[enema SECTION EDITOR THADDEUS .DRYA.MD The Phenotype of Leber Congenital Amaurosis in Patients With AIPL1 Mutations Sharola Dharmaraj, MD, FRCS; Bart P. Leroy, MD; Melanie M. Sohocki, PhD; Robert K. Koenckoop, MD, PhD; Isabelle Perrault, PhD; Khalid Anwar, MD; Shagufta Khalig, PRD; R. Summathi Devi, MD; David G. Birch, PhD: Elaine De Pool, MD; Natalio Izquierdo, MD; Lionel Van Maldergem, MD; Mohammad Ismail, MD: Annette M. Payne, PhD; Graham E. Holder, PhD; Shomi S. Bhattacharya, PhD; Alan C. Bird, MD, FRCOphth: Josseline Kaplan, MD, PhD; Irene H. Mawmence, MD Objectives: To describe the phenotype of Leber con- genital amaurosis (LCA) in 26 probands with muta- tions in aryl hydrocarbon receptor interacting protein- like 1 protein (AIPL1) and compare it with phenotypes of other LCA-related genes, To describe the electroreti- rogram (ERG) in heterozygote carriers. Methods: Patients with AIPLI-related LCA were iden- ified in a cohort of 303 patients with LCA by polymer- ase chain reaction single-strand confirmational polymor- phism mutation screening and/or direct sequencing. Phenotypic characterization included clinical and ERG evaluation. Seven heterozygous carrier parents also un- derwent ERG testing. Results: Seventeen homozygotes and 9 compound het- cerozygotes were identified. The W278X mutation was most equent (48% of alleles). Visual acuities ranged from light perception to 20/400, Variable retinal appear- ances, ranging [rom near normal to varying degrees of chorioretinal atrophy and intraretinal pigment migra- tion, were noted. Atrophic and/or pigmentary macular changes were present in 16 (80%) of 20 probands. Kera- toconus and cataracts were identified in 5 (26%) of 19 patients, all of whom were homozygotes. The ERG of a parent heterozygote carrier revealed significantly re- duced rod function, while ERGs for 6 other carrier par- ents were normal Conelusions: The phenotype of LCA in patients with AIPLI mutations is relatively severe, with a maculopa- thy in most patients and keratoconts and cataract in a large subset. Rod ERG abnormalities may be present in heterozygous carriers of AIPLI mutations Clinical Relevaneet Understanding and recognizing the phenotype of LCA may help in defining the course and severity ofthe disease. Identifying the gene defect is the first step in preparation for therapy since molecular di agnosis in LCA will mandate the choice of treatment Arch Ophthalmol, 2004;122:1029-1037 EBER CONGENITAL AMAURO- sis (LCA) was first di scribed by Theodore Leber in 1809! asa congenital form of been reported." Currently, mutations in different retinal genes have been shown to cause LCA. The genes include (1) ret nal guanylate cyclase (GUCY2D)," (2) reti- Author afitions are sted at the endo the article retinitis pigmentosa. It rep- resents a clinically and genetically heter- ogencous disorder with severe visual {impairment from bitth? Fundus exami- nation results are not frequently initially normal, but chorioretinal atrophy, nar- rowing of the retinal vasculature, intra- al pigment migration, white fundus flecks, and macular aplasia have been de- scribed."* The retinal basts of the visual loss is shown by absent or severely dimin- {shed rod and cone responses on electro- jography (ERG). Nystagmus, enoph- thalmos, sluggish pupillary responses, keratoconus, cataracts, and hyperopia have also been described." Leber congenital amaurosis is ust ally inherited as an autosomal recessive trait, although dominant inheritance has (aepnnyre0) SRCTORMTALMOT VOUS Ta (©2004 American Med Downloaded From: http:/jamanetwork.com/ on 11/27/2016 nal pigment epithelium-specific 65kD protein (RPE6S),"* (3) cone-rod ho- meobox (CRX),°** (4) crumbs gene ho- molog of CRBI.