Medicine:Leber's congenital amaurosis

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Leber's congenital amaurosis
SymptomsVisual impairment, sensitivity to light[1]
Types> 12 types[1]
CausesGenetic (autosomal recessive)[1]
Frequency1 in 40,000 newborns[1]

Leber's congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.[2]

One form of LCA was successfully treated with gene therapy in 2008.[3][4][5][6]

It affects about 1 in 40,000 newborns.[1] LCA was first described by Theodor Leber in the 19th century.[7][8] It should not be confused with Leber's hereditary optic neuropathy, which is a different disease also described by Theodor Leber.

Signs and symptoms

The term congenital refers to a condition present from birth (not acquired) and amaurosis refers to a loss of vision not associated with a lesion. However, beyond these general descriptions, the presentation of LCA can vary, because it is associated with multiple genes.[9][10]

LCA is typically characterized by nystagmus,[9] sluggish or absent pupillary responses,[10] and severe vision loss or blindness.[9]


It is usually autosomal recessive; however, importantly for family planning, it is sometimes autosomal dominant. It is a disorder thought to be caused by abnormal development of photoreceptor cells.[9]

OMIM currently recognizes 18 types of LCA.[9]

Type OMIM Gene Locus[9]
LCA1 Template:OMIM4 GUCY2D,[11] 17p13.1
LCA2 Template:OMIM4 RPE65[12] 1p31.3-p31.2
LCA3 Template:OMIM4 SPATA7 14q31.3
LCA4 Template:OMIM4 AIPL1[13][14] 17p13.2
LCA5 Template:OMIM4 LCA5[15] 6q14.1
LCA6 Template:OMIM4 RPGRIP1 14q11.2
LCA7 Template:OMIM4 CRX[16] 19q13.3
LCA8 Template:OMIM4 CRB1[16] 1q31-q32.1
LCA9 Template:OMIM4 NMNAT1[17][18][19][20] 1p36.22
LCA10 Template:OMIM4 CEP290 12q21.32
LCA11 Template:OMIM4 IMPDH1 7q32.1
LCA12 Template:OMIM4 RD3 7q32.1
LCA13 Template:OMIM4 RDH12 1q32.3
LCA14 Template:OMIM4 LRAT 14q24.1
LCA15 Template:OMIM4 TULP1 4q31
LCA16 Template:OMIM4 KCNJ13 2q37
LCA17 Template:OMIM4 GDF6 8q22
LCA18 Template:OMIM4 PRPH2 6p21

The gene CEP290 has been associated with Joubert syndrome, as well as type 10 LCA.[21]


Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Miraca Genetics Laboratories in Houston, TX; Asper Biotech in Tartu, Estonia; CGC Genetics in Porto, Portugal; CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Canada; and Reference Laboratory Genetics - Barcelona, Spain.[22]


One form of LCA, patients with LCA2 bearing a mutation in the RPE65 gene, has been successfully treated in clinical trials using gene therapy. The results of three early clinical trials were published in 2008 demonstrating the safety and efficacy of using adeno-associated virus to deliver gene therapy to restore vision in LCA patients. In all three clinical trials, patients recovered functional vision without apparent side-effects.[3][4][5][6] These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.

The results of a phase 1 trial conducted by the University of Pennsylvania and Children’s Hospital of Philadelphia and published in 2009 showed sustained improvement in 12 subjects (ages 8 to 44) with RPE65-associated LCA after treatment with AAV2-hRPE65v2, a gene replacement therapy.[23] Early intervention was associated with better results.[23] In that study, patients were excluded based on the presence of particular antibodies to the vector AAV2 and treatment was only administered to one eye as a precaution.[23] A 2010 study testing the effect of administration of AAV2-hRPE65v2 in both eyes in animals with antibodies present suggested that immune responses may not complicate use of the treatment in both eyes.[24]On 19 December 2017, the U.S. Food and Drug Administration approved voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. Patients must have viable retinal cells as a prerequisite for the intraocular administration of Luxturna.[25]

Eye Surgeon Dr. Al Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Children's Hospital.[3][26]

Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy.[27]

Popular culture

  • In the episode "The Blackout in the Blizzard" (season 6, episode 16) of the television drama Bones, Dr. Jack Hodgins and his pregnant wife Angela Montenegro, who is an LCA carrier, have to wait during a citywide blackout for Hodgins's genetic test results, to see if he is also an LCA carrier. He does indeed turn out to be a carrier, giving their unborn child a 25% chance of having LCA.
  • In the television series ER (season 14, episode 12 named "Believe the Unseen") Dr. Abby Lockhart diagnoses a young foster girl with Leber's congenital amaurosis. The girl to this point hid her condition from her foster families. The episode contains some information about symptoms, clinical diagnosis and mentions gene replacement therapy and clinical trials as hope for help in managing the condition.
  • In the Korean drama The King of Dramas (episode 16, "In Search Of Lost Time") Anthony Kim, played by Kim Myung-min, is diagnosed with Leber's congenital amaurosis, the same disease that made his mother blind.
  • 4 year old Gavin who suffers from a form of LCA was made famous in 2013 by a YouTube video showing him using his white cane for the first time to navigate down a curb.[28] He later appeared on the TV show Little Big Shots.

