Leber Congenital Amaurosis

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Classification according to ICD-10
H54 Visual impairment including blindness (binocular or monocular)
ICD-10 online (WHO version 2019)

The Leber congenital amaurosis (Greek ἀμαυρός (amauros) = "dark, blind"), also known as congenital tapeto-retinal amaurosis or LCA , is a congenital dysfunction of the pigment epithelium of the retina with degenerative manifestations of the choroid . It is a hereditary disease and was first described in 1869 by the German ophthalmologist and scientist Theodor Carl Gustav von Leber . Those affected are born blind or visually impaired , and the likelihood of subsequent siblings becoming ill is around 25%. More than 10% of all congenital blindness cases can be traced back to Leber's congenital amaurosis.

Genetic diagnostics

Leber congenital amaurosis is usually autosomal - recessive inherited, but also autosomal rarely dominant . So far, different mutations have been identified as the causes of the disease . So far, 15 subtypes have been defined due to different defects:

  1. 17p13.1 LCA 1 homozygosity of the GUCY2D gene
  2. 1p31 LCA 2 homozygosity or compound heterozygosity of the RPE65 gene
  3. 14q31.3 LCA 3 homozygosity of the SPATA7 gene
  4. 17p13.1 LCA 4 homozygosity or compound heterozygosity of the AIPL1 gene
  5. 6q14.1 LCA 5 mutation in the LCA5 gene
  6. 14q11 LCA 6 homozygosity or compound heterozygosity of the RPGRIP1 gene
  7. 19q13.3 LCA 7 homo- or heterozygosity of the CRX gene
  8. 1q31-q32.1 LCA 8 homozygosity or compound heterozygosity of the CRB1 gene (note. Retinitis pigmentosa type 12 is associated with changes in the same gene)
  9. 1p36 LCA 9 mutation in the LCA9 gene
  10. 12q21.32 LCA 10 homozygosity or compound heterozygosity of the CEP290 gene
  11. 7q31.3-q32 LCA 11 heterozygosity of the IMPDH1 gene
  12. 1q32.3 LCA 12 mutation in the RD3 gene (retinal degeneration 3)
  13. 14q11 + 14q24.1 LCA 13 homozygosity or compound heterozygosity of the RDH12 gene (note. Retinitis pigmentosa type 53 is associated with changes in the same gene)
  14. 4q32.1 LCA 14 homozygosity of the LRAT gene
  15. 6p21.3 LCA 15 homozygosity or compound heterozygosity of the TULP1 gene (note. Retinitis pigmentosa type 14 is associated with changes in the same gene)

Among other things, the so-called RPE65 gene seems to be affected, the defects of which lead to an alteration of an enzyme which plays an important role in the regeneration of rhodopsin (visual purple). Another abnormality is the occurrence in related marriages .

Clinical picture

In addition to the drastic reduction in visual acuity with corresponding visual field restrictions - usually up to complete blindness - there are often nystagmus with strabismus , reduced sensitivity to glare and direct light reaction of the pupil , as well as hyperopia and later sometimes lens opacity , keratoconus or keratoglobus . The retinal findings may initially be normal, but then, as the disease progresses, show significant damage to the pigment epithelium with depigmentation and a "pepper and salt-like" fundus image, as well as atrophy of the optic nerve ( optic atrophy ). Ultimately, only an electrophysiological examination in the form of an electroretinography (ERG) provides a clear explanation of the clinical picture and the differentiation from other congenital optic nerve atrophies .

Therapy options

After Leber's congenital amaurosis was considered incurable for a long time, genetic research has achieved initial successes in terms of a possible treatment that should enable the defective RPE65 gene to be exchanged by cloning and injecting a certain adenovirus under the retina. Children particularly affected by the disease should be able to see here in the long term. Animal experiments showed better results in young animals than in older ones.

