A Case of PRPH2-associated Retinal Dystrophy as a Rare Cause of Electronegative ERG

A Case of PRPH2-associated Retinal Dystrophy as a Rare Cause of Electronegative ERG | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Case of PRPH2-associated Retinal Dystrophy as a Rare Cause of Electronegative ERG Bridget Moran, Kirk AJ Stephenson, Adrian Dockery, Jacqueline Turner, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8765134/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract A 37-year-old female presented with approximately 7 years of nyctalopia but had no central vision complaints. She was found to have a predominantly macular dystrophy with flecks and visual acuity of 20/25 in each eye. However, her full-field electroretinogram (ERG) showed an electronegative configuration (or reduced b:a ratio) under both scotopic and photopic conditions suggestive of inner retinal dysfunction of both the rod and cone systems. This phenomenon has only once been described with PRPH2 -related retinopathy and the mechanism of dysfunction is particularly interesting, considering that PRPH2 is expressed in rod and cone photoreceptor outer segments, not in the photoreceptor inner segments or bipolar cells where post-phototransduction activity occurs. Thus, unknown downstream post-phototransduction effects are possible. Four paternal relatives also affected by PRPH2 -retinopathy are presented, all of whom have a similar fundus appearance, though none have the electronegative ERG, highlighting the remarkable intrafamilial variability phenotype associated with pathogenic PRPH2 variants. PRPH2 electronegative ERG inherited retinal disease electroretinogram Figures Figure 1 Figure 2 Introduction The PRPH2 gene (peripherin-2, chromosome 6p) encodes a transmembrane protein expressed in rod and cone photoreceptor outer segments (1). Deleterious PRPH2 variants are implicated in 3–5% of inherited retinal diseases (IRD) (2, 3). PRPH2 phenotypes are heterogeneous including restricted macular or diffuse pan-retinal disease and can be congenital or adult-onset, typically with autosomal dominant inheritance. Functional impact ranges from severe visual impairment to asymptomatic maculopathy. Electroretinography (ERG) is a useful tool to measure objective retinal function and monitor progression of degenerative conditions. When the ERG b-wave (post-phototransduction origin) is of lower amplitude than the preserved a-wave (photoreceptor origin), it is termed electronegative ERG, which suggests dysfunction of the inner retina (4). Herein, we report a case of PRPH2 -IRD with an electronegative ERG, despite the assumption of photoreceptor-level dysfunction. Case Presentation A 37-year-old woman presented with progressive nyctalopia, delayed dark adaptation and scotopic visual field loss for the past 7-years. She had amblyopia treatment as a child but had no nystagmus. She had no significant medical history but there was a strong family history of PRPH2 -associated IRD (Figures E1/2, proband is patient III-2). On examination, best corrected visual acuity (BCVA) was 6/7.5 in each eye (RE +4.00D/-4.00Dx160 o , LE +3.75/-4.25x5 o ) and Goldmann visual fields were full. Anterior segment examination was unremarkable. Her fundal exam (Figure 1A,B) revealed multiple discrete focal hyperpigmented deep retinal lesions in the fovea and diffuse arteriolar attenuation. Fundus autofluorescence (FAF) demonstrated symmetrical innumerable hypoautofluorescent lesions throughout the posterior pole extending beyond the vascular arcades and few hyperautofluorescent foci in the central macula (Figure 1C,D). Optical coherence tomography showed evidence of ellipsoid zone (EZ) and retinal pigment epithelial thickening suggesting deposition (Figure 1E,F). There were focal areas of EZ atrophy and migration of hyperreflective material into the outer nuclear layer. Clinically, this was consistent with a Stargardt-like maculopathy. ERG (Figure 2A, Table S1) demonstrated reduced DA0.01 b-wave amplitudes and normal DA3.0/10.0 a-waves suggesting preserved rod photoreceptor function (i.e., phototransduction). The DA 3.0 and 10.0 b-waves were disproportionately reduced in amplitude, suggestive of a post-phototransduction defect. The b:a ratios were reduced at RE 1.02, LE 1.07 for DA 3.0 (normal mean 1.83 ±0.30) and RE 0.68, LE 0.90 for DA10.0 (normal mean 1.60 ±0.23). Light adapted (LA) single flash 3.0 2Hz and 30Hz stimuli responses were within the normal range for amplitude and latency. LA b:a ratio was 2.66 and 2.97 for right and left eyes, respectively (normal mean 4.34 ±0.70). (Table S2) These disproportionately abnormal b-waves were suggestive of generalized rod & cone postsynaptic dysfunction. Pattern ERG (15 o field) showed reduction of both P50 and N95 amplitudes though N95:P50 ratio was preserved, suggesting macular dysfunction (Figure 2B, Table S3). Panel-based genetic testing identified a pathogenic missense variant in PRPH2 :c.457A>G,p.(Lys153Glu) and no other candidate variants. Her father (Figure E1, II-1), brother (III-1) and uncle (II-3) and cousins (III-6, III-7) also carried this variant. Her father had more advanced retinal degeneration with a similar distribution but ERG was extinguished at 65-years-old. Her uncle had a moderate maculopathy phenotype but intact cone responses, mildly reduced rod responses and normal b:a ratio (RE 3.0, LE 2.77) at 62-years-old. This family highlights the significant clinical and electrophysiological heterogeneity of PRPH2 -IRD. Outcome and Follow-Up Though her nyctalopia was unchanged, she had evidence of gradual macular atrophic changes in keeping with the historical ‘retinal degeneration slow’ ( RDS ) nomenclature for PRPH2 . Thus, her diagnosis was refined to macular dystrophy with panretinal post-phototransduction dysfunction. As no disease-modifying therapies are approved for PRPH2 -retinopathy, the mainstays of treatment are refractive correction, reduction of oxidative stress (e.g., diet, exercise, UV protection, smoking