*** (5) retinitis pigmen- tosa GTPase regulator-interacting protein (RPGRIP-1),** and (6) AIPLI, encoding, the aryl hydrocarbon receptor interact- ing protein-like 1 protein.” The AIPLI gene consists of 6 exons and encodes a protein of 38 amino acids. This sequence includes 3 tetratricopep- le repeat motifs thought to be associ- ated with protein-protein interaction, and tts similarity with aryl hydrocatbon inte acting protein is suggestive ofa protein fold- ing function." The exact functions of the AIPLI gene are not fully understood. How- ever, recent data suggest that the protein may be involved in photoreceptor diffe 1 Association, All rights reserved.‘entiation during development and subsequent survival of photoreceptors.” Indeed, through interaction with the NUBI protein, t might be involved in regulation of the cell-eyele progression during photoreceptor mavura- tion.” Mutations in AIPLI account for 7% of LCA Clinical outcomes differed for patients with LCA and. GUCY2D mutations when compared with those with RPEOS defects" in terms of the natural history of this disorder. In addition, some heterozygous carriers of GUCY2D mutations, who have offspring with LCA, have ‘been shown to have significant cone abnormalities on ERG. results, with essentially normal rod ERG findings.” Most heterozygotes with RPEOS mutations have normal ERG findings. * The purpose ofthis large study isto deseribe the phe- notype of LCA in patients with AIPLI mutations and com- pare it with the known phenotypes of patients with mu- lations in other LCA genes, The phenotype of 26 patients with LCA of different ethnic origins with mutations in AIPLI is described. The genotype of most patients has previously been published." The ERG and clinical find- ings in a female heterozygous carrier are also reported (es Informed consent was obtained from all patients involved in this study or Irom thet legal guardians in accordance with the Declaration of Helsinki, The review and ethics boards of the institutions approved this study. OPHTHALMIC EVALUATIONS The clinical diagnosts of LCA was made on the basis ofthe fol- lowing diagnostic criteria: severe visual impairment fom birth ‘or during early infancy accompanied by nystagmus, absent oF very sluggish pupillary responses, and absent or markedly re- dluced rod and cone ERGs. All ERGs were performed accord- ing to the International Society for Clinical Electrophysiology of Vision standards.” The examinations were undertaken in 3 centers and included sllamp biomicroscopy. retinoscopy, and indirect ophthalmoscopy following pupillary dilation (Table 1) Clinical pictares were taken, and Keratometry was performed. GENETIC EVALUATIONS DNA was extracted from peripheral blood leukocytes or check sabe, A cohort of303 patents with LCA was sercened formu tions in AIPLI Patents were rom a wide range of acta and tne backgrounds The 6 exons of AIL were screened use ingsingle-stand conformation polymorphism analysis (SSCP) tellowed by direct sequencing Woe an tberrnt iran pal- tern was noted om the SSCF gels In 39 probands: det se- quencing was used to screen for mutation in APL, while in thevthers SSCP was inital undertaken using primers sd Comiition previously described" The enotypeot most ol he tients with AIPLI-elated LCA in this study bas been pub [shed previously (Figure 1) (es Mutations in AIPLI were detected in 26 probands with LCA (Figure 1). Seventeen probands were homozy- _gotes, while 9 were compound heterozygotes. Twei four of the 52 mutated AIPLI alleles carried the W278X mutation. All sequence changes identified