View source for Leber's congenital amaurosis

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'''Leber's congenital amaurosis''' ('''LCA''') is a rare [[heredity|inherited]] [[List of eye diseases and disorders|eye disease]] that appears at [[congenital|birth]] or in the first few months of life, and affects around 1 in 80,000 of the population.<ref>{{cite journal | author= Stone EM | title= Leber congenital amaurosis — a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture | journal= Am J Ophthalmol | volume = 144 | issue = 6 | pages = 791–811 |date=December 2007 |pmid=17964524 |doi=10.1016/j.ajo.2007.08.022 |url=http://www.ajo.com/article/PIIS0002939407007672/}}</ref> One form of LCA became well known in the scientific community following its [[Adeno associated virus and gene therapy of the human retina|successful treatment]] with [[gene therapy]] in 2008.<ref name="Maguire, 2008">{{cite journal  |vauthors=Maguire AM, Simonelli F, Pierce EA, etal |title=Safety and efficacy of gene transfer for Leber's congenital amaurosis |journal=N. Engl. J. Med. |volume=358 |issue=21 |pages=2240–8 |date=May 2008 |pmid=18441370 |pmc=2829748 |doi=10.1056/NEJMoa0802315 |url=}}</ref><ref  name="Simonelli, 2010">{{cite journal  |vauthors=Simonelli F, Maguire AM, Testa F, etal |title=Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration |journal=Mol. Ther. |volume=18 |issue=3 |pages=643–50 |date=March 2010 |pmid=19953081 |pmc=2839440 |doi=10.1038/mt.2009.277 |url=}}</ref><ref name="Cideciyan, 2009">{{cite journal  |vauthors=Cideciyan AV, Hauswirth WW, Aleman TS, etal |title=Vision 1 year after gene therapy for Leber's congenital amaurosis |journal=N. Engl. J. Med. |volume=361 |issue=7 |pages=725–7 |date=August 2009 |pmid=19675341 |pmc=2847775 |doi=10.1056/NEJMc0903652 |url=}}</ref><ref name="Bainbridge, 2008">{{cite journal  |vauthors=Bainbridge JW, Smith AJ, Barker SS, etal |title=Effect of gene therapy on visual function in Leber's congenital amaurosis |journal=N. Engl. J. Med. |volume=358 |issue=21 |pages=2231–9 |date=May 2008 |pmid=18441371 |doi=10.1056/NEJMoa0802268 |url=}}</ref>

LCA was first described by [[Theodor Leber]] in the 19th century.<ref>{{WhoNamedIt |synd|1189|Leber's congenital amaurosis}}</ref><ref>{{cite journal | author = Leber T | title = Über Retinitis pigmentosa und angeborene Amaurose | journal = Archiv für Ophthalmologie | volume = 15 | issue = 3 | pages= 1–25 |year= 1869 |language= German |doi= 10.1007/BF02721213}}</ref>  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.<ref name=OMIMLCA/><ref name=GR/>

LCA is typically characterized by [[pathologic nystagmus|nystagmus]],<ref name=OMIMLCA/> sluggish or absent [[Pupillary reflex|pupillary responses]],<ref name=GR>{{cite journal | pmid=20301475 | journal=GeneReviews | title= Leber Congenital Amaurosis. |author=Weleber RG, Francis PJ, Trzupek KM, Beattie C.}}</ref> and severe [[vision loss]] or [[blindness]].<ref name=OMIMLCA/>

==Genetics==
It is an [[autosomal recessive]] disorder thought to be caused by abnormal development of [[photoreceptor cell]]s.<ref name=OMIMLCA/>

[[OMIM]] currently recognizes 18 types of LCA:<ref name=OMIMLCA>{{OMIM|204000| LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1}}</ref>

