlapping features.

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Management

Ocular

  1. Regular ophthalmic follow-up:
    • Monitor disease progression.13
  2. Cataracts:
    •  May require surgery to remove cataract if this develops.
  3. Low vision rehabilitation:
    • To enhance visual function and maximise independence in daily activities. Utilise low vision aids (e.g., magnifiers, telescopes), provide orientation and mobility training, and offer adaptive technology solutions.

Systemic

  1. Renal follow-up:
    • Management of renal complications includes blood pressure control, dietary adjustments, and, in advanced cases, renal replacement therapy.
  2. Multi-disciplinary team:
    • This will include ocular and renal physicians.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic Counsellors (GCs) and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They inform patients of the diagnosis in a private room and provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research

Ongoing research focuses on understanding the molecular pathways disrupted by SLS-associated gene mutations.

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Further information and support

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References

  1. Senior B, Friedmann AI, Braudo JL. Juvenile familial nephropathy with tapetoretinal degeneration. Am J Ophthalmol. 1961;52:625-633.
  2. Kaur A, Dhir SK, Goyal G, Mittal N, Goyal RK. Senior Loken Syndrome. J Clin Diagn Res. 2016 Nov;10(11):SD03-SD04. doi: 10.7860/JCDR/2016/21832.8816. Epub 2016 Nov 1. PMID: 28050464; PMCID: PMC5198417.
  3. Turagam MK, Velagapudi P, Holley JL. Senior-Loken and other renal-retinal syndromes: A case report and review. Int J Nephrol Urol. 2009;1(2):143-152.
  4. Simms RJ, Hynes AM, Eley L, Sayer JA. Nephronophthisis: a genetically diverse ciliopathy. Int J Nephrol. 2011;2011:527137.
  5. Hildebrandt F, Waldherr R, Kutt R, Brandis M. The nephronophthisis complex: clinical and genetic aspects. Clin Investig. 1992;70:802-808.
  6. Bergmann C. Educational paper: ciliopathies. Eur J Pediatr. 2012;171(9):1285-1300.
  7. Roozbeh J, Sharifian M, Hosseini H, Sagheb MM, Behzadi S, Raeisjalali GA, et al. Senior-Loken syndrome in an Iranian family. Saudi J Kidney Dis Transpl. 2010;21(4):735-737.
  8. Otto EA, Loeys B, Khanna H, et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005;37:282-288.
  9. Abeshi A, Zulian A, Beccari T, Dundar M, Colombo L, Bertelli M. Genetic testing for Senior-Loken syndrome. EuroBiotech J. 2017;1(s1):99-101.
  10. Aggarwal HK, Jain D, Yadav S, Kaverappa V, Gupta A. Senior-Loken syndrome with rare manifestations: a case report. Eurasian J Med. 2013 Jun;45(2):128-131. doi: 10.5152/eajm.2013.25. PMID: 25610265; PMCID: PMC4261493.
  11. Sergouniotis PI, Hadfield KD, Black GC. Fundus examination pointing to the diagnosis of Senior-Loken syndrome. JAMA Ophthalmol. 2016;134(8):e161299. doi: 10.1001/jamaophthalmol.2016.1299.
  12. Aguilera A, Rivera M, Gallego N, Nogueira J, Ortuno J. Sonographic appearance of the juvenile nephronophthisis-cystic renal medulla complex. Nephrol Dial Transplant. 1997;12:625-626.
  13. R H. Senior-Loken syndrome – a ciliopathy. J Clin Diagn Res. 2014 Nov;8(11):MD04-05. doi: 10.7860/JCDR/2014/9688.5120. Epub 2014 Nov 20. PMID: 25584255; PMCID: PMC4290257.

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Updated on June 2, 2024
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