After the first promising results, recent research results have shown that initially positive effects have apparently diminished again in some patients treated with gene therapy. In particular, the studies also left the question of the choice of persons eligible for treatment and of the dosage. Regardless of this, in 2014 the FDA classified the therapy as a potential breakthrough, which enabled the start of a further phase III study and thus the continuation of the research work. The first results of this study have already been presented and have the consequence that the manufacturing company wants to apply to the FDA for approval of the treatment method despite unanswered questions and sometimes critical assessments. In mid-2017, S. Russell and colleagues reported successful gene therapy for the defective RPE65 gene using adenovirus-based gene therapy (vector: an adeno-associated virus with RPE65 called AAV2-hRPE65v2).

Historical aspects

Theodor von Leber described the clinical picture for the first time in 1869. Two years later, he recognized and published their frequent occurrence in blood relatives . In 1957, Carl Henry Alström was able to prove an autosomal recessive inheritance for 10% of all cases of congenital blindness in Sweden .

See also

Web links

Wiktionary: Amaurosis  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ a b c Axenfeld, Pau: Textbook and Atlas of Ophthalmology . Gustav Fischer Verlag, Stuttgart 1980, ISBN 3-437-00255-4 , p. 550.
  2. ^ A b Wolfgang Hammerstein and Walter Lisch: Ophthalmologische Genetik. Enke Verlag, Stuttgart 1985, ISBN 3-432-94941-3 , p. 8.
  3. ↑ OMIM Phenotype Map , online here
  4. ↑ Leber Congenital Amaurosis. In: Orphanet (Rare Disease Database).
  5. ↑ a b OMIM: # 204000 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  6. ↑ OMIM: # 204100 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  7. ↑ OMIM: # 604232 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  8. ↑ OMIM: # 604393 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  9. ↑ OMIM: # 604537 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  10. ↑ OMIM: # 613826 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  11. ↑ OMIM: # 613829 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  12. ↑ OMIM: # 613835 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  13. ↑ OMIM: # 608553 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  14. ↑ T Jeffrey Keen, Moin D Mohamed, Martin McKibbin, Yasmin Rashid, Hussain Jafri, Irene H Maumenee, Chris F Inglehearn: Identification of a locus (LCA9) for Leber's congenital amaurosis on chromosome 1p36. In: European Journal of Human Genetics . 11, pp. 420-423, doi: 10.1038 / sj.ejhg.5200981 .
  15. ↑ OMIM: # 611755 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  16. ↑ OMIM: # 613837 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  17. ↑ OMIM: # 610612 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  18. ↑ OMIM: # 612712 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  19. ↑ OMIM: # 613341 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  20. ↑ OMIM: # 613843 Leber Congenital Amaurosis.  In: Online Mendelian Inheritance in Man . (English)
  21. ^ Rudolf Sachsenweger: Neuroophthalmology . Thieme Verlag, Stuttgart 1983, ISBN 978-3-13-531003-9 , p. 112.
  22. ↑ Leber Congenital Amaurosis. In: Orphanet (Rare Disease Database).
  23. ↑ Retina Science: Leber Congenital Amaurosis
  24. ↑ Albert M Maguire et al .: Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. In: The Lancet. 374, 2009, pp. 1597-1605, doi: 10.1016 / S0140-6736 (09) 61836-5 .
  25. ↑ Gene therapy maintains visual performance in children with hereditary blindness. ( Memento of the original from October 28, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Deutsches Ärzteblatt , Monday, October 26, 2009. @1@ 2Template: Webachiv / IABot / www.aerzteblatt.de
  26. ↑ Leber Congenital Amaurosis: Decreasing Effect of Gene Therapy . Deutsches Ärzteblatt, May 2015
  27. ↑ First results of the gene therapy study for RPE65 mutation published in USA. CONCEPT Ophthalmologie.de, October 2015 ( Memento of the original from March 4, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.concept-ophthalmologie.de
  28. ^ Andrew Pollack: Eye Treatment Closes In on Being First Gene Therapy Approved in US New York Times, October 5, 2015
  29. ↑ S. Russell, J. Bennett, J. A. Wellman et al. : Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomized, controlled, open-label, phase 3 trial. In: Lancet 390 (10097) of July 13, 2017, pp. 849-860, doi: 10.1016 / S0140-6736 (17) 31868-8 , PMID 28712537