BACKGROUND: Leber’s congenital amaurosis (LCA) accounts for 5% of inherited retinal disease and is

usually inherited as an autosomal recessive trait. Genetic and clinical heterogeneity exist. Mutations

have been described in the RPE65, CRB1, RPGRIP1, AIPL1, GUCY2D, and CRX genes and other pedigrees

show linkage to the LCA3 and LCA5 loci. The latter is a new locus which maps to 6q11-q16. The

ocular findings and the evolution of the macula staphyloma are described in five members of a Pakistani

family with consanguinity and a mutation in the LCA5 gene.



\ud
METHODS: 13 family members including five affected individuals consented to DNA analysis and ocular

examination including fundal photography.



RESULTS: Ocular abnormalities are described. The most striking feature was the progression of macula

abnormalities in three brothers resulting in a colobomatous appearance in the eldest compared to only

mild atrophy in the youngest. The phenotypic pattern of this mutation in this Pakistani family contrasts

with the “Old Order River Brethren” who were of Swiss descent, in whom the mutation was first

described.





CONCLUSION: The evolution of a new phenotypic picture is presented to a mutation in LCA5

Inglehearn, C.F.

Jafri, H.

McKibbin, M.A.

Mohamed, M.D.

Raashed, Y.

Topping, N.C

English

BACKGROUND: Leber’s congenital amaurosis (LCA) accounts for 5% of inherited retinal disease and is

usually inherited as an autosomal recessive trait. Genetic and clinical heterogeneity exist. Mutations

have been described in the RPE65, CRB1, RPGRIP1, AIPL1, GUCY2D, and CRX genes and other pedigrees

show linkage to the LCA3 and LCA5 loci. The latter is a new locus which maps to 6q11-q16. The

ocular findings and the evolution of the macula staphyloma are described in five members of a Pakistani

family with consanguinity and a mutation in the LCA5 gene.





METHODS: 13 family members including five affected individuals consented to DNA analysis and ocular

examination including fundal photography.



RESULTS: Ocular abnormalities are described. The most striking feature was the progression of macula

abnormalities in three brothers resulting in a colobomatous appearance in the eldest compared to only

mild atrophy in the youngest. The phenotypic pattern of this mutation in this Pakistani family contrasts

with the “Old Order River Brethren” who were of Swiss descent, in whom the mutation was first

described.





CONCLUSION: The evolution of a new phenotypic picture is presented to a mutation in LCA5

