Skip to main content
SpringerLink
Log in

Genetische und klinische Heterogenität bei LCA-Patienten

Das Ende der Einheitlichkeit

Genetic and clinical heterogeneity in LCA patients

The end of uniformity

  • Originalien
  • Published:
Der Ophthalmologe Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Zusammenfassung

Hintergrund

Die Diagnose kongenitale Lebersche Amaurose (LCA) umfasst Patienten mit frühkindlicher Netzhautdystrophie und früher Erblindung.

Methoden

In einer Fallserie mit 135 Familien mit schwerer frühkindlicher Netzhautdystrophie wurde die übliche ophthalmologische Untersuchung um eine Zweifarbenschwellenperimetrie, eine Fundusautofluoreszenz (FAF) und eine optische Kohärenztomographie (OCT) erweitert. Eine molekulargenetische Untersuchung von AIPL1, CRB1, CRX, GUCY2D, LRAT, RPE65, RPGRIP und TULP1 schloss sich an.

Ergebnisse

GUCY2D-Mutationen erzeugten bei unauffälligem Fundus den schwersten Phänotyp. Bei RPE65-Mutationen konnte trotz unauffälliger Funduskopie keine FAF nachgewiesen werden. CRB1-Mutationen zeigten im OCT eine Verdickung der Neuroretina. CRX-Mutationen korrelierten mit einer progressiven Zapfen-Stäbchen-Dystrophie.

Schlussfolgerung

Eine Genotyp-Phänotyp-Korrelation für ausgewählte Gene erlaubt eine optimierte Strategie für die molekulargenetische Untersuchung.

Abstract

Background

Leber congenital amaurosis (LCA) usually describes patients with severely reduced vision due to a retinal dystrophy in early childhood.

Methods

In 135 families in a case series with severely reduced vision due to a retinal dystrophy in early childhood a complete ophthalmologic examination was extended by two-color threshold perimetry, fundus autofluorescence (FAF), und optical coherence tomography (OCT). Mutation screening included AIPL1, CRB1, CRX, GUCY2D, LRAT, RPE65, RPGRIP, and TULP1.

Results

GUCY2D mutations caused the most severe phenotype with severely reduced vision from birth but unremarkable fundus appearance. RPE65 mutations were correlated with an obvious lack of FAF. CRB1 mutations showed a significantly thickened retina on OCT. CRX mutations were associated with a progressive form of cone-rod dystrophy.

Conclusion

A genotype-phenotype correlation for selected genes allows an optimized strategy for the molecular genetic work-up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1

Literatur

  1. Acland GM, Aguirre GD, Ray J et al. (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28: 92–95

    Article  PubMed  Google Scholar 

  2. Bernal S, Calaf M, Garcia-Hoyos M et al. (2003) Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa. J Med Genet 40: e89

    Article  PubMed  Google Scholar 

  3. Booij JC, Florijn RJ, Brink JB ten et al. (2005) Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. J Med Genet 42: e67

    Article  PubMed  Google Scholar 

  4. Bowne SJ, Sullivan LS, Mortimer SE et al. (2006) Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and Leber congenital amaurosis. Invest Ophthalmol Vis Sci 47: 34–42

    Article  PubMed  Google Scholar 

  5. Hollander AI den, Heckenlively JR, Born LI van den et al. (2001) Leber congenital amaurosis and retinitis pigmentosa with coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am J Hum Genet 69: 198–203

    Article  PubMed  Google Scholar 

  6. Hollander AI den, Koenekoop RK, Yzer S et al. (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet 79: 556–561

    Article  PubMed  Google Scholar 

  7. Dharmaraj S, Leroy BP, Sohocki MM et al. (2004) The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations. Arch Ophthalmol 122: 1029–1037

    Article  PubMed  Google Scholar 

  8. Dharmaraj SR, Silva ER, Pina AL et al. (2000) Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genet 21: 135–150

    Article  PubMed  Google Scholar 

  9. Drexler W, Morgner U, Ghanta RK et al. (2001) Ultrahigh-resolution ophthalmic optical coherence tomography. Nat Med 7: 502–507

    Article  PubMed  Google Scholar 

  10. Dryja TP, Adams SM, Grimsby JL et al. (2001) Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet 68: 1295–1298

    Article  PubMed  Google Scholar 

  11. Friedman JS, Chang B, Kannabiran C et al. (2006) Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet 79: 1059–1070