See also


  1. 1.0 1.1 1.2 1.3 1.4 "Leber congenital amaurosis" (in en). August 2010. Retrieved 14 May 2017. 
  2. Stone, Edwin M. (2007). "Leber Congenital Amaurosis–A Model for Efficient Genetic Testing of Heterogeneous Disorders: LXIV Edward Jackson Memorial Lecture". American Journal of Ophthalmology 144 (6): 791–811.e6. doi:10.1016/j.ajo.2007.08.022. PMID 17964524. 
  3. 3.0 3.1 3.2 "Safety and efficacy of gene transfer for Leber's congenital amaurosis". N. Engl. J. Med. 358 (21): 2240–8. May 2008. doi:10.1056/NEJMoa0802315. PMID 18441370. 
  4. 4.0 4.1 "Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration". Mol. Ther. 18 (3): 643–50. March 2010. doi:10.1038/mt.2009.277. PMID 19953081. 
  5. 5.0 5.1 "Vision 1 year after gene therapy for Leber's congenital amaurosis". N. Engl. J. Med. 361 (7): 725–7. August 2009. doi:10.1056/NEJMc0903652. PMID 19675341. 
  6. 6.0 6.1 "Effect of gene therapy on visual function in Leber's congenital amaurosis". N. Engl. J. Med. 358 (21): 2231–9. May 2008. doi:10.1056/NEJMoa0802268. PMID 18441371. 
  7. Leber's congenital amaurosis at Who Named It?
  8. Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose" (in German). Archiv für Ophthalmologie 15 (3): 1–25. doi:10.1007/BF02721213. 
  9. 9.0 9.1 9.2 9.3 9.4 9.5 Online Mendelian Inheritance in Man (OMIM) LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1 -204000
  10. 10.0 10.1 "Leber Congenital Amaurosis.". GeneReviews. 1993. PMID 20301475. 
  11. "Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis". Nat. Genet. 14 (4): 461–4. December 1996. doi:10.1038/ng1296-461. PMID 8944027. 
  12. "Mutations in RPE65 cause Leber's congenital amaurosis". Nat. Genet. 17 (2): 139–41. October 1997. doi:10.1038/ng1097-139. PMID 9326927. 
  13. "Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis". Invest. Ophthalmol. Vis. Sci. 47 (3): 1167–76. March 2006. doi:10.1167/iovs.05-0848. PMID 16505055. 
  14. "Inherited child blindness probed". BBC News. 2005-09-19. Retrieved 2007-09-21. 
  15. "A Novel Locus for Leber Congenital Amaurosis Maps to Chromosome 6q". The American Journal of Human Genetics 66 (1): 319–326. January 2000. doi:10.1086/302719. PMID 10631161. 
  16. 16.0 16.1 "Genetic and clinical heterogeneity in LCA patients. The end of uniformity" (in German). Ophthalmologe 104 (6): 490–8. June 2007. doi:10.1007/s00347-007-1533-x. PMID 17525851. 
  17. Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y, Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R (July 2012). "Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration". Nature Genetics 44 (9): 1035–9. doi:10.1038/ng.2356. PMID 22842230. 
  18. "NMNAT1 mutations cause Leber congenital amaurosis". Nature Genetics 44 (9): 1040–5. July 2012. doi:10.1038/ng.2361. PMID 22842227. 
  19. "Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis". Nature Genetics 44 (9): 972–4. July 2012. doi:10.1038/ng.2370. PMID 22842231. 
  20. "Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy". Nature Genetics 44 (9): 975–7. July 2012. doi:10.1038/ng.2357. PMID 22842229. 
  21. "Lumpers or splitters? The role of molecular diagnosis in Leber congenital amaurosis". Ophthalmic Genet. 27 (4): 113–5. 2006. doi:10.1080/13816810601013146. PMID 17148037. 
  22. "GeneTests: Leber Congenital Amaurosis". 
  23. 23.0 23.1 23.2 Maguire, Albert M; High, Katherine A; Auricchio, Alberto; Wright, J Fraser; Pierce, Eric A; Testa, Francesco; Mingozzi, Federico; Stone, Edwin et al. (2009). "Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial". Lancet 374 (9701): 1597–1605. doi:10.1016/S0140-6736(09)61836-5. PMID 19854499. 
  24. Amado, D. et al. (2010). "Safety and Efficacy of Subretinal Readministration of a Viral Vector in Large Animals to Treat Congenital Blindness". Science Translational Medicine 2 (21): 21ra16. doi:10.1126/scitranslmed.3000659. PMID 20374996. 
  25. "Approved Products - LUXTURNA". 
  26. "ABC News: Miracle Cure for Nearly Blind Youth". Retrieved 2008-04-27. 
  27. Williams, M. L.; Coleman, J. E.; Haire, S. E.; Aleman, T. S.; Cideciyan, A. V.; Sokal, I.; Palczewski, K.; Jacobson, S. G. et al. (2006). "Lentiviral Expression of Retinal Guanlylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness". PLOS Medicine 3 (6): e201. doi:10.1371/journal.pmed.0030201. PMID 16700630. 
  28. "4 yr old Gavin using his white cane to navigate down a curb independently". 

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