{| class="wikitable"
| '''Type''' || '''[[OMIM]]''' || '''[[Gene]]''' || '''[[Locus (genetics)|Locus]]<ref name=OMIMLCA/>'''
 |- 
 | LCA1  || {{OMIM4|204000}}  || [[GUCY2D]],<ref name="=Perraul, 1996">{{cite journal  |vauthors=Perrault I, Rozet JM, Calvas P, etal |title=Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis |journal=Nat. Genet. |volume=14 |issue=4 |pages=461–4 |date=December 1996 |pmid=8944027 |doi=10.1038/ng1296-461 |url=}}</ref> || 17p13.1
 |- 
 | LCA2 || {{OMIM4|204100}}  || [[RPE65]]<ref name="Marlhens, 1997">{{cite journal  |vauthors=Marlhens F, Bareil C, Griffoin JM, etal |title=Mutations in RPE65 cause Leber's congenital amaurosis |journal=Nat. Genet. |volume=17 |issue=2 |pages=139–41 |date=October 1997 |pmid=9326927 |doi=10.1038/ng1097-139 |url=}}</ref> || 1p31.3-p31.2
 |- 
 | LCA3 || {{OMIM4|609868}}  || [[SPATA7]] || 14q31.3 
 |- 
 | LCA4 || {{OMIM4|604393}}  || [[AIPL1]]<ref name="Yzer, 2006">{{cite journal  |vauthors=Yzer S, Leroy BP, De Baere E, etal |title=Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis |journal=Invest. Ophthalmol. Vis. Sci. |volume=47 |issue=3 |pages=1167–76 |date=March 2006 |pmid=16505055 |doi=10.1167/iovs.05-0848 |url=}}</ref><ref>{{cite news |url=http://news.bbc.co.uk/2/hi/health/4250226.stm |title= Inherited child blindness probed |accessdate=2007-09-21 |format= |work=BBC News | date=2005-09-19}}</ref> || 17p13.2
 |- 
 | LCA5 || {{OMIM4|604537}}  || [[LCA5]]<ref name="Dharmaraj, 2000">{{cite journal  |vauthors=Dharmaraj S, etal |title=A Novel Locus for Leber Congenital Amaurosis Maps to Chromosome 6q |journal=The American Journal of Human Genetics |volume=66 |issue=1 |pages=319–326 |date=January 2000 |pmid=10631161 |doi=10.1086/302719 |pmc=1288337}}</ref> || 6q14.1
 |- 
 | LCA6 || {{OMIM4|605446}}  || [[RPGRIP1]] || 14q11.2 
 |- 
 | LCA7 || {{OMIM4|602225}}  || [[CRX (gene)|CRX]]<ref name="Preising, 2007">{{cite journal |author=Preising MN, Paunescu K, Friedburg C, Lorenz B |title=Genetic and clinical heterogeneity in LCA patients. The end of uniformity |language=German |journal=Ophthalmologe |volume=104 |issue=6 |pages=490–8 |date=June 2007 |pmid=17525851 |doi=10.1007/s00347-007-1533-x |url=}}</ref> || 19q13.3
 |- 
 | LCA8 || {{OMIM4|604210}}  || [[CRB1]]<ref name="Preising, 2007"/>|| 1q31-q32.1
 |- 
 | LCA9 || {{OMIM4|608553}}  || [[NMNAT1]]<ref name="Koenekoop et al., 2012">{{cite journal |author=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 |title=Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration |journal=Nature Genetics |volume=44 |issue=9 |pages=1035–9 |date=July 2012 |pmid=22842230 |doi=10.1038/ng.2356 |url= |pmc=3657614}}</ref><ref name="Falk et al., 2012">{{cite journal |author=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 |title=NMNAT1 mutations cause Leber congenital amaurosis |journal=Nature Genetics |volume=44 |issue=9 |pages=1040–5 |date=July 2012 |pmid=22842227 |doi=10.1038/ng.2361 |url= |pmc=3454532}}</ref><ref name="Chiang et al., 2012">{{cite journal |author=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 |title=Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis |journal=Nature Genetics |volume=44 |issue=9 |pages=972–4 |date=July 2012 |pmid=22842231 |doi=10.1038/ng.2370 |url=}}</ref><ref name="Perrault et al., 2012">{{cite journal |author=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 |title=Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy |journal=Nature Genetics |volume=44 |issue=9 |pages=975–7 |date=July 2012 |pmid=22842229 |doi=10.1038/ng.2357 |url=}}</ref>|| 1p36.22 
 |- 
 | LCA10 || {{OMIM4|610142}}  || [[CEP290]] || 12q21.32 
 |- 
 | LCA11 || {{OMIM4|146690}}  || [[IMPDH1]] || 7q32.1
 |- 
 | LCA12 || {{OMIM4|180040}}  || [[RD3]] || 7q32.1
 |- 
 | LCA13 || {{OMIM4|608830}}  || [[RDH12]] || 1q32.3
 |- 
 | LCA14 || {{OMIM4|604863}}  || [[Lecithin retinol acyltransferase|LRAT]] || 14q24.1 
 |- 
 | LCA15 || {{OMIM4|602280}}  || [[TULP1]] || 4q31 
|- 
 | LCA16 || {{OMIM4|603208}}  || [[KCNJ13]] || 2q37 
|- 
 | LCA17 || {{OMIM4|601147}}  || [[GDF6]] || 8q22 
|- 
 | LCA18 || {{OMIM4|179605}}  || [[PRPH2]] || 6p21
|}