in our pa- tients were absent in 205 control samples, (agpnnyreo) SRCTORATATMOT VOUS (©2004 American Med Downloaded From: http:/jamanetwork.com/ on 11/27/2016 NIGHT BLINDNESS, PHOTOATTRACTION, AND PHOTOAVERSION Night blindness was reported in 13 probands and pho- toaversion in 4. Photoattraction (staring at lights) was noted in 2 probands (Table 1). VISUAL ACUITIES AND CYCLOPLEGIC REFRACTIONS Visual acuities were found to vary between probands and ranged [rom 20/400 to light perception, Nine patientshad light perception, Seven patients had hand motion vision (Fable 1). Cycloplegie refractions performed in 10 pa- tients showed hyperopia in 8 (+3.00 diopters [D] to +7.00 1D) and myopia in 2 (-0.50 D to -2.75 D). RETINAL AND MACULAR APPEARANCE Twenty-four probands with an AIPLI-related LCA geno- type had some form of pigmentary retinopathy that ranged from mild midperipheral salt and pepper-like retinopa- thy to diffuse and severe chorioretinopathy (Figures 2, 3,4, 8, 6 and 7). The youngest patient with pigmen” tary changes was + months old. Two patients, a 2-year- old and a 3-year-old, had essentially normal retinas with indistinct foveal relexes. A maculopathy of variable ap- pearance was noted in a significant number of patients (Pigures 2, 3, 4,5, and 7). Information about the macu- lar appearance was available in 20 of the 26 probands. Maculopathy was noted in 16 (80"%) of 20 probands. In + probands, all young children (ranging from ages 2 years), an abnormal indistinet foveal reflex was noted, which likely represents an early stage of maculopathy This strongly suggests that a significant number of pa dents with LCA and AIPLI mutations develop a macu- lopathy. The maculopathy ranged in appearance from mild foveal atrophy with variable degrees of macular stip- pling to aplasia. The youngest patient with macular al- ophy was 8 years old (Table 1) KERATOCONUS AND CATARACTS Information about the presence of keratoconus was avail- able in 19 probands (Table 1). Keratoconus was diag- nosed in 6 probands (32%), and cataracts were noted in association with the Kerataconus in 5 of these 6 pa- dents, Distinct hydrops with scarring and breaks in the Descemet membrane were noted in proband 17. The cats- racts ranged from cortical changes to posterior subeap- sular cataracts, Of interest, keratoconus and cataracts were only seen in patients who were homozygous for AIPLI smulations, Keratoconus was not observed in patients with compound heterozygous musations, The youngest pa- dent with keratoconts and eataract was aged 10 years OPTIC DISC APPEARANCE Varying degrees of optic nerve pallor were noted in all patients alter the age of 6 years. The optic nerve head ap- peared normal in children younger than 6 years, except in an infant (Table 1) 1 Association, All rights reserved.‘Table 1. Clinical and Genetc Characteristics of 26 Probands With A/PL Mutations TAPLT woe ate ae vu ae Pgmentay Aetazton, rronane orig _"“Aielet Alte? examination sty Al) Maculapaty Paar _eratacnus cataract Retapsnyloptete Tae wate hy megh UF Wild Waits Absnce Asuna Sere WA 2 Bangucesh waex wax say Lp Sem Moduate Moder id Sere A 3 baum vost Vie am of Mid” Mi Absence” Rbsince Absnce NA 4 Fane Ye VISE we MWR MMR MA Sere 800 5) Paine 160X016 ‘ay LP Mid drat ld Mode Sere A 6 Morcco AN07P TOTP u som mk MAMMA Sure 700 7 gad cork ey HM Mid daate Absence Absnce Swvere © -050, 8 su warex waTex ay FE Magers Mil Absence Abunce Sere A © ug” waren werex sry LP Magers Modu id Sere Sere A et ee MK Pratcet M—Marte Md Ace Absa See A 31 Patan warex — warex Wey Prtonot LP Sew Mate Modesty Abtncn Sore A 32 Paisanwarex ware By WA LP Sem Mode Moderate Modente