Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome SOPHIE SCHEIDECKER, SARAH HULL, YAUMARA PERDOMO, FOUZIA STUDER, VALE´RIE PELLETIER, JEAN MULLER, CORINNE STOETZEL, ELISE SCHAEFER, SABINE DEFOORT-DHELLEMMES, ISABELLE DRUMARE, GRAHAM E. HOLDER, CHRISTIAN P. HAMEL, ANDREW R. WEBSTER, ANTHONY T. MOORE, BERNARD PUECH, AND HE´LE`NE J. DOLLFUS PURPOSE: To describe a series of patients with Bardet- with Bardet-Biedl syndrome. (Am J Ophthalmol Biedl syndrome (BBS) and predominantly retinal cone 2015;160(2):364–372. Ó 2015 by Elsevier Inc. All dysfunction, a previously only rarely reported association. rights reserved.) DESIGN: Retrospective observational case series. METHODS: Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular ARDET-BIEDL SYNDROME IS AN EMBLEMATIC CILIOP- phenotyping, which included fundus examination, Gold- athy associated with severe and early-onset retinal mann visual fields, fundus autofluorescence imaging dystrophy, postaxial polydactyly, early obesity, renal B 1 (FAF), optical coherence tomography (OCT), and elec- dysfunction, hypogonadism, and learning difficulties. It is troretinography (ERG). Mutational screening in the genetically heterogeneous, with 20 BBS genes identified BBS genes was performed either by direct Sanger (BBS1 to BBS20)todate,2,3 all of which encode proteins sequencing or targeted next-generation sequencing. involved in the development and the maintenance of the RESULTS: All 7 patients had proven BBS mutations; 1 primary cilium. had a cone dystrophy phenotype on ERG and 6 had a The retinal dystrophy associated with Bardet-Biedl syn- cone-rod pattern of dysfunction. Macular atrophy was drome is usually severe but expression can be variable. Elec- present in all patients, usually with central hypofluores- troretinography (ERG) is an important diagnostic cence surrounded by a continuous hyperfluorescent ring investigation and can be abnormal prior to the develop- on fundus autofluorescence imaging. OCT confirmed ment of fundus abnormalities. A rod-cone dystrophy is usu- loss of outer retinal structure within the atrophic areas. ally present, with initial symptoms of night blindness and No clear genotype-phenotype relationship was evident. constricted peripheral fields with later central retinal 4 CONCLUSIONS: Patients with Bardet-Biedl syndrome involvement. Cone-rod dystrophy has also been reported usually develop early-onset retinitis pigmentosa. In but is very uncommon.5 contrast, the patients described herein, with molecularly The present report describes 7 patients with molecularly confirmed Bardet-Biedl syndrome, developed early cone confirmed Bardet-Biedl syndrome who have predominantly dysfunction, including the first reported case of a cone cone dysfunction, contrasting with previous series and dystrophy phenotype associated with the disorder. The expanding the phenotype that can be associated with the findings significantly expand the phenotype associated disorder. Supplemental Material available at AJO.com. Accepted for publication May 8, 2015. From the Service de Ge´ne´tique Me´dicale, Institut de Ge´ne´tique Neuro-ophtalmologie, CHRU de Lille, Lille, France (S.D.-D., I.D., Me´dicale d’Alsace, Centre de Re´fe´rence pour les Affections Rares en B.P.); Visual Neuroscience, UCL Institute of Ophthalmology, London, Ge´ne´tique Ophtalmologique (CARGO) (S.S., Y.P., F.S., V.P., E.S., and Moorfields Eye Hospital NHS Trust, London, United Kingdom H.J.D.), and Laboratoire de Diagnostic Ge´ne´tique, Institut de (G.E.H.); Genetic Sensory Diseases, CHU Montpellier, Montpellier, Ge´ne´tique Me´dicale d’Alsace (J.M.), Hoˆpitaux Universitaires de France (C.P.H.); Department of Ophthalmology, University of Strasbourg, Strasbourg, France; Inherited Eye Diseases, UCL Institute of California, San Francisco Medical School, san Francisco, California Ophthalmology, London, and Moorfields Eye Hospital NHS Trust, (A.T.M.). London, United Kingdom (S.H., A.R.W., A.T.M.); Laboratoire de Inquiries to He´le`ne J. Dollfus, Service de Ge´ne´tique Me´dicale, Institut Ge´ne´tique Me´dicale, Institut de Ge´ne´tique Me´dicale d’Alsace, de ge´ne´tique Me´dicale d’Alsace, CARGO - Laboratoire de Ge´ne´tique INSERM U1112, Faculte´ de Me´decine, Universite´ de Strasbourg, Me´dicale, INSERM U1112, 11 rue Humann, 67085 Strasbourg Cedex, Strasbourg, France (C.S., H.J.D.); Service d’exploration de la Vision et France; e-mail: [email protected] 364 Ó 2015 BY ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.05.007 METHODS of the study was more than 8 years. The patient in Case 1 initially underwent homozygosity mapping (GeneChip THIS IS A RETROSPECTIVE, OBSERVATIONAL CASE SERIES. Human Mapping 250K Nsp Array) (Platform IGBMC) Seven patients