The gene {{Gene|CEP290}} has been associated with [[Joubert syndrome]], as well as type 10 LCA.<ref name="Traboulsi, 2006">{{cite journal |author=Traboulsi EI, Koenekoop R, Stone EM |title=Lumpers or splitters? The role of molecular diagnosis in Leber congenital amaurosis |journal=Ophthalmic Genet. |volume=27 |issue=4 |pages=113–5 |year=2006 |pmid=17148037 |doi=10.1080/13816810601013146}}</ref>

==Testing==

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.<ref>{{cite web | url=https://www.genetests.org/disorders/?disid=2671 | title=GeneTests: Leber Congenital Amaurosis}}</ref>

==Treatment==

{{Main|Adeno associated virus and gene therapy of the human retina}}

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.<ref name="Maguire, 2008"/><ref  name="Simonelli, 2010"/><ref name="Cideciyan, 2009"/><ref name="Bainbridge, 2008"/> 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.<ref name="Maguire, High, 2009">{{cite journal|last1=Maguire|first1=Albert M|last2=High|first2=Katherine A|last3=Auricchio|first3=Alberto|last4=Wright|first4=J Fraser|last5=Pierce|first5=Eric A|last6=Testa|first6=Francesco|last7=Mingozzi|first7=Federico|last8=Stone|first8=Edwin |author9=''et al'' |title=Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial|journal=Lancet|volume=374|issue=9701|year=2009|pages=1597–1605 |doi=10.1016/S0140-6736(09)61836-5 |pmid=19854499|display-authors=8|last10=Rossi|first10=Settimio|last11=Fulton|first11=Ann|last12=Marshall|first12=Kathleen A|last13=Banfi|first13=Sandro|last14=Chung|first14=Daniel C|last15=Morgan|first15=Jessica IW|last16=Hauck|first16=Bernd|last17=Zelenaia|first17=Olga|last18=Zhu|first18=Xiaosong|last19=Raffini|first19=Leslie|last20=Coppieters|first20=Frauke|last21=De Baere|first21=Elfride|last22=Shindler|first22=Kenneth S|last23=Volpe|first23=Nicholas J|last24=Surace|first24=Enrico M|last25=Acerra|first25=Carmela|last26=Lyubarsky|first26=Arkady|last27=Redmond|first27=T Michael|last28=Stone|first28=Edwin|last29=Sun|first29=Junwei|last30=McDonnell|first30=Jennifer Wellman}}</ref> Early intervention was associated with better results.<ref name="Maguire, High, 2009"/>  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.<ref name="Maguire, High, 2009"/> 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.<ref name="Amado, 2010">{{cite journal|last1=Amado|first1=D.|last2=Mingozzi|first2=F. |last3=Bennicelli|first3=J. L.|last4=Chen|first4=Y.|last5=High|first5=K. A.|last6=Maguire|first6=A. M. et al.|last7=Bote|first7=E.|last8=Grant|first8=R. L.|last9=Golden|first9=J. A.|last10=Narfstrom|first10=K.|last11=Syed|first11=N. A.|last12=Orlin|first12=S. E.|last13=High|first13=K. A.|last14=Maguire|first14=A. M.|last15=Bennett|first15=J.|title=Safety and Efficacy of Subretinal Readministration of a Viral Vector in Large Animals to Treat Congenital Blindness|journal=Science Translational Medicine |volume=2|issue=21 |year=2010 |page=21ra16 |doi=10.1126/scitranslmed.3000659 |pmid=20374996}}</ref>