Meera A 12 Uged’warex Werk 3) Purest HMR Absa Anny Amor «7.0 14 Panagal warex — wa7ex Preset LP WAKA Some 00 15 Boia warex ware MMR WA WAR Sate 18 Begum waTex — waTEx Ma Mid Mid MA WAS Na 7 da Rael TL ‘By Maderte Moderate Sere Sewe Medosts «800 a wy Mid id Absence Absuncs Sere A 18 Ung vin ate wz ey VFR Abunce Asenco Absent 600 20 ngs” ares ay Swen Mid Absence Absencs Medata—-275 2 fanes Til pas u Ce ee ee eS 22 Und ay a wz ay FR Abunce Absence Absences Absnco +850 es Op a Tay Prion ot Hd Mester A 24 and” W2TEK —WS22R~G Sy —Pregonot FF FR Abana Arce Md 2.00 25 Fnce 27K SOONG NALA Som 2% Und WaTEX 6d 25p Ty Pronk 203200 Mh Wid Aare Aen See NA Abbrvaons: DOP. digio-oelar phenomenon Fst ad tllowng HM, han ight blindness; PA, phtaaersion, PAT, paoaaction ERG FINDINGS The ERG findings obtained in the 3 sets of clinically nor- smal parents of probands 7,10, and 26 who carry the AIPLI mulation ina heterozygous state did not show any abnor- malities. However, the ERG of 1 carrier parent of pro- band 2 with the W8SX mutation showed significant rod abnormalities (Figure 8). she did not have any ocular ‘complaints, and her clinical examination findings were nor- mal. This 47-year-old mother had vision of 20/20 OU. Al- though her retinal examination results were unremark- able, full-field flash ERG showed rod b-wave amplitudes tobe reduced to approximately one third of normal, with no change in implicit time. This is well below the lower limit of normal. The 30-Hz flicker and single lash cone (agpnnyreo) SRCTORATALMOT VOUS TO a (©2004 American Medical Assoc Downloaded From: http:/jamanetwork.com/ on 11/27/2016 71 cto; IFR, stint ova lL, ght perception NA, nt aval; ‘APL Vo VME ATP bala ss a. ca | wr mu ‘ pye ys ye yelt «| oust Lomas vasa Hero vin ok isaks fas Figure 1, Sri of he AILPLT oe muaton inthe 2 probands. th he lati locaton of the lation, All rights reserved.Figure 2. W2B7XIW276X mutation, proband 12325 year of age, Postrioe _‘Flgure 3. W86N/X mutton, proband 2a 20 yeas of gp. Supetie palit ee, shoving atopic macular area optic nave par ard rigger, et eye, showing itaretnal pigment accumulation, optic pigmentary change. ev pal, and atophic macula wth pigment changes. Figure 3. WZB7X278X mutation, proband Bat years of ge Lat ae Figure 0. T114UP376S mutation, proband 20218 years of age Perghara ‘aly macular anges shoving ail pigmentary pitta druptin rans mating, Figure 4. WEBKEEX mutation, proband 2230 yar of age Postar Figure 7. T1T4UP376S mutton, proband 20218 years of age. ght ee, pal, oy, shaw atrophic alr ad etal igre eithelu Showing mac clebraike phy ani dope nea pal. {Isrptin and optic revpallr. Downloaded From: http:/jamanetwork.com/ on 11/27/2016Ses o Tei hate Paws ae ‘soy to ai soy voy 1 200 moet sy say aw a w a We =e oar ae sy vou se ai sy soe se amv ow " sy. ow ow Brennen When es Wie sae am we ye vou oe oye swat se ane ow ow bravia w ah anntaarlan i, OAM ery was sae ar ws se se 204 m oe soe w. w. w. ow ae Tar we Figure 8. Top ow, Eleoratnaram (EN). ghee ofthe 47-yar-o, eteroygous carr parent of proband 2 crying te WES AIPL mutation shows {Sean reduced ample of specie selop to on tr of nama vale and of maximal ombned od and can response cone spate 20H ctr an single flash cone ERGs are wit normal mis. Second row ERG of proband 2a 27 yar of age (aryig the WBBXWSEX mutation) showing no Imesurble responses Thi on, ERG of proband 2's -ys-l fo, Tyla nama fangs ina 4-year cal responses were within normal limits (Pigure8).