White Rose Research Online

Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus

This is a repository copy of Progression of phenotype in Leber's congenital amaurosis witha mutation at the LCA5 locus.White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/234/Article:Mohamed, M.D., Topping, N.C, Jafri, H. et al. (3 more authors) (2003) Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus. British Journal of Ophthalmology, 87 (4). pp. 473-475. ISSN 0007-1161 https://doi.org/10.1136/bjo.87.4.473eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse See Attached Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. CLINICAL SCIENCEProgession of phenotype in Leber’s congenital amaurosiswith a mutation at the LCA5 locusM D Mohamed, N C Topping, H Jafri, Y Raashed, M A McKibbin, C F Inglehearn. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Br J Ophthalmol 2003;87:473–475Background: Leber’s congenital amaurosis (LCA) accounts for 5% of inherited retinal disease and isusually inherited as an autosomal recessive trait. Genetic and clinical heterogeneity exist. Mutationshave been described in the RPE65, CRB1, RPGRIP1, AIPL1, GUCY2D, and CRX genes and other pedi-grees show linkage to the LCA3 and LCA5 loci. The latter is a new locus which maps to 6q11-q16. Theocular findings and the evolution of the macula staphyloma are described in five members of a Paki-stani family with consanguinity and a mutation in the LCA5 gene.Methods: 13 family members including five affected individuals consented to DNA analysis and ocu-lar examination including fundal photography.Results: Ocular abnormalities are described. The most striking feature was the progression of maculaabnormalities in three brothers resulting in a colobomatous appearance in the eldest compared to onlymild atrophy in the youngest. The phenotypic pattern of this mutation in this Pakistani family contrastswith the “Old Order River Brethren” who were of Swiss descent, in whom the mutation was firstdescribed.Conclusion: The evolution of a new phenotypic picture is presented to a mutation in LCA5.Leber’s congenital amaurosis (LCA) is the name ascribed to agroup of inherited retinal dystrophies representing thecommonest genetic cause of visual impairment in infantsand children.1 The heritable nature and consanguinity as anassociation were recognised by Leber in the original report ofthis disorder.2 Subsequent reports confirmed the majority ofaffected pedigrees exhibit an autosomal recessive mode ofinheritance.3 4 Locus heterogeneity was originally suspected in1963, from the observation that unaffected children were bornto parents with phenotypically the same disorder.5Currently six genes in which mutations are implicated inthe pathogenesis of LCA have been cloned,6–11 and threefurther loci are known to exist from linkage studies.12–15 In onegenetic survey assessing the frequency of mutations in threeknown genes considered to have a major role in LCA, only15.9% of the sample population harboured disease-causingmutations.16 This implies a substantial proportion of caseswith LCA result from mutations in as yet unidentified genes.This phenotypic variation seen in LCA is a consequence of thisgenetic heterogeneity.The spectrum of clinical features seen in LCA is welldocumented,17 as is the natural history in this disorder.18 How-ever, the descriptions from these large series describe trends ofdisease progression in groups of individuals with differentgenetic defects.This report presents a unique chronological window intothe phenotype and progression of LCA within a singleconsanguineous family, in whom genetic analysis hasconfirmed linkage to the LCA5 locus on 6q11-16.12METHODSWe examined 13 members of a large consanguineouspedigree, which included five affected individuals (Fig 1). Thefamily was identified via our ocular genetics research clinic inPakistan and all the individuals were subject to a full ophthal-mic examination by two independent ophthalmologists usingdirect and indirect ophthalmoscopy through dilated pupils.Inclusion criteria for diagnosis with LCA included docu-mented poor vision from early infancy and exclusion of otherretinal disorders. Electrodiagnostic tests were not available tous in this rural developing world setting. However, in view ofthe similar symptomatology between the affected individuals,it was assumed they all expressed an identical disease pattern.Fundus photographs were taken of the eldest three brothers(Figs 2, 3, and 4) whose ages ranged between 21 and 30 years.Genomic DNA extraction was performed from peripheralblood leucocytes using standard techniques. Genotyping wasperformed by choosing microsatellite markers flanking