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Leber's congenital amaurosis

Leber's congenital amaurosis
Classification and external resources
ICD-10 H35.5
ICD-9-CM 362.76
OMIM 204000 204100 604232 604393 604537 605446 602225 604210 608553
DiseasesDB 33192
  • Leber Congenital Amaurosis

Leber's congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life, and affects around 1 in 80,000 of the population.[1] One form of LCA became well known in the scientific community following its successful treatment with gene therapy in 2008.[2][3][4][5]

LCA was first described by Theodor Leber in the 19th century.[6][7] It should not be confused with Leber's hereditary optic neuropathy, which is a different disease also described by Theodor Leber.


  • Signs and symptoms 1
  • Genetics 2
  • Testing 3
  • Treatment 4
  • In Popular Culture 5
  • See also 6
  • References 7
  • Further reading 8
  • External links 9

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.[8][9]

LCA is typically characterized by nystagmus,[8] sluggish or absent pupillary responses,[9] and severe vision loss or blindness.[8]


It is an autosomal recessive disorder thought to be caused by abnormal development of photoreceptor cells.[8]

OMIM currently recognizes 18 types of LCA:[8]

Type OMIM Gene Locus[8]
LCA1 GUCY2D,[10] 17p13.1
LCA2 RPE65[11] 1p31.3-p31.2
LCA3 SPATA7 14q31.3
LCA4 AIPL1[12][13] 17p13.2
LCA5 LCA5[14] 6q14.1
LCA6 RPGRIP1 14q11.2
LCA7 CRX[15] 19q13.3
LCA8 CRB1[15] 1q31-q32.1
LCA9 NMNAT1[16][17][18][19] 1p36.22
LCA10 CEP290 12q21.32
LCA11 IMPDH1 7q32.1
LCA12 RD3 7q32.1
LCA13 RDH12 1q32.3
LCA14 LRAT 14q24.1
LCA15 TULP1 4q31
LCA16 KCNJ13 2q37
LCA17 GDF6 8q22
LCA18 PRPH2 6p21

The gene CEP290 has been associated with Joubert syndrome, as well as type 10 LCA.[20]


Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; University of Iowa John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Baylor College of Medicine 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.[21]


One form of LCA, patients with LCA2 bearing a mutation in the RPE65 gene, has been successfully treated by gene therapy in clinical trials. The results of three early clinical trials were published in 2008 demonstrating the safety and efficacy of adeno-associated virus to restore vision in LCA patients. In all three clinical trials, patients recovered functional vision without apparent side-effects.[2][3][4][5] 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.[22] Early intervention was associated with better results.[22] 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.[22] 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.[23]

Eye Surgeon Dr. Al Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Children's Hospital.[2][24]

Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy.[25]

In 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.[26]