‘The ERG responses were reproducible on repetition. COMPARING THE LCA PHENOTYPES The LCA phenotypes with mutationsin the otherLCA genes (GUCY2D, RPEOS, CRX, CRBI, and RPGRIPI) were com- pared with the LCA phenotypes of the current study and \abulated in Tables 2, 3, 4, 5, and 6. The AIPLi-related LCA phenotype issevere in nature, with pronounced mact- lar involvement in individuals older than 6 years with vary- ing degrees of opticnerve pallor. Additional findings of kers- toconuis and catarset could be present, Both GUCY2D-related and AIPLI-related LCA phe- notypes have markedly decreased visual acuities, visual fields, and ERGs."*'** However, maculopathy, remark- able peripheral pigmentary changes, cataract, and sig- nificant optic disc pallor were not detected in patients with mutations in GUCY2D."*" Keratoconus was re ported by El-Shanti et al ina Jordanian pedigree. Com- (aepnuyreo) SRCTORATALMOT VOUS TOA ae (©2004 American Med Downloaded From: http:/jamanetwork.com/ on 11/27/2016 led sista (crying the WBN WBBX mutation shoving no maserale response, Fourth pared with the reported GUCY2D phenotype," the AIPL1 phenotype appears to be similar in severity of vi sual loss. Phenotypical dilferences exist in the pattern of pigmentary changes, cataract, and keratocontis, which are more frequent in AIPLI-related LCA (Table 2). The RPEOS phenotype reported in earlier studies” sana shows that the visual acuities, visual fields, and ERG ‘measurements were better than in the AIPLI phenotype. Patients with RPEOS-related LCA may develop a mild mact- lopathy, and the documented peripheral retinal changes are characterized as grainy and/or salt and pepper-like. The ‘maculopathy of patients with AIPLL-related LCA appears tobe more pronounced in all probands older than 6 years, while the peripheral retinal changes range from mouling, to bone spicule-like formation. Cataract and keratocu- rnuis were present in one third of the patients with AIPLI- related LCA. Lorenz et al conclude that patients with LCA and RPE6S mutations are distinguishable on clinical grounds, based on their measurable visual acuities, their {ransient visual improvement in childhood followed by de- 1 Association, All rights reserved.‘Table 2. Comparisons of Leber Congenital Amaurosis Phenotypes: Palients With GUCYZD Mutations vs Patients With A/PL Mutations =. 2 cm = se TE eR EE aire mera sey SE eno sms BEE re Begs ge a = om = Eager te 3 ae se Malate eg a ee ee aa ‘age & ms ‘Table 3. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With APEES Mutations vs Patients With A/PL1 Mutations = 7 = See re erent eee ei, Feoactle aioe yoni 13 ES fo ath oan | (btw terioration in later life, measurable cone ERGs (which also diminish in later life), measurable visual fields, and sig- nificant night blindness. The data from our study suggest that patients with LCA and mutationsin AIPLI do not have a similar course (Table 3). From the several reported cases of patients with, LCA and CRX mutations, visual acuities of 20/300 to light perception, with 1 case of 20/80, were described. #9131935 Marked atrophy in the macula was recorded in 71% of CRX-related LCA, while in AIPLI- related LCA, maculopathy was pronounced in 80% of the patients after 6 years of age. Marked pigmentary reti- opathy was noticed in 84% of patients with AIPLI- related LCA unlike in CRX-related LCA, where it was ob- served in 33% (Table 4), (aepanyre0) SRCTORATALMOT VOUS TOA ae ©2004 American Medi Downloaded From: http:/jamanetwork.com/ on 11/27/2016 Compared with that of patients with CREI mut ons, the phenotype of our patients with AIPLI mut ons appears to be less variable and more severe, Small white dots and zonal retinal/choroidal hypoplasia were seen in the patients with CRBJ-related LCA® but not in patients with AIPLI-related LCA (Table 5). The pres ence of cataract, keratoconus, and optic dise pallor were not reported in the CRBI-related LCA phenotype. The constant features reported in the CRBI-related pheno- type were moderate to high hyperopia, the relatively early appearance of yhite spots and mummalar pigment camps The RPGRIPI-related LCA phenotype has been re- ported in 3 patients.» Visual acuity was light pereep- on. Hyperopia and absence of intraretinal pigment mi 1 Association, All rights reserved.