Bitner-Glindzicz, Maria

Chan, Choi M

Chinnery, Patrick F

Duncan, Holly J

Keane, Pearse A

Majander, Anna

Michaelides, Michel

Moore, Anthony T

Subash, Malavika

Webster, Andrew R

Yu-Wai-Man, Patrick

English

Apollo (Cambridge)

    1 Lamination of the outer plexiform layer in optic atrophy caused by dominant WFS1 mutations Majander A1, Bitner-Glindzicz M2, Chan CM1, Duncan HJ3, Chinnery PF4,5,6, Subash M1, Keane PA1, Webster AR1, Moore AT1,7, Michaelides M1, Yu-Wai-Man P1,3,4  1Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK. 2Great Ormond Street Hospital, Great Ormond Street, London, UK. 3Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK. 4Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 5Medical Research Council Mitochondrial Biology Unit, Cambridge, UK 6Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, UK 7 Ophthalmology Department, UCSF School of Medicine, San Francisco, CA     2  Corresponding Authors Dr Anna Majander UCL Institute of Ophthalmology and Moorfields Eye Hospital 162 City Road, London, EC1V 2PD, United Kingdom Tel: +44-0207 566 2265 E-mail: a.majander@ucl.ac.uk  Dr Patrick Yu-Wai-Man Wellcome Trust Centre for Mitochondrial Research Institute of Genetic Medicine, Newcastle University Newcastle upon Tyne, NE1 3BZ, United Kingdom Tel: +44-191-241-8854, Fax: +44-191-241-8666 E-mail:Patrick.Yu-Wai-Man@ncl.ac.uk    3  Financial Support: This research has been supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC) and the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. AM also receives funding from Suomen Silmätutkimusseura ry:n Apurahasäätiö (Finland). MM also receives funding from Fight For Sight (UK), Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), Retinitis Pigmentosa Fighting Blindness, and The Wellcome Trust [099173/Z/12/Z]. MM is supported by an FFB Career Development Award. PAK is a NIHR Clinician Scientist. PFC is a Wellcome Trust Senior Fellow in Clinical Science and a UK NIHR Senior Investigator who also receives funding from the MRC (UK), Parkinson’s UK, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust. PYWM is a Medical Research Council (MRC, UK) Clinician Scientist. PYWM also receives funding from Fight for Sight (UK) and the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration. The funding organizations had no role in the design or conduct of this research.  Disclosures All the listed authors in this manuscript report no relevant financial disclosures or conflicts of interest.  Running title OPL lamination in optic atrophy secondary to dominant WFS1 mutations  Keywords Autosomal dominant optic atrophy; DIDMOAD; optical coherence tomography; WFS1; Wolfram syndrome      4 Address for reprints Dr Patrick Yu-Wai-Man Wellcome Trust Centre for Mitochondrial Research Institute of Genetic Medicine, Newcastle University Newcastle upon Tyne, NE1 3BZ, United Kingdom Tel: +44-191-241-8854, Fax: +44-191-241-8666 E-mail:Patrick.Yu-Wai-Man@ncl.ac.uk   Word count: 1,012 Title: 77 characters (no spaces) One figure: Figure 1 2 online supplement tables: Table 1 and Table 2      5 Wolfram syndrome, or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy (OA), and 1 deafness), is a neurodegenerative disorder with heterogeneous clinical manifestations caused by 2 homozygous or compound heterozygous recessive mutations in the WFS1 gene (OMIM 606201).1 3 More recently, the phenotypic spectrum has expanded to include patients with dominant 4 inheritance and limited clinical features, in particular OA in association with diabetes mellitus and/or 5 sensorineural deafness.1 WFS1 encodes for an endoplasmic reticulum transmembrane protein, 6 Wolframin, which is highly expressed in retinal tissues, including retinal ganglion cells, the 7 photoreceptor inner segments, and the inner nuclear layer (INL) of the human eye, and mouse 8 Müller cells.2,3 Thinning of the peripapillary nerve fibre and macular retinal ganglion cell layers are 9 typical features of WFS1-related optic atrophy, but careful genotype-phenotype correlations have 10 not yet been established. Here, we report on a comprehensive macular OCT imaging study of 14 11 patients with OA secondary to mutations in WFS1 and the identification of a distinct outer plexiform 12 layer (OPL) abnormality, which associates exclusively with dominant missense WFS1 mutations 13 (Table 1, available at www.aaojournal.org). 14  Averaged B-scans of 26 eyes from 14 patients with confirmed pathogenic WFS1 mutations 15 were retrospectively reviewed from our SpectralisTM (Heidelberg Engineering Ltd., Heidelberg, 16 Germany) databases. A prominent feature in the macular SD-OCT images of 15 eyes from 8 patients 17 harbouring dominant WFS1 mutations (Patients 1-8) was an abnormal reflectivity of the OPL, which 18 was not observed in 11 eyes from 6 patients with recessive WFS1 mutations (Figure 1 and Table 1, 19 available at www.aaojournal.org). The OPL was comprised of three distinct laminae: an innermost 20 highly reflective lamina; a middle non-reflective lamina; and an outermost highly reflective lamina. 