Eye Surgeon Dr. Al Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Children's Hospital.<ref name="Maguire, 2008"/><ref>{{cite web
 |url=http://abcnews.go.com/GMA/Story?id=4739586&page=1 |title=ABC News: Miracle Cure for Nearly Blind Youth |accessdate=2008-04-27 |format= |work=}}</ref>

Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using [[gene therapy]].<ref name="Williams, 2006">{{cite journal|last1=Williams |first1=M. L.|last2=Coleman |first2=J. E. |last3=Haire |first3=S. E. |last4=Aleman |first4=T. S.|last5=Cideciyan |first5=A. V.|last6=Sokal |first6=I. |last7=Palczewski |first7=K. |last8=Jacobson |first8=S. G.|last9=Semple-Rowland |first9=S. L. |title= Lentiviral Expression of Retinal Guanlylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness |journal=PLOS Medicine |volume=3|issue=6 |year=2006 |page=e201|pmid=16700630}}</ref>

==In Popular Culture==
*In the episode ''The Blackout in the Blizzard'' (season 6, episode 16) of the television drama ''[[Bones (TV series)|Bones]]'', Dr. [[Jack Hodgins (Bones)|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 (TV 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.<ref>https://www.youtube.com/watch?v=BsXa-mAKDVs</ref>

==See also==
* [[Bleach and recycle]]

==References==
{{Reflist|2}}

==Further reading==
* {{cite web |url=http://www.smithsonianmag.com/science-nature/Jocelyn-Kaiser-Contributor.html |title=Jocelyn Kaiser on "Gene Therapy in a New Light" |pages=124 |work=Science & Nature &#124; Smithsonian Magazine }}
* {{cite book |author=Lewis, Ricki |title=The Forever Fix: Gene Therapy and the Boy Who Saved It |publisher=St. Martin's Press |location=New York |year=2012 |isbn=0-312-68190-9 |oclc=740628904 }}

==External links==
* [http://www.tfrr.org Foundation for Retinal Research]
*[http://www.ncbi.nlm.nih.gov/books/NBK1298/ GeneReview/NIH/UW entry on Leber Congenital Amaurosis]
* [http://www.wonderbaby.org/articles/lca-faq.html Leber's Congenital Amaurosis FAQ] from WonderBaby.org
* [http://www.amdsupport.ca/articles/67/1/Gene-Therapy-May-Lead-to-Cure-for-Macular-Degeneration/Page1.html Leber's Congenital Amaurosis Treated with Gene Therapy]
* [http://psychologydictionary.org/lebers-disease/ Psychology Dictionary]

{{Eye pathology}}
{{Cell surface receptor deficiencies}}

[[Category:Articles with inconsistent citation formats]]
[[Category:Visual disturbances and blindness]]
[[Category:Cell surface receptor deficiencies]]
[[Category:Rare diseas]]