‘Table 4. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With CAX Mutations vs Patients With A/PL1 Mutations Sample seu, React, umes se eae ‘Sue ome ange “lots” sual Feld letortnogam Mocuopaty Reino Kectacoas cara alot Seeregy om Mig Tone 60 Rey Tae Praia — Prpanin Rist Pret erst TF CB ane ei: ‘ai eae Sena i conan me peste Sasa a Sharoy Bonga" Ccurmesuiy 28 APLI20400t Spates Mandewcule Nondeweule Pegi Miabone Prsin Pesantin Prsnt Tg 0% ino” "speueite Salis Se 1@ tere Peston 70 Eiretny pets pres ne ie bi od ‘Table 5. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With CAB7 Mutations vs Patients With APL Mutatlons* sampte euty, — matacton, Pamestary source “En onee Mange “Hopes” eel Fil Eecreinagram Macslpstiy Retmopsoy Kercones —catrst ian. 19 ORT Bouton Decqasede__Preatin Pesan Present Aba we cs at endsectte "Same P'S ume 26 APLY 200 0 rte, Monecordble Nenéucable Pronguesd “Maradhone Pracrtin Preurtin Prost ‘tay igi So ‘maui’ “Spcaleie ‘S Serie Poker Petepion 5700) omenary pains penis years Fataae Ege t tage (hatte an ea) ‘Abbrvaon: RPE, tial pigment plum, “alummalr penton the aan anal zonal atrophy wth hypop study bu abst in th cut sty Small tral dts wer present nan asia of th chaiocapilars an RPE ware prsent in some patti the Loary ctl ofthe patios the oly tal study Bu abet nthe caren sty. iso Palas Wi Aron? Matatons ve Pallets Min PLT ions one sampie ety, erator, Pignenary ire source "Suu" ones Range "plat ViualFlaa_Eecvortnegrom Mseuopty —Retioputy_Kertocones _cnaact Patt Dije 3 APGRIPT Ligh 2010 +600 Nowecorable Nondsecabla Absent of Reporedin. Abert Absent Preset ae Peccopton ‘asate id fiayeore Curem 25 APL 20MQ010 Spates Nondetecuble Nondetele Poneuced Mrkadbore Presrtin.Pesntin Pesan ‘ay Tg S01 madk "speuee Salih” Salt aters Pierson FO tery er flrs J (hatte ae Zoo) ‘gration were noted in 2 patients. However, bone spieule like pigmentary deposits in the midperipheral zone were noted in a third palient. No evidence of maculopathy as seen in the patients with AIPLI-related LCA was ob- served (Table 6). Lb} The retinal phenotype of AIPLI-related LCA is that of a severe, congenital retinal dystrophy with a notable macu- lopathy. The retinal appearances in our patients ranged from near normal (ina 3-year-old and a6-year-old) to se verely atrophic (and in all patients older than 6 years) with marked maculopathy and pigmentary retinopathy. Vary- ing degrees of intraretinal pigment migration cullminat- (agpnnyreo) SRCTORATATMOT VOUS ©2004 American Medi Downloaded From: http:/jamanetwork.com/ on 11/27/2016 ing in bone spicule-like pigment and gross pigment clumps: in the retinas were observed. Overall, a high prevalence of macular lesions was observed in our patients com- pared with patients with LCA caused by mutations in the ther 5 genes implicated in this disease. Atrophic mact- lar lesions were particularly frequent and were observed {in 16 (80%) of 20 patients; 11 harbored a premature stop- codon mutation, either in a homozygous or a heterozy- gous state, Macular involvement as seen on ophthalmos- copy likely begins with an indistinct dull or irregular foveal reflex and progresses to a diffuse il-delined area of re nal pigment stippling