See also


  1. ^ Stone EM (December 2007). "Leber congenital amaurosis — a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture". Am J Ophthalmol 144 (6): 791–811.  
  2. ^ a b c Maguire AM, Simonelli F, Pierce EA, et al. (May 2008). "Safety and efficacy of gene transfer for Leber's congenital amaurosis". N. Engl. J. Med. 358 (21): 2240–8.  
  3. ^ a b Simonelli F, Maguire AM, Testa F, et al. (March 2010). "Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration". Mol. Ther. 18 (3): 643–50.  
  4. ^ a b Cideciyan AV, Hauswirth WW, Aleman TS, et al. (August 2009). "Vision 1 year after gene therapy for Leber's congenital amaurosis". N. Engl. J. Med. 361 (7): 725–7.  
  5. ^ a b Bainbridge JW, Smith AJ, Barker SS, et al. (May 2008). "Effect of gene therapy on visual function in Leber's congenital amaurosis". N. Engl. J. Med. 358 (21): 2231–9.  
  6. ^ Leber's congenital amaurosis at Who Named It?
  7. ^ Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose". Archiv für Ophthalmologie (in German) 15 (3): 1–25.  
  8. ^ a b c d e f Online 'Mendelian Inheritance in Man' (OMIM) LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1 -204000
  9. ^ a b Weleber RG, Francis PJ, Trzupek KM, Beattie C. "Leber Congenital Amaurosis.". GeneReviews.  
  10. ^ Perrault I, Rozet JM, Calvas P, et al. (December 1996). "Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis". Nat. Genet. 14 (4): 461–4.  
  11. ^ Marlhens F, Bareil C, Griffoin JM, et al. (October 1997). "Mutations in RPE65 cause Leber's congenital amaurosis". Nat. Genet. 17 (2): 139–41.  
  12. ^ Yzer S, Leroy BP, De Baere E, et al. (March 2006). "Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis". Invest. Ophthalmol. Vis. Sci. 47 (3): 1167–76.  
  13. ^ "Inherited child blindness probed". BBC News. 2005-09-19. Retrieved 2007-09-21. 
  14. ^ Dharmaraj S, et al. (January 2000). "A Novel Locus for Leber Congenital Amaurosis Maps to Chromosome 6q". The American Journal of Human Genetics 66 (1): 319–326.  
  15. ^ a b Preising MN, Paunescu K, Friedburg C, Lorenz B (June 2007). "Genetic and clinical heterogeneity in LCA patients. The end of uniformity". Ophthalmologe (in German) 104 (6): 490–8.  
  16. ^ 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.  
  17. ^ Falk MJ, Zhang Q, Nakamaru-Ogiso E, Kannabiran C, Fonseca-Kelly Z, Chakarova C, Audo I, Mackay DS, Zeitz C, Borman AD, Staniszewska M, Shukla R, Palavalli L, Mohand-Said S, Waseem NH, Jalali S, Perin JC, Place E, Ostrovsky J, Xiao R,Bhattacharya SS, Consugar M, Webster AR, Sahel JA, Moore AT, Berson EL, Liu Q,Gai X, Pierce EA (July 2012). "NMNAT1 mutations cause Leber congenital amaurosis". Nature Genetics 44 (9): 1040–5.  
  18. ^ Chiang PW, Wang J, Chen Y, Fu Q, Zhong J, Chen Y, Yi X, Wu R, Gan H, Shi Y, Chen Y, Barnett C, Wheaton D, Day M, Sutherland J, Heon E, Weleber RG, Gabriel LA, Cong P, Chuang K, Ye S, Sallum JM, Qi M (July 2012). "Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis". Nature Genetics 44 (9): 972–4.  
  19. ^ Perrault I, Hanein S, Zanlonghi X, Serre V, Nicouleau M, Defoort-Delhemmes S, Delphin N, Fares-Taie L, Gerber S, Xerri O, Edelson C, Goldenberg A, Duncombe A, Le Meur G, Hamel C, Silva E, Nitschke P, Calvas P, Munnich A, Roche O, Dollfus H, Kaplan J, Rozet JM (July 2012). "Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy". Nature Genetics 44 (9): 975–7.  
  20. ^ Traboulsi EI, Koenekoop R, Stone EM (2006). "Lumpers or splitters? The role of molecular diagnosis in Leber congenital amaurosis". Ophthalmic Genet. 27 (4): 113–5.  
  21. ^ "GeneTests: Leber Congenital Amaurosis". 
  22. ^ a b c 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.  
  23. ^ Amado, D.; Mingozzi, F.; Bennicelli, J. L.; Chen, Y.; High, K. A.; Maguire, A. M.; Bote, E.; Grant, R. L.; Golden, J. A.; Narfstrom, K.; Syed, N. A.; Orlin, S. E.; High, K. A.; Maguire, A. M.; Bennett, J.; 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.  
  24. ^ "ABC News: Miracle Cure for Nearly Blind Youth". Retrieved 2008-04-27. 
  25. ^ Williams, M. L.; Coleman, J. E.; Haire, S. E.; Aleman, T. S.; Cideciyan, A. V.; Sokal, I.; Palczewski, K.; Jacobson, S. G.; Semple-Rowland, S. L. (2006). "Lentiviral Expression of Retinal Guanlylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness". PLOS Medicine 3 (6): e201.  
  26. ^

Further reading

  • """Jocelyn Kaiser on "Gene Therapy in a New Light. Science & Nature | Smithsonian Magazine. p. 124. 
  • Lewis, Ricki (2012). The Forever Fix: Gene Therapy and the Boy Who Saved It. New York: St. Martin's Press.  

External links

  • Foundation for Retinal Research
  • GeneReview/NIH/UW entry on Leber Congenital Amaurosis
  • Leber's Congenital Amaurosis FAQ from
  • Leber's Congenital Amaurosis Treated with Gene Therapy
  • Psychology Dictionary
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