21 To a certain extent, OPL thickness varied depending on the angle between the OCT laser beam and 22 the retinal layers. Beam positions that were more perpendicular to the Henle’s fibre tracks resulted 23 in a thicker OPL compared with beam positions that were parallel to these tracks, as illustrated by 24     6 the left eye of Patient 5 (Figure 1). However, in several eyes, an abnormally thick OPL was visualized 25 even with straight OCT beam positions, as for Patient 6 (Figure 1). In the majority of patients, the 26 middle OPL lamina formed a nearly confluent ring centred at the fovea and extending 1-1.5 mm 27 from the foveolar centre up to the optic disc. Perifoveal volumetric retinal scans were obtained for 28 22 eyes from 12 patients in our WFS1 cohort. Automated segmentation and retinal layer thickness 29 analysis were carried out using the automated retinal Heidelberg Engineering segmentation tool 30 included in the Spectralis Glaucoma Module software (version 6.0) after manual confirmation of 31 each layer (Table 2, available at www.aaojournal.org).  Marked thinning of the GCL-IPL complex was 32 observed consistent with OA. All 11 eyes with abnormal OPL lamination had significantly thicker OPL 33 and, more importantly, combined OPL and ONL complex compared with control eyes, or the eyes of 34 patients without OPL lamination. Compared with control eyes, INL thickness was increased in 4 eyes 35 (Patients 2, 5, 8) with INL cystoid changes (Figure 1), but also in 5 other eyes with OPL lamination 36 and in 3 eyes without OPL abnormality (Table 2, available at www.aaojournal.org). Our study had 37 ethical and institutional approval and its design complied with the Declaration of Helsinki. 38 We have identified a previously unreported macular OCT feature in patients with Wolfram-39 related optic atrophy that is associated with dominant, but not recessive, WFS1 mutations. The 40 lamination of the OPL was characterised by three distinct sublayers: (1) an innermost highly-41 reflective lamina, similar to what is frequently identified as the OPL in normal eyes; (2) a non-42 reflective cleft-like middle lamina; and (3) an outermost highly-reflective lamina with characteristics 43 of Henle’s fibre layer. Our retrospective study did not enable a systematic evaluation of the effect of 44 angle changes on the OPL reflectivity. Further work is needed to clarify whether the outermost 45 lamina has truly abnormal reflectivity and whether the middle lamina represents an additional 46 spatial structure or merely abnormal OCT reflectivity. However, as the thickness of combined OPL 47 and ONL complex should not be sensitive to OCT angle changes, its significantly increased thickness 48     7 in eyes with abnormal OPL lamination suggests that an additional space could indeed account for the 49 laminated OPL structure observed in this patient subgroup with dominant WFS1 mutations. 50 Taking into consideration the spatial relationships between the three OPL laminae and 51 previously published histological studies,4 we propose that the middle cleft-like lamina is located 52 between the synaptic and pedicles sublayers of the OPL. This region has also been shown to possess 53 a particular retinal architecture with bending Müller cells.5 Wolframin is highly expressed in Müller 54 cells and this cell type has been implicated in the development of OPL and INL edema, and changes 55 within Henle’s fibre layer.4,5 The Müller cell is, therefore, an attractive candidate for the 56 development of the observed OPL lamination. 57  Interestingly, OPL lamination was only associated with dominant missense WFS1 mutations. 58 It was not identified in any of the 6 patients harbouring recessive homozygous or compound 59 heterozygous WFS1 mutations. This distinct OPL abnormality has not previously been reported in the 60 context of optic atrophy and it could represent a specific deleterious effect of dominant WFS1 61 mutations. The missense variants identified in our patients are predicted to result in only a minor 62 reduction in wolframin protein level.1 Depletion of the native wild-type wolframin protein, which is 63 thought to be the major pathophysiological mechanism in recessive Wolfram syndrome, is therefore 64 unlikely to be implicated in the aetiology of the OPL lamination. Instead, dominant missense WFS1 65 mutations could result in a dysfunctional aberrant wolframin protein. 