Leber congenital amaurosis
|Leber congenital amaurosis|
|Other names: Leber's congenital amaurosis|
|Symptoms||Visual impairment, sensitivity to light|
|Types||> 12 types|
|Causes||Genetic (autosomal recessive)|
|Frequency||1 in 40,000 newborns|
Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.
It affects about 1 in 40,000 newborns. 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.
One form of LCA was successfully treated with gene therapy in 2008.
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 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.
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; 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 Biogene 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 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. 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. 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.
Retina surgeon Dr. Albert 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 March 2020, doctors at the Casey Eye Institute of the Oregon Health & Science University injected a CRISPR-modified virus into a patient's eye in an attempt to treat LCA10.
- 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 "Believe the Unseen") Dr. Abby Lockhart diagnoses a young foster girl with Leber 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 congenital amaurosis, the same disease that made his mother blind.
- Four-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. He later appeared on the TV show Little Big Shots.
- ↑ 1.0 1.1 1.2 1.3 1.4 "Leber congenital amaurosis". Genetics Home Reference. August 2010. Archived from the original on 19 September 2020. Retrieved 14 May 2017.
- ↑ Stone EM (December 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. doi:10.1016/j.ajo.2007.08.022. PMID 17964524.
- ↑ Leber's congenital amaurosis at Who Named It?
- ↑ Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose". Archiv für Ophthalmologie (in Deutsch). 15 (3): 1–25. doi:10.1007/BF02721213. S2CID 543893.
- ↑ 5.0 5.1 5.2 Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, et al. (May 2008). "Safety and efficacy of gene transfer for Leber's congenital amaurosis". The New England Journal of Medicine. 358 (21): 2240–8. doi:10.1056/NEJMoa0802315. PMC 2829748. PMID 18441370.
- ↑ 6.0 6.1 Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, et al. (March 2010). "Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration". Molecular Therapy. 18 (3): 643–50. doi:10.1038/mt.2009.277. PMC 2839440. PMID 19953081.
- ↑ 7.0 7.1 Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, et al. (August 2009). "Vision 1 year after gene therapy for Leber's congenital amaurosis". The New England Journal of Medicine. 361 (7): 725–7. doi:10.1056/NEJMc0903652. PMC 2847775. PMID 19675341.
- ↑ 8.0 8.1 Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al. (May 2008). "Effect of gene therapy on visual function in Leber's congenital amaurosis". The New England Journal of Medicine. 358 (21): 2231–9. CiteSeerX 10.1.1.574.4003. doi:10.1056/NEJMoa0802268. PMID 18441371.
- ↑ 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
- ↑ 10.0 10.1 Weleber, R. G.; Francis, P. J.; Trzupek, K. M.; Beattie, C.; Adam, M. P.; Ardinger, H. H.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Stephens, K.; Amemiya, A. (1993). "Leber Congenital Amaurosis". GeneReviews. PMID 20301475.
- ↑ Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, et al. (December 1996). "Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis". Nature Genetics. 14 (4): 461–4. doi:10.1038/ng1296-461. PMID 8944027. S2CID 21269014.
- ↑ Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, et al. (October 1997). "Mutations in RPE65 cause Leber's congenital amaurosis". Nature Genetics. 17 (2): 139–41. doi:10.1038/ng1097-139. PMID 9326927. S2CID 19648351.
- ↑ Yzer S, Leroy BP, De Baere E, de Ravel TJ, Zonneveld MN, Voesenek K, et al. (March 2006). "Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis". Investigative Ophthalmology & Visual Science. 47 (3): 1167–76. doi:10.1167/iovs.05-0848. PMID 16505055.
- ↑ "Inherited child blindness probed". BBC News. 2005-09-19. Archived from the original on 2008-04-07. Retrieved 2007-09-21.
- ↑ Dharmaraj S, Li Y, Robitaille JM, Silva E, Zhu D, Mitchell TN, et al. (January 2000). "A novel locus for Leber congenital amaurosis maps to chromosome 6q". American Journal of Human Genetics. 66 (1): 319–26. doi:10.1086/302719. PMC 1288337. PMID 10631161.
- ↑ 16.0 16.1 Preising MN, Paunescu K, Friedburg C, Lorenz B (June 2007). "[Genetic and clinical heterogeneity in LCA patients. The end of uniformity]". Der Ophthalmologe (in Deutsch). 104 (6): 490–8. doi:10.1007/s00347-007-1533-x. PMID 17525851. S2CID 46054872.
- ↑ Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, et al. (September 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, et al. (September 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, et al. (September 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. S2CID 27501557.
- ↑ Perrault I, Hanein S, Zanlonghi X, Serre V, Nicouleau M, Defoort-Delhemmes S, et al. (September 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. S2CID 205345854.
- ↑ Traboulsi EI, Koenekoop R, Stone EM (December 2006). "Lumpers or splitters? The role of molecular diagnosis in Leber congenital amaurosis". Ophthalmic Genetics. 27 (4): 113–5. doi:10.1080/13816810601013146. PMID 17148037. S2CID 802192.
- ↑ "GeneTests: Leber Congenital Amaurosis". Archived from the original on 2016-08-21. Retrieved 2015-08-07.
- ↑ 23.0 23.1 23.2 Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, et al. (November 2009). "Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial". Lancet. 374 (9701): 1597–605. doi:10.1016/S0140-6736(09)61836-5. PMC 4492302. PMID 19854499.
- ↑ Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y, et al. (March 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. PMC 4169124. PMID 20374996.
- ↑ "Approved Products - LUXTURNA". FDA. 2019-04-05. Archived from the original on 2019-04-23. Retrieved 2021-09-18.
- ↑ "ABC News: Miracle Cure for Nearly Blind Youth". Archived from the original on 2021-05-17. Retrieved 2008-04-27.
- ↑ Williams ML, Coleman JE, Haire SE, Aleman TS, Cideciyan AV, Sokal I, et al. (June 2006). "Lentiviral expression of retinal guanylate cyclase-1 (RetGC1) restores vision in an avian model of childhood blindness". PLOS Medicine. 3 (6): e201. doi:10.1371/journal.pmed.0030201. PMC 1463903. PMID 16700630.
- ↑ "In A 1st, Scientists Use Revolutionary Gene-Editing Tool To Edit Inside A Patient". Archived from the original on 2021-08-17. Retrieved 2021-09-18.
- ↑ "4 yr old Gavin using his white cane to navigate down a curb independently". Archived from the original on 2021-02-25. Retrieved 2021-09-18.
- Gambino, Megan (December 17, 2008). "Jocelyn Kaiser on 'Gene Therapy in a New Light'". Science & Nature. Smithsonian. p. 124. Archived from the original on 25 June 2013. Retrieved 22 May 2021.
- Lewis, Ricki (2012). The Forever Fix: Gene Therapy and the Boy Who Saved It. New York: St. Martin's Press. ISBN 978-0-312-68190-6. OCLC 740628904.
- GeneReview/NIH/UW entry on Leber Congenital Amaurosis Archived 2021-04-11 at the Wayback Machine
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