theLCA5 region. Standard polymerase chain reaction (PCR) tech-niques were employed to generate allele fragments whichunderwent electrophoresis on an ABI 377 automated DNAanalyser and analysed using GeneScan 3.1.2 and Genotyper2.0 software. Using the Cyrillic pedigree drawing package andLINKSYS data management package, the LINKAGE suite ofprograms was utilised to generate a lod score.Figure 1 Family tree of subjects examined.See end of article forauthors’ affiliations. . . . . . . . . . . . . . . . . . . . . . .Correspondence to:Mr Moin Mohamed,Department ofOphthalmology, St James’sUniversity Hospital, BeckettStreet, Leeds LS7 7TF, UK;moinm@hotmail.comAccepted for publication12 August 2002. . . . . . . . . . . . . . . . . . . . . . .473www.bjophthalmol.comRESULTSLinkage to the LCA5 locus was confirmed by linkage analysis.A multipoint lod score of 3.75 was generated using microsat-ellite markers D6S391 and D6S968 against LCA5. All affectedindividuals had a non-syndromic form of LCA with normalneurological examination and intelligence. Ocular examina-tion revealed a best corrected visual acuity of perception oflight. Pendular nystagmus was present in the three adults androving eye movements in the two children (Table 1).The anterior segment examination was essentially normalwith no evidence of keratoconus or cataract. The vitreous wasclear in the younger family members but a vitreous opacitywas noticed unilaterally in the three elder brothers.Fundal examination revealed bilateral and symmetricalretinal changes. Detailed fundal examination of the youngestchild was not possible in view of the roving eye movements. Inthe other four individuals retinal vessel attenuation wasnoticed and “waxy” optic nerve pallor was seen only in theeldest affected brother. Examination of the posterior polerevealed the most striking features where a progressively moresevere degenerate appearance was seen. In the 6 year old child,mild perifoveal atrophic changes were noted while in the 21year old increasing pigmentary disturbance was noted (Fig 2).In the 25 year old a definite atrophic region surrounded bypigmentary changes were seen (Fig 3), while in the 30 year oldan even more marked staphylomatous region of atrophy andpigmentary change was seen (Fig 4).Table 1 Subject characteristicsSubject Age Eye movement Vitreous Macula White dots SpiculationV2 2 Roving Clear Not seen Not seen Not seenV1 6 Roving Clear Minimal atrophy Equatorial NoneIV5 21 Pendular nystagmus Opacity LE Atrophy Equatorial EquatorialIV4 25 Pendular nystagmus Opacity RE Atrophy and pigment clumps Equatorial NoneIV3 30 Pendular nystagmus Opacity LE Staphyloma Equatorial Peripheral and equatorialFigure 2 Subject IV5 aged 21:minimal atrophy at macula. (A) Rightfundus, (B) left fundusFigure 3 Subject IV4 aged 25:atrophy at macula with pigment rimand clumps. (A) Right fundus, (B) leftfundusFigure 4 Subject IV3 aged 30:macula staphyloma. (A) Right fundus,(B) left fundus474 Mohamed, Topping, Jafri, et alwww.bjophthalmol.comSimilarly in the retinal periphery progressive changes wereseen. Extensive white dots at the level of the retinal pigmentepithelium (RPE) were seen in the 6 year old, and theseappeared to take a larger rounder appearance with agrey-green hue in the three elder brothers.DISCUSSIONThis report presents the progressive features of LCA seenwithin a single pedigree arising from a mutation in the LCA5gene. In this family, progression with age is seen with thedevelopment of nystagmus, vitreous opacity, peripheral retinaldots and, most strikingly, the macular staphylomatousappearance. However, despite this progressive picture thevisual acuity is poor from birth.The progressive nature of the condition is well known fromexamination of individual cases as well as larger studies ofpooled patients in whom clinical heterogeneity is seen whenlooking across a broad age range. Here we present a uniqueview into the evolution of this disorder and particularly theprogressive retinal changes seen within a single pedigree. Asthe affected individuals are all from the same consanguineousfamily we assume they have the same underlying defect. Weacknowledge that environmental factors may also have had arole in the pathogenesis, but in the cases presented a strongcorrelation between severity of ocular fundus signs and age isdemonstrated. Although not all the retinal dystrophies involveretinal degeneration, the end point of the majority of thesediseases is photoreceptor cell death. Animal models suggest amechanism of death by an apoptotic pathway and not a directconsequence of the biochemical abnormality.19 So, despitemany different patterns of pigmentary or atrophic funduschanges, they