    Article  PubMed  Google Scholar 

  12. Gregory-Evans K, Kelsell RE, Gregory-Evans CY et al. (2000) Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase. Ophthalmology 107: 55–61

    Article  PubMed  Google Scholar 

  13. Gu S, Lennon A, Li Y et al. (1998) Tubby-like protein-1 mutations in autosomal recessive retinitis pigmentosa. Lancet 351: 1103–1104

    Article  PubMed  Google Scholar 

  14. Gu S, Thompson DA, Srisailapathy Srikumari CR et al. (1997) Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet 17: 194–197

    Article  PubMed  Google Scholar 

  15. Hanein S, Perrault I, Gerber S et al. (2004) Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat 23: 306–317

    Article  PubMed  Google Scholar 

  16. Hanein S, Perrault I, Olsen P et al. (2002) Evidence of a founder effect for the RETGC1 (GUCY2D) 2943delG mutation in Leber congenital amaurosis pedigrees of Finnish origin. Hum Mutat 20: 322–323

    Article  Google Scholar 

  17. Huang D, Swanson EA, Lin CP et al. (1991) Optical coherence tomography. Science 254: 1178–1181

    PubMed  Google Scholar 

  18. Jacobson SG, Cideciyan AV, Aleman TS et al. (2003) Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum Mol Genet 12: 1073–1078

    Article  PubMed  Google Scholar 

  19. Janecke AR, Thompson DA, Utermann G et al. (2004) Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. Nat Genet 36: 850–854

    Article  PubMed  Google Scholar 

  20. Keen TJ, Mohamed MD, McKibbin M et al. (2003) Identification of a locus (LCA9) for Leber’s congenital amaurosis on chromosome 1p36. Eur J Hum Genet 11: 420–423

    Article  PubMed  Google Scholar 

  21. Koenekoop RK, Fishman GA, Iannaccone A et al. (2002) Electroretinographic abnormalities in parents of patients with Leber congenital amaurosis who have heterozygous GUCY2D mutations. Arch Ophthalmol 120: 1325–1330

    PubMed  Google Scholar 

  22. Leber T (1869) Über Retinitis pigmentosa und angeborene Amaurose. Graefes Arch Clin Exp Ophthalmol 15: 1–25

    Google Scholar 

  23. Lorenz B, Andrassi M, Kretschmann U (2003) Phenotype in two families with RP3 associated with RPGR mutations. Ophthalmic Genet 24: 89–101

    Article  PubMed  Google Scholar 

  24. Lorenz B, Gyürüs P, Preising M et al. (2000) Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci 41: 2735–2742

    PubMed  Google Scholar 

  25. Lorenz B, Wabbels B, Wegscheider E et al. (2004) Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65. Ophthalmology 111: 1585–1594

    Article  PubMed  Google Scholar 

  26. Lotery AJ, Jacobson SG, Fishman GA et al. (2001) Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch Ophthalmol 119: 415–420

    PubMed  Google Scholar 

  27. Marmor MF, Holder GE, Seeliger MW et al. (2004) Standard for clinical electroretinography (2004 update). Doc Ophthalmol 108: 107–114

    Article  PubMed  Google Scholar 

  28. Morimura H, Fishman GA, Grover SA et al. (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc Natl Acad Sci U S A 95: 3088–3093

    Article  PubMed  Google Scholar 

  29. Paunescu K, Preising MN, Friedburg C et al. (2006) Variation of phenotype in patients with compound heterozygous mutations of RetGC1 depending on the affected domains. Invest Ophthalmol Vis Sci 47: eAbstract 5802

    Google Scholar 

  30. Paunescu K, Preising MN, Janke B et al. (in press) Genotype-Phenotype correlation in a german family with a novel complex CRX mutation extending the open reading frame. Ophthalmology: Epub 22.02.2007

  31. Paunescu K, Wabbels B, Preising MN et al. (2005) Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations. Graefes Arch Clin Exp Ophthalmol 243: 417–426

    Article  PubMed  Google Scholar 

  32. Perrault I, Hanein S, Gerber S et al. (2004) Retinal dehydrogenase 12 (RDH12) mutations in Leber congenital amaurosis. Am J Hum Genet 75: 639–646

