Leber's congenital amaurosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D.  Associate Editor(s)-in-Chief: Jyostna Chouturi, M.B.B.S 
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. One form of LCA became well known in the scientific community following its successful treatment with gene therapy in 2008.
LCA was first described by Theodor Leber in the 19th century. 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.
LCA is typically characterized by nystagmus, sluggish or absent pupillary responses, and severe vision loss or blindness.
It is an autosomal recessive disorder thought to be caused by abnormal development of photoreceptor cells.
OMIM currently recognizes 18 types of LCA:
The gene CEP290 has been associated with Joubert syndrome, as well as type 10 LCA.
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.
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. 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. Early intervention was associated with better results. 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. 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.
Eye Surgeon Dr. Al Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Children's Hospital.
Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy.
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.
- ↑ 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. doi:10.1016/j.ajo.2007.08.022. PMID 17964524.
- ↑ 2.0 2.1 2.2 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. doi:10.1056/NEJMoa0802315. PMC 2829748. PMID 18441370.
- ↑ 3.0 3.1 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. doi:10.1038/mt.2009.277. PMC 2839440. PMID 19953081.
- ↑ 4.0 4.1 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. doi:10.1056/NEJMc0903652. PMC 2847775. PMID 19675341.
- ↑ 5.0 5.1 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. doi:10.1056/NEJMoa0802268. PMID 18441371.
- ↑ Template:WhoNamedIt
- ↑ Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose". Archiv für Ophthalmologie (in German). 15 (3): 1–25. doi:10.1007/BF02721213.
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Online Mendelian Inheritance in Man (OMIM) LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1 -204000
- ↑ 9.0 9.1 Weleber RG, Francis PJ, Trzupek KM, Beattie C. "Leber Congenital Amaurosis". GeneReviews. PMID 20301475.
- ↑ 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. doi:10.1038/ng1296-461. PMID 8944027.
- ↑ Marlhens F, Bareil C, Griffoin JM, et al. (October 1997). "Mutations in RPE65 cause Leber's congenital amaurosis". Nat. Genet. 17 (2): 139–41. doi:10.1038/ng1097-139. PMID 9326927.
- ↑ 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. doi:10.1167/iovs.05-0848. PMID 16505055.
- ↑ "Inherited child blindness probed". BBC News. 2005-09-19. Retrieved 2007-09-21.
- ↑ 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. doi:10.1086/302719. PMC 1288337. PMID 10631161.
- ↑ 15.0 15.1 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. doi:10.1007/s00347-007-1533-x. PMID 17525851.
- ↑ 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. PMC 3657614. PMID 22842230.
- ↑ 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. doi:10.1038/ng.2361. PMC 3454532. PMID 22842227.
- ↑ 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. doi:10.1038/ng.2370. PMID 22842231.
- ↑ 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. doi:10.1038/ng.2357. PMID 22842229.
- ↑ 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. doi:10.1080/13816810601013146. PMID 17148037.
- ↑ "GeneTests: Leber Congenital Amaurosis".
- ↑ 22.0 22.1 22.2 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.
- ↑ 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. doi:10.1126/scitranslmed.3000659. PMID 20374996.
- ↑ "ABC News: Miracle Cure for Nearly Blind Youth". Retrieved 2008-04-27.
- ↑ 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. PMID 16700630.
- ↑ https://www.youtube.com/watch?v=BsXa-mAKDVs
- "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. ISBN 0-312-68190-9. OCLC 740628904.
- Foundation for Retinal Research
- GeneReview/NIH/UW entry on Leber Congenital Amaurosis
- Leber's Congenital Amaurosis FAQ from WonderBaby.org
- Leber's Congenital Amaurosis Treated with Gene Therapy
- Psychology Dictionary