Leber's congenital amaurosis: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
No edit summary
Line 2: Line 2:
{{CMG}} {{AE}} {{JC}}
{{CMG}} {{AE}} {{JC}}


{{Infobox_Disease
{{Infobox disease
  | Name          = {{PAGENAME}}
  | Name          = Leber's congenital amaurosis
  | Image          =  
  | Image          =  
  | Caption        =  
  | Caption        =  
  | Diseases
  | DiseasesDB    = 33192
| ICD10          = {{ICD10|H|35|5|h|53}}
| ICD9          = {{ICD9|362.76}}
| ICDO          =
| OMIM          = 204000
| OMIM_mult      = {{OMIM2|204100}} {{OMIM2|604232}} {{OMIM2|604393}} {{OMIM2|604537}} {{OMIM2|605446}} {{OMIM2|602225}} {{OMIM2|604210}} {{OMIM2|608553}}
| MedlinePlus    =
| eMedicineSubj  =
| eMedicineTopic =
| MeshID        =
| GeneReviewsNBK  = NBK1298
| GeneReviewsName = Leber Congenital Amaurosis
}}
}}
'''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>


==Overview==
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.
'''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


It was first described by Theodore Leber in the 19th century.<ref>{{WhoNamedIt|synd|1189}}</ref><ref>T. Leber. Über Retinitis pigmentosa und angeborene Amaurose. Archiv für Ophthalmologie, Berlin, 1869, 15, 3: 1-25.</ref> (It should not be confused with [[Leber's hereditary optic neuropathy]], which is a different disease also described by Theodore 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/>


==Presentation==
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/>
[[Amaurosis]] refers to a loss of vision not associated with a [[lesion]], and [[congenital]] refers to a condition present from birth (not acquired). 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 no [[Pupillary reflex|pupillary responses]], and severe [[vision loss]] or [[blindness]].  


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


There is evidence tying type 1 LCA to {{Gene|GUCY2D}},<ref name="pmid8944027">{{cite journal |author=Perrault I, Rozet JM, Calvas P, ''et al'' |title=Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis |journal=Nat. Genet. |volume=14 |issue=4 |pages=461–4 |year=1996 |pmid=8944027 |doi=10.1038/ng1296-461}}</ref> and type 2 to {{Gene|RPE65}}.<ref name="pmid9326927">{{cite journal |author=Marlhens F, Bareil C, Griffoin JM, ''et al'' |title=Mutations in RPE65 cause Leber's congenital amaurosis |journal=Nat. Genet. |volume=17 |issue=2 |pages=139–41 |year=1997 |pmid=9326927 |doi=10.1038/ng1097-139}}</ref>
[[OMIM]] currently recognizes 18 types of LCA:<ref name=OMIMLCA>{{OMIM|204000| LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1}}</ref>
 
Other genes which have been implicated include {{Gene|CRB1}},<ref name="pmid17525851">{{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=Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft |volume=104 |issue=6 |pages=490–8 |year=2007 |pmid=17525851 |doi=10.1007/s00347-007-1533-x}}</ref> {{Gene|CRX}}, <ref name="pmid17525851"> </ref> and {{Gene|AIPL1}}.<ref name="pmid16505055">{{cite journal |author=Yzer S, Leroy BP, De Baere E, ''et al'' |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 |year=2006 |pmid=16505055 |doi=10.1167/iovs.05-0848}}</ref><ref>{{cite web |url=http://news.bbc.co.uk/2/hi/health/4250226.stm |title=BBC NEWS | Health | Inherited child blindness probed |accessdate=2007-09-21 |format= |work=}}</ref>
 
[[OMIM]] currently recognizes 11 types of LCA:<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=204000 |title=OMIM - LEBER CONGENITAL AMAUROSIS, TYPE I; LCA1 |accessdate=2007-09-21 |format= |work=}}</ref>


{| class="wikitable"
{| class="wikitable"
| '''Type''' || '''[[OMIM]]''' || '''[[Gene]]''' || '''[[Locus (genetics)|Locus]]'''
| '''Type''' || '''[[OMIM]]''' || '''[[Gene]]''' || '''[[Locus (genetics)|Locus]]<ref name=OMIMLCA/>'''
  |-  
  |-  
  | LCA1  || {{OMIM2|204000}}  || {{Gene|GUCY2D}} || 17p13.1
  | 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 || {{OMIM2|204100}}  || {{Gene|RPE65}} || 1p31
  | 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 || {{OMIM2|604232}}  || {{Gene|RDH12}} || 14q23.3
  | LCA3 || {{OMIM4|609868}}  || [[SPATA7]] || 14q31.3  
  |-  
  |-  
  | LCA4 || {{OMIM2|604393}}  || {{Gene|AIPL1}} || 17p13.1
  | 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 || {{OMIM2|604537}}  || {{Gene|LCA5}} || 6q14
  | 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 || {{OMIM2|605446}}  || {{Gene|RPGRIP1}} || 14q11
  | LCA6 || {{OMIM4|605446}}  || [[RPGRIP1]] || 14q11.2
  |-  
  |-  
  | LCA7 || {{OMIM2|602225}}  || {{Gene|CRX}} || 19q13.3
  | 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 || {{OMIM2|604210}}  || {{Gene|CRB1}} || 1q31-q32.1
  | LCA8 || {{OMIM4|604210}}  || [[CRB1]]<ref name="Preising, 2007"/>|| 1q31-q32.1
  |-  
  |-  
  | LCA9 || {{OMIM2|608553}}  || {{Gene|LCA9}} || 1p36
  | 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 || {{OMIM2|610142}}  || {{Gene|CEP290}} || 12q21.33
  | LCA10 || {{OMIM4|610142}}  || [[CEP290]] || 12q21.32
  |-  
  |-  
  | LCA11 || {{OMIM2|146690}}  || {{Gene|IMPDH1}} || 7q31.3-q32
  | 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="pmid17148037">{{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>
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==
==Testing==
Project 3000, a foundation started by [[Chicago Cubs]] [[first baseman]] [[Derrek Lee]] and [[Boston Celtics]] owner [[Wycliffe Grousbeck|Wyc Grousbeck]], works to have the approximately 3,000 people in the [[United States]] with the [[disease]] genetically tested.  <ref>[http://www.carverlab.org/request/request.shtml Genetic testing available for Leber's Congenital Amaurosis through Project 3000]</ref><ref>{{cite web |url=http://www.usatoday.com/sports/baseball/nl/cubs/2006-09-29-lee-daughter_x.htm |title=USATODAY.com - Cubs' Lee vows to fight daughter's rare disease |accessdate=2007-09-21 |format= |work=}}</ref>