with Bardet-Biedl syndrome from 6 un- (HomoSNP in house software) identifying a putative locus related families were identified as having cone or cone- in which a mutation was detected by Sanger sequencing. rod dystrophy on ERG. Patients in Cases 1 and 2 were Targeted Sanger sequencing of the more frequently examined in the Center for Rare Genetic Ophthalmo- involved BBS genes (BBS1, BBS10, and BBS12) allowed logic Diseases (CARGO) in the Strasbourg University the molecular diagnosis for Cases 2 and 4. Cases 3, 5, and Hospital (Strasbourg, France); in Cases 3 and 4 at Moor- 6 were diagnosed by using targeted exome sequencing of fields Eye Hospital (London, UK); and in Cases 5–7 in the BBS genes.7 The screening of BBS1-BBS12 and of other the University Hospital of Lille (Lille, France). Ethical ciliopathy genes (AHI1, NPHP2-NPHP8, MKS1, MKS3, approval was obtained from the local ethics committee TTC21B, ALMS1) was undertaken for Case 7 by a program of Strasbourg University Hospital and Lille Hospital performed by the Centre National de Se´quenc¸age (Evry, and The Research Management Committee of Moor- France) in 2009–2010. fields Eye Hospital. All patients had a standard ophthalmic examination, including best-corrected visual acuity, slit-lamp examina- tion, dilated fundus examination, and ERG. Visual fields RESULTS were assessed with a Goldmann perimeter in Cases 1, 2, and 5–7. Full-field ERG was recorded according to the THE OPHTHALMOLOGIC AND EXTRAOCULAR FEATURES OF guidelines of the International Society for Clinical Elec- the 7 patients are detailed in Table 1 and the ERG findings trophysiology of Vision (ISCEV) in all centers.6 Full- in Table 2. Fundus photographs and FAF and OCT images field ERG was performed in Cases 1, 3, and 4 with the appear in Figures 1 and 2, with ERG imaging appearing in Espion system (Diagnosys LLC, Lowell, MA, USA), Figure 3. and in Cases 2 and 5–7 with a Metrovision system The patient in Case 1 was born from related Syrian par- (Pe´renchies, France). The diagnosis of cone dystrophy ents (second degree of consanguinity) and has a similarly was based on progressive decline of visual acuity, severe affected older brother. The patient presented with central retinal dysfunction, and reduced and delayed reduced visual acuity at the age of 6 years. He later devel- cone responses on full-field ERG with normal rod- oped photophobia and macular atrophy was confirmed at mediated responses at the time of diagnosis. Cone-rod age 10 years. Fundus examination at age 37 years showed dystrophy has both abnormal cone and rod responses central macular atrophy. OCT showed reduced macular on full-field ERG, with cone function being more thickness and absence of the foveal ellipsoid photore- severely affected. Spectral-domain optical coherence to- ceptor line. Central abnormal hypoautofluorescence mography (OCT) and fundus autofluorescence imaging surrounded by a ring of hyperautofluorescence was present (FAF) were performed for Cases 1–4 with a spectral- in both eyes, whereas the periphery disclosed normal domain OCT device (Spectralis OCT; Heidelberg Engi- autofluorescence. Goldmann visual fields showed good neering, Germany) and for Cases 5–7 with Cirrus preservation of peripheral isopters, but there was a failure HD-OCT (Carl Zeiss Meditec, Oberkochen, Germany). to detect the I1e stimulus centrally in each eye. The ERG FAF in Cases 5–7 was performed by means of a confocal showed abnormal cone responses with mildly abnormal scanning laser ophthalmoscope (Heidelberg Retina rod function. The patient had scars from surgical removal Angiograph; Heidelberg Engineering, Dossenheim, Ger- of hexadactyly, obesity (body mass index 38.6 kg/m2), many). learning difficulties, hypogonadism, dyslipidemia, hepatic The study protocol adhered to the tenets of the Declara- steatosis, and diabetes. He also suffered from depression tion of Helsinki and received approval from the local ethics and sleep apnea. SNP (single nucleotide polymorphism) committee. Written informed consent was obtained from analysis showed homozygosity in the BBS5 region and each subject prior to genetic investigation. Sanger sequencing revealed a homozygous p.M1L muta- tion in BBS5. GENETIC ANALYSIS: DNA of the patients was extracted The patient in Case 2 was born to unrelated parents. from peripheral blood lymphocytes. The analysis was He presented at age 45 years with reduced visual acuity. performed in either the research setting of the Medical Ge- There was bilateral macular atrophy on fundus exami- netics Laboratory (Institut de Ge´ne´tique Me´dicale nation. FAF showed an area of central hypoautofluores- d’Alsace, University of Strasbourg, INSERM U1112) or cence corresponding to