and atrophy, leading to a marked atrophic maculopathy. Owing to the differences in age at the time of first examination, it was not possible to deter- mine the accurate age of onset of the maculopathy Association, AI rights reserved,The heterozygous carrier parent of the W88X mulation was found to have a significant and reproduc- ible rod ERG abnormality with essentially normal cone ERG resulis. These ERG findings are significanily dif- ferent from the heterozygous carriers of GUCY2D muta- tions, who have significant cone ERG abnormalities but relatively normal rod ERG findings."” The rod ERG abnormalities in the AIPLI carrier correlate with recent reports showing AIPLI expression exclusively in rod photoreceptors in the differentiated retina."’ However, more ERGs in carriers of AIPLI mutations need to be studied to better understand the role of AIPLI ia rela- tion to rod function. The presence of keratoconus in patients with LEA has been well documented.""" The high incidence of kera- tocontis in patients with a homozygous sequence change ‘of AIPLI in our cohort may well be significant. Kerato- ‘conus was observed in 6 probands, all with homozy- {otis mutations. There is no definitive consensus about the origin of keratocontts in patients with LCA. The in- ‘idence of keratacontis has been reported to be as high 48 54.5 cases per 100.0 in the general population, and it has been noted in 299% of children with LCA and 2% of all children with blindness.” Keratoconuis in patients With LCA occured in 23% of O- to 14-year-olds and in 30% of 15-10 45-year-olds, further illustrating the later ‘onset of the pathologie corneal features in comparison ‘with the retinal dysplasia.” The absence of keratoconts prior to 9 years of age also has been well documented” and isthe case nour cohort too. Cataract has been associated with many’ diferent \ypes of retinal dystrophy. Its association with retinitis pigmentosa has been well documented,” Cataract has been noted ator beyond the second decade of hfe in pa tients with LCA.**In this study, eataracts were observed in 5 probands (27%). Progressive retinal degenerative ‘changes association with keratocontsand cataract have Ihcen reported during the course ofthe disorder.*"? The incidence of bth keratoconus nd cataract increased with increasing age in our cohort. The LCA phenotypes are highly variable"? and change with age,” and the phenotypes associated with the currently known LCA genes overlap." Compart- sons between the reported LCA phenotypes of different studies? are hampered by lack of uniform assess- ment strategies, age matching, and uniform follow-up. Despite these obvious dificult, itis important to study these LCA phenotypes in anelfort to understand the evo- lution of disease based on genotype In summary, patients with AIPLI-telated LCA ap- pear t have a particulary severe phenotype, character- teed by marked visual impairment, nondetectable fields and ERGs, opticdise pallor, maculopathy, peripheral ei- nal bone spicule-like pigmentation, and a significant prevalence of keratoconus and cataract Mutations in AIPL1 disrupt the normal function of photoreceptors. AIPLI isnot only expressed in mature rod photoreceptors" but also during development in both rods and cones.” The dyshunctional role of AIPL! in pho- toreceptor cell cycle progression leads to photoreceptor cell death during development by disrupting the nor- smal regulation of the ce eyel.”” More detailed under- (aepnnyreo) SRCTORATALMOT VOUS TOA a (©2004 American Med Downloaded From: http:/jamanetwork.com/ on 11/27/2016 standing of the pathogenesis of each molecular subtype of LCA will provide further