Genetic tests and research are currently being performed at the [[University of Iowa]] Carver Lab by Drs. Edwin Stone and Val Sheffield.
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==
==Treatment==
Researchers at [[Moorfields Eye Hospital]] in London are conducting the first [[gene therapy]] clinical trial for patients with RPE65 LCA.<ref>{{cite web |url=http://news.bbc.co.uk/1/hi/health/6609205.stm |title=BBC NEWS | Health | Gene therapy first for poor sight |accessdate=2007-09-21 |format= |work=}}</ref> There has been some success in a mouse model with this approach.<ref name="pmid16223604">{{cite journal |author=Pang JJ, Chang B, Kumar A, ''et al'' |title=Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis |journal=Mol. Ther. |volume=13 |issue=3 |pages=565–72 |year=2006 |pmid=16223604 |doi=10.1016/j.ymthe.2005.09.001}}</ref>
 
{{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==
==References==
{{Reflist|2}}
{{Reflist|2}}


== External links ==
==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.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.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]


[[Category:Ophthalmology]]
{{Eye pathology}}
[[fi:Leberin synnynnäinen amauroosi]]
{{Cell surface receptor deficiencies}}
 


{{eye-stub}}
[[Category:Articles with inconsistent citation formats]]
{{disease-stub}}
[[Category:Visual disturbances and blindness]]
{{Eye pathology}}
[[Category:Cell surface receptor deficiencies]]
{{WikiDoc Help Menu}}
[[Category:Rare diseas]]
{{WikiDoc Sources}}

Revision as of 15:35, 4 November 2015

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jyostna Chouturi, M.B.B.S [2]

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

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

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]

Genetics

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 Template:OMIM4 GUCY2D,[10] 17p13.1
LCA2 Template:OMIM4 RPE65[11] 1p31.3-p31.2
LCA3 Template:OMIM4 SPATA7 14q31.3
LCA4 Template:OMIM4 AIPL1[12][13] 17p13.2
LCA5 Template:OMIM4 LCA5[14] 6q14.1
LCA6 Template:OMIM4 RPGRIP1 14q11.2
LCA7 Template:OMIM4 CRX[15] 19q13.3
LCA8 Template:OMIM4 CRB1[15] 1q31-q32.1
LCA9 Template:OMIM4 NMNAT1[16][17][18][19] 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.[20]

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.[21]

Treatment

Main article: 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.[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

References

  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. doi:10.1016/j.ajo.2007.08.022. PMID 17964524.
  2. ↑ 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. ↑ 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. ↑ 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. ↑ 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.
  6. ↑ Template:WhoNamedIt
  7. ↑ Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose". Archiv für Ophthalmologie (in German). 15 (3): 1–25. doi:10.1007/BF02721213.
  8. ↑ 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. ↑ 9.0 9.1 Weleber RG, Francis PJ, Trzupek KM, Beattie C. "Leber Congenital Amaurosis". GeneReviews. PMID 20301475.
  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. doi:10.1038/ng1296-461. PMID 8944027.
  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. doi:10.1038/ng1097-139. PMID 9326927.
  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. doi:10.1167/iovs.05-0848. PMID 16505055.
  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. doi:10.1086/302719. PMC 1288337. PMID 10631161.
  15. ↑ 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.
  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. doi:10.1038/ng.2356. PMC 3657614. PMID 22842230.
  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. doi:10.1038/ng.2361. PMC 3454532. PMID 22842227.
  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. doi:10.1038/ng.2370. PMID 22842231.
  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. doi:10.1038/ng.2357. PMID 22842229.
  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. doi:10.1080/13816810601013146. PMID 17148037.
  21. ↑ "GeneTests: Leber Congenital Amaurosis".
  22. ↑ 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.
  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. doi:10.1126/scitranslmed.3000659. PMID 20374996.
  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. PMID 16700630.
  26. ↑ https://www.youtube.com/watch?v=BsXa-mAKDVs

Further reading

External links

Template:Cell surface receptor deficiencies

Retrieved from "https://www.wikidoc.org/index.php?title=Leber%27s_congenital_amaurosis&oldid=1183139"