66 WFS1 is a highly polymorphic gene and determining the mode of inheritance or the 67 pathological significance of a specific WFS1 variant is not always straightforward, especially in 68 singleton cases with no access to other family members. Our study has revealed an interesting 69 association between dominant missense WFS1 mutations and distinct OPL lamination on SD-OCT, 70 which was not observed in patients with recessive WFS1 mutations. Future work in other 71 independent patient cohorts with Wolfram syndrome will confirm whether this OCT feature could be 72 used to distinguish between dominant and recessive forms of the disease. 73     8 References 74 1 de Heredia ML, Clèries R, Nunes V. Genotypic classification of patients with Wolfram 75 syndrome: insights into the natural history of the disease and correlation with 76 phenotype. Genet Med 2013;15:497-506. 77 2 Schmidt-Kastner R, Kreczmanski P, Preising M, et al. Expression of the diabetes risk gene 78 wolframin (WFS1) in the human retina. Exp Eye Res 2009;89:568-74. 79 3 Kawano J, Tanizawa Y, Shinoda K. Wolfram syndrome 1 (Wfs1) gene expression in the 80 normal mouse visual system. J Comp Neurol 2008;510:1-23  81 4 Curcio CA, Messinger JD, Sloan KR, et al. Human chorioretinal layer thicknesses measured in 82 macula-wide, high-resolution histologic sections. Invest Ophthalmol Vis Sci 83 2011;52:3943-54.  84 5 Matet A, Savastano MC, Rispoli M, et al. En face optical coherence tomography of foveal 85 microstructure in full-thickness macular hole: A model to study perifoveal Müller cells. 86 Am J Ophthalmol 2015;159:1142–51. 87  88 89     9 A figure legend:  90 Figure 1.  Macular SD-OCT images of Patient 1 showing outer plexiform layer (OPL) lamination and of 91 Patient 13 without this defect (upper panel). The lower panels show OCT images of Patients 2-8 with 92 OPL lamination, with the right eye on the left and the left eye on the right. The localization of the 93 layers that were not imaged through the optical axis are indicated within the inserts. The yellow 94 arrows indicate the cleft-like middle structure of the OPL. The red arrows highlight areas of cystoid 95 inner nuclear layer (INL) edema.96       Table 1. WFS1 genotype and clinical characteristics of the patients in our study cohort. Patient Sex Inheritance (Family ) WFS1 mutation(s)* Extraocular findings OA age (y)** BCVA (logMAR) Macular SD-OCT RE LE Age (y)** OPL cleft*** 1 F AD (1) c.2390A>T: p.Asp797Val SNHL, DM2 45 1.10 NI 69 + 2 F AD (2) c.2051C>T: p.Ala684Val SNHL, epilepsy, hypertension 5 0.60 0.60 46 + 3 M AD (2) c.2051C>T: p.Ala684Val SNHL 23 0.48 0.60 23 + 4 F AD (3) c.968A>G: p.His323Arg SNHL U 0.30 0.43 44 + 5 F AD (3) c.968A>G: p.His323Arg SNHL 4 0.00 0.00 8 + 6 M de novo (4) c.937C>T: p.His313Tyr c.-170-9_14dupTGCCCC SNHL, DM1, short stature 7 0.10 0.20 10 + 7 F AD (5) c.2051C>T: p.Ala684Val SNHL 78 1.98 1.98 78 + 8 F AD (6) c.2161A>T: p.Asn721Tyr SNHL 50 1.98 1.98 51 + 9 M AR (7) c.505G>A: p.Glu169Lys c.874C>A: p.Pro292Thr DM1, DI, NB 9 2.28 2.28 45 - 10 M AR (7) c.505G>A: p.Glu169Lys c.874C>A: p.Pro292Thr DM1, DI, NB U 1.30 NI 46 - 11 F AR (8) c.2648_2651delTCTT: p.Phe883SerfsX68 c.1597C>T: p.Pro533Ser DI UC 23 0.60 0.60 44 - 12 F AR (8) c.2648_2651delTCTT: p.Phe883SerfsX68 c.1597C>T: p.Pro533Ser DI UC 37 0.78 0.78 52 - 13 F AR (9) c.2643_2644delC: p.Phe883LeufsX56  (homozygous) SNHL, DM1, DI PS, NEU 15 1.30 1.30 25 - 14 F AR (10) c.409_424dup1: p.Val142GlyfsX10 c.2262_2263delCT: p.Cys755SerfsX3 SNHL, DM1 31 1.00 1.00 35 -  * WFS1 genetic testing was conducted by the West Midlands Regional Genetic Laboratory, Birmingham, UK.  ** Age at the time of diagnosis of optic atrophy (OA) and when macula SD-OCT imaging was performed.  Images were retrieved from the SpectralisTM (Heidelberg Engineering Ltd., Heidelberg, Germany) databases of Moorfields Eye Hospital, London, UK and the Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK. Our study had local ethical and institutional approval, and its design complied with the Declaration of Helsinki. ***The presence (+) or absence (-) of an outer plexiform layer (OPL) lamination is indicated. Abbreviations: DI, Diabetes insipidus; DM1, Diabetes mellitus type 1; DM2, Diabetes mellitus type 2; LE, left eye; NB, Neurogenic bladder; NEU, intermittent myoclonus, occasional balance problem, postural hypotension; NI, not included into the study; NP, not performed; OA; optic atrophy; OPL; outer plexiform layer; PS, bipolar affective disorder RE, right eye; RNFL, peripapillary retinal nerve fiber layer thickness; SNHL, sensorineural hearing loss; U, Unknown; UC, urinary and faecal incontinence. 

Lamination of the Outer Plexiform Layer in Optic Atrophy Caused by Dominant WFS1 Mutations.

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Lamination of the Outer Plexiform Layer in Optic Atrophy Caused by Dominant WFS1 Mutations.

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