    Article  PubMed  Google Scholar 

  33. Perrault I, Rozet JM, Calvas P et al. (1996) Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat Genet 14: 461–464

    Article  PubMed  Google Scholar 

  34. Perrault I, Rozet JM, Gerber S et al. (2000) Spectrum of retGC1 mutations in Leber’s congenital amaurosis. Eur J Hum Genet 8: 578–582

    Article  PubMed  Google Scholar 

  35. Puliafito CA, Hee MR, Schuman JS et al. (eds) (1995) Optical coherence tomography of ocular disease. Slack Inc, Thorofare, New Jersey

  36. Senechal A, Humbert G, Surget MO et al. (2006) Screening genes of the retinoid metabolism: novel LRAT mutation in Leber congenital amaurosis. Am J Ophthalmol 142: 702–704

    Article  PubMed  Google Scholar 

  37. Sohocki MM, Bowne SJ, Sullivan LS et al. (2000) Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat Genet 24: 79–83

    Article  PubMed  Google Scholar 

  38. Sohocki MM, Perrault I, Leroy BP et al. (2000) Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Mol Genet Metab 70: 142–150

    Article  PubMed  Google Scholar 

  39. Thompson DA, Gyürüs P, Fleischer LL et al. (2000) Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci 41: 4293–4299

    PubMed  Google Scholar 

  40. Thompson DA, Janecke AR, Lange J et al. (2005) Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Hum Mol Genet 14: 3865–3875

    Article  PubMed  Google Scholar 

  41. Valente EM, Silhavy JL, Brancati F et al. (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38: 623–625

    Article  PubMed  Google Scholar 

  42. Yzer S, Fishman GA, Racine J et al. (2006) CRB1 heterozygotes with regional retinal dysfunction: implications for genetic testing of Leber congenital amaurosis. Invest Ophthalmol Vis Sci 47: 3736–3744

    Article  PubMed  Google Scholar 

  43. Yzer S, Leroy BP, De Baere E et al. (2006) Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 47: 1167–1176

    Google Scholar 

  44. Zernant J, Kulm M, Dharmaraj S et al. (2005) Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest Ophthalmol Vis Sci 46: 3052–3059

    Article  PubMed  Google Scholar 

  45. Zhang Q, Acland GM, Zangerl B et al. (2001) Fine mapping of canine XLPRA establishes homology of the human and canine RP3 intervals. Invest Ophthalmol Vis Sci 42: 2466–2471

    PubMed  Google Scholar 

Download references

Danksagung

Wir danken den Familien und Patienten für ihre Kooperation und Geduld bei den Untersuchungen. Ebenso gilt unser Dank Prof. U. Kellner, Prof. G. Kommerell und Prof. K. Rüther für die Überweisung von Patienten. Frau U. Brauer, Frau D. Glatz und Frau R. Foeckler haben exzellente Arbeit bei der Genotypisierung geleistet. Dem Geschick und der Geduld von Frau U. Biendl und Frau B. Langer ist es zu verdanken, dass die nicht immer einfachen elektrophysiologischen und psychophysischen Untersuchungen verwertbare Ergebnisse lieferten.

Für die finanzielle Unterstützung des Projekts bedanken wir uns bei der Deutschen Forschungsgemeinschaft (DFG Lo457/3, Lo457/5), der Pro Retina Deutschland e.V. und der Regensburger Forschungsförderung in der Medizin (ReForM).

Interessenkonflikt

Es besteht kein Interessenkonflikt. Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen. Die Präsentation des Themas ist unabhängig und die Darstellung der Inhalte produktneutral.

Author information

Author notes

  1. K. Paunescu

    Present address: Augenklinik am Universitätsklinikum Erlangen, Erlangen, Deutschland

Authors and Affiliations

  1. Abt. für Kinderophthalmologie, Strabismologie und Ophthalmogenetik, Klinikum der Universität Regensburg, 93042, Regensburg, Deutschland

    M.N. Preising, K. Paunescu, C. Friedburg &  B. Lorenz

Authors
  1. M.N. Preising
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Paunescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Friedburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Lorenz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Preising, M., Paunescu, K., Friedburg, C. et al. Genetische und klinische Heterogenität bei LCA-Patienten. Ophthalmologe 104, 490–498 (2007). https://doi.org/10.1007/s00347-007-1533-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00347-007-1533-x

Schlüsselwörter

Keywords

Search

Navigation