are the result of degeneration by a single path-way. The process by which these particular patterns arise ispoorly understood.This pedigree describes changes arising from a specificmutation in a single gene. In the field of retinal dystrophies,allelic variation is common resulting in different diseases aris-ing from different mutations within a single gene. This ishighlighted by the only other report of Leber’s congenitalamaurosis10 caused by a mutation at the LCA5 locus. Thisreport was of disease in a different population, the “Old RiverBrethren,” who presumably have a different mutation in thisgene. The fundal appearance in that pedigree was reported tobe normal for most, with progressive peripheral retinalmottling.In contrast, LCA with CRB1 mutations have been noticed tohave two fairly consistent phenotypic features: the relativelyearly appearance of white spots and pigment clumps and thepresence of moderate to high hyperopia.7 Mutations in theGUCY2D and RPE65 genes both give a normal fundal appear-ance at birth followed by a “salt and pepper” appearancedespite very different functional outcomes.20In the future we can expect to see extensive databases,which provide us with projected pattern of disease progressfor specific mutations in individual genes, with essentiallyeach variation being a specific disease process.ACKNOWLEDGEMENTThe authors gratefully acknowledge the Wellcome Trust who fundedthis research (award 061682/dcp).. . . . . . . . . . . . . . . . . . . . .Authors’ affiliationsM D Mohamed, N C Topping, M A McKibbin, Department ofOphthalmology, St James’s University Hospital, Beckett Street, LeedsLS7 7TF, UKM D Mohamed, C F Inglehearn, Vision Research Group, MolecularMedicine, University of Leeds, Leeds, UKH Jafri, Y Raashed, Department of Obstetrics and Gynaecology, FatimaJinnah Medical College, Lahore, PakistanREFERENCES1 Taylor DS. Paediatric ophthalmology. 2nd ed. Oxford: BlackwellScience 1997::561–3.2 Leber T. Ueber Retinitis Pigmentosa Und Angeborene Amaurose. ArchOphthalmol 1869;15:1–25.3 Lambert SR, Sherman S, Taylor D, et al. Concordance and recessiveinheritance of Leber’s congenital amaurosis. Am J Med Genet1993;46:275–7.4 Schappert-Kimmijser J, Henkes HE,Van den Bosch J. Amaurosiscongenita (Leber). Arch Ophthalmol 1959;61:211–18.5 Waardenburg PJ, Schappret-Kimmijser J. On various recessive biotypesof Leber’s congenital amaurosis. Acta Ophthalmol 1963;41:317–20.6 Marlens F, Bareil C, Griffoin JM, et al. Mutations in RPE65 cause Leber’scongenital amaurosis. Nat Genet 1996;14:415–20.7 Lotery AJ, Jacobson SG, Fishman GA, et al. Mutations in the CRB1 genecause Leber’s congenital amaurosis. Arch Ophthalmol2001;119:415–20.8 Dryja TP, Adams SM, Grisby JL, et al. Null RPGRIP 1 alleles in patientswith Leber’s congenital amaurosis. Am J Human Genet2001;68:1295–8.9 Perrault I, Rozet JM, Calvas P, et al. Retinal specific guanylate cyclasegene mutations in Leber’s congenital amaurosis. Nat Genet1996;14:461–4.10 Sohocki MM, Browne SJ, Sullivan LS, et al. Mutations in a newphotoreceptor-pineal gene on 17p cause Leber’s congenital amaurosis.Nat Genet 2000;24:79–83.11 Freund CL, Wang QL, Chen S, et al. De novo mutations in the CRXhomeobox gene associated with Leber’s congenital amaurosis. NatGenet 1998;18:311–12.12 Dharmaraj S, Li Y, Robitaille JM, et al. A novel locus for Lebercongenital amaurosis on chromosome 6q. Am J Hum Genet2000;66:319–26.13 Stockton DW, Lewis RA, Aboud EB, et al. A novel locus for Lebercongenital amaurosis on chromosome 14q24. Hum Genet1998;103:328–33.14 Rozet JM, Perrault I, Gerber S, et al. Is guanylate cyclase activatingprotein (GCAP 30) the fourth gene for LCA? Invest Ophthalmol Vis Scisuppl 2000;abstract 889.15 http:/www.sph.uth.tmc.edu/Retnet/home.htm.16 Lotery AJ, Namperumalsamy P, Jacobson SG, et al. Mutation analysis ofthree genes in patients with Leber’s congenital amaurosis. ArchOphthalmol 2000;118:538–43.17 Smith D, Oestreicher J, Musarella M. Clinical spectrum of Leber’scongenital amaurosis in the second to fourth decades of life.Ophthalmology 1990;97:1156–61.18 Heher KL, Trabousli EI, Maumenee IH. The natural history of Leber’scongenital amaurosis. Ophthalmology 1992;99:241–5.19 Travis GH. Mechanisms of cell death in inherited retinal dystrophies. AmJ Hum Genet 1998;62:503–8.20 Perrault I, Rozet J, Gerber S, Ghazi I, et al. Leber’s congenitalamaurosis. Mol Genet Metab 1999;68:100–208.Progession of phenotype in Leber’s congenital amaurosis with a mutation at the LCA5 locus 475www.bjophthalmol.com

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Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus

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