insight into treatment Submitted for publication October 10, 2002; final revision received April 3, 2003; accepted June 6, 2003. From the Johns Hopkins Center for Hereditary Eye Dis- cases, Baltimore, Md (Drs Dharmaraj, De Pool, and Maumenee); the Departments of Molecular Genetics (Drs Leroy, Payne, and Bhattacharya) and Clinical Ophthal- mology (Drs Bird and Leroy), Institute of Ophthalmology, University College of London, London, England: the De- partment of Ophthalmology and Center for Medical Genet- ics, Ghent University Hospital, Ghent, Belgium (Dr Lerey); the Departments of Ophthalmology and Pathology, Colum- bia University, New York, NY (Dr Sohocki); MeGill Ocular Geneties Lab, Montreal Children’s Hospital, Montreal, Que- bee (Dr Koenekoop); Unite de Recherches sur les Handicaps Genetiques de Enfant, Inserm U393, Hopital des Enfants Malades, Paris, France (Drs Perrault and Kaplan); the Bio- ‘medical and Genetic Engineering Division, Dr AQ Khan Re- search Laboratories, Islamabud, Pakistan (Drs Anwar, Khali and Ismail); Stanley Medical College, University of Madras, Madras, India (Dr Devi); The Retinal Foundation ofthe South- west Dallas, Tex (Dr Birch); Instituto de Glaucoma y Ge- netic a Ocular, Rio Piedras, Puerto Rico (Dr lequierdo); Cen- trede Genetique Humaine Institut de Pathologie ele Genctique, Loverval, Belgium (Dr Van Maldergem); the Department of Biological Sciences, Brunel University, London (Dr Payne); the Electrophysiology Department, Moorfields Eye Hospital, London (Dr Holder). The authors have no relevant financial interes in this article This research was supported by grants from the Foun- dation for Retinal Research, Highland Park, Il: the Edel & Kricble Funds ofthe Johns Hopkins Center for Hereditary Eye Diseases, Baltimore, Md; the Grousbeck Family Foundation, Stanford, Calif; the Fonds voor Research in Oftalmologie! Fonds de a Recherche en Ophtalmologic, Edegem, Antwerp, Belgium (Dr Leroy); the Bijzonder Onderzocksfonds of Ghent University, Ghent, Belgium (Dr Leroy); the Founda- tion Fighting Blindness-Canada, Toronto, Ontario (Dr Koenen- oop); the Canadian Institutes of Health Research, Ottawa, Ontario (Dr Koenenkoop); Fonds de la recherche en Santé du ‘Quebéc, Montréal, Quebec (Dr Koenenkoop); the Kirchgess- nner Foundation, Los Angeles, Calif (Dr Sohocki); the Knights Templar Eye Foundation, Chicago, II (Dr Sohocki); the Foun- dation Fighting Blindness, Owings Mills, Md (Dr Sohocki); Fight for Sight, New York (Dr Sohocki); the Research Divi- sion of Prevent Blindness America, Schaumburg, Ill (Dr So- hhocki); and William R. Acquavella (Dr Sohocki) Dr Sohockiis the William R. Acquavella Scholar of Oph- thalmic Research, Columbia University, New York These authors contributed equally to the study: Sha- rola Dharmaraj, MD, FRCS, and Bart P. Leroy, MD. ‘Wethank the families for support and cooperation. We also thank the photography departments of all the insti- tutes for their professional assistance and to Olof Sundin, PAD, for reviewing the manuscript Correspondence: Sharola Dharmaraj, MD, FRCS, The Johns Hopkins Center for Hereditary Eye Diseases, Maumence ‘517, Wilmer Eye Institute, Johns Hopkins Medical In- stitutions, 600 N Wolfe St, Baltimore, MD 21287-9237 (sdharmaraj@jhmi.edu) 1 Association, All rights reserved.Ls} Lobe. Uber Retin imate un geo np Opiate 1869151820. Camuzat Rov IM, De tal side genetic hetarogeneyLat congenial amaurasi (LA) nd mapping of LAT teheamosane 17913, than ent 100697 798 901 Waardarburg PS. Congental and ear inal eal dstuncion (igh (ya) atypia and amauon of Leber rarer Fences [Mio Oe. 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