avoidance) and provision of supports (e.g., mobility, low vision). Discussion We report a case of PRPH2 -IRD with a Stargardt-like maculopathy phenotype, though with unexpected pan-retinal involvement and post-synaptic dysfunction on ERG. This case highlights a discordance between disease severity (largely restricted to posterior pole), fundal appearance (macular dystrophy) and electrophysiology (electronegative ERG) which is characteristic of PRPH2 -IRD. The pedigree is also typical of the significant intrafamilial clinical heterogeneity. Structure-function mismatch is described in PRPH2 -IRD, particularly between FAF and ERG (5). Concomitant rod and cone photoreceptor dysfunction has also been noted, regardless of FAF appearance, likely due to expression of the PRPH2 transmembrane channel in both rod and cone outer segment disc membranes. However, variants affecting different protein domains may have preferential effects on either rods (e.g., p.Lys153Arg) or cones (e.g., p.Arg172Trp) (5). A series by Ba-Abbad et al. reported 6 patients with PRPH2 -IRD and electronegative ERG, 4 of whom carried the c.514C>T,p.Arg172Trp allele (6). A related publication reported a 44-year-old female (also PRPH2 :c.514C>T variant) with an electronegative ERG suggesting a variant-specific effect on post-synaptic function (7). These patients predominantly had a macular dystrophy phenotype but ERG suggested generalized post-phototransduction dysfunction for DA-maximal (4/6), LA-single flash (3/6) and long flash (3/5) stimuli. Heath-Jeffery et al. found that had an electronegative waveform was more common for photopic (31%) than scotopic (8%) ERG (5). Most PRPH2 variants causing a macular dystrophy phenotype (or sometimes RP) are located on the large extracellular D1 loop [amino acid (aa)123–264] of the PRPH2 protein, including the current (c.457A>G, aa153) and previous (c.514C>T, aa172) missense variants associated with electronegative ERG (1). A different mutation at aa153 (p.Lys153Arg) has been reported, with greater reduction of rod maximal amplitudes, though no comment was made regarding b:a ratio (8). However, the identification of another deleterious variant at the same position (aa153) supports the critical nature of this residue for normal photoreceptor outer segment function (meeting American College of Medical Genetics and Genomics PM5 criteria) (8). The lysine residue at this position is critical in the formation of a hydrophobic pocket domain which influences dimerization with aa221 (serine) of ROM1 (9, 10). Lysine chains play prominent roles in both membrane stability and cell signalling, thus loss of a lysine residue at this position may explain both the expected photoreceptor membrane instability and the unexpected post-phototransduction disorder. The mechanism underlying an electronegative ERG in a condition primarily affecting photoreceptor outer segments is unknown, however we discuss four possibilities. 1) Although a ‘pseudo-electronegative ERG’ for DA stimulation may be caused by ‘mid-stage’ rod-cone dystrophy (i.e. photopic hill phenomenon in the dark), the reported electronegative PRPH2 -IRD cases (c.457A>G and c.514C>T) had normal photoreceptor function (ERG a-wave) but b:a ratio was reduced for photopic and scotopic stimuli suggesting a post-phototransduction impairment for both rod and cone systems (6). 2) Altered/absent PRPH2 protein may directly or indirectly influence pre-synaptic or post-synaptic membrane activity via interaction with other molecules (e.g., ROM1 ) though the exact mechanism is unknown (8). 3) This patient could be affected by two separate IRDs; however, no other disease-causing variants were detected on a comprehensive testing platform and she lacks many of the other features of conditions with an electronegative ERG (e.g., macular schisis in males, nystagmus). 4) There could be an acquired cause for electronegative ERG but the patient had no active illnesses, history of malignant melanoma or vasculopathic features to explain selective inner retinal dysfunction. Conclusion The current case is the youngest patient yet reported with an electronegative ERG related to PRPH2 -IRD, and the first instance of the variant [ PRPH2 :c.457A>G, p.(Lys153Glu)] being linked to this phenotype. This case also demonstrates that significant intra-familial variability can manifest despite a shared variant. Declarations Declaration of Interest: The authors have no conflicting interests to declare. Declaration of Generative AI use: No AI was used in any part of the creation of this manuscript. Data availability declaration: All data underlying the results are available as part of the publication and no additional source data are required Funding statement: No funding was provided for the completion of this manuscript. Ethical statement: This case report was part of a study approved by the local institutional ethics review board (1.378.1358). Consent to Participate declaration: Not applicable Consent to Publish declaration: The patient provided written informed consent for publication. Author contributions: IF conceived the original idea. IF, JT, JO’B and AD supplied study materials. BM drafted the initial manuscript. BM, KS, TB and DK further refined the manuscript. All authors approved the submitted version of the manuscript. References Boon CJ, den Hollander AI, Hoyng CB, Cremers FP, Klevering BJ, Keunen JE. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res. 2008;27(2):213–35. Pontikos N, Arno G, Jurkute N, Schiff E, Ba-Abbad R, Malka S, et al. Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom. Ophthalmology. 2020;127(10):1384–94. Goetz KE, Reeves MJ, Gagadam S, Blain D, Bender C, Lwin C, et al. Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network. Am J Med Genet C Semin Med Genet. 2020;184(3):828–37. Jiang X, Mahroo OA. Negative electroretinograms: genetic and acquired causes, diagnostic approaches and physiological insights. Eye (Lond). 2021;35(9):2419–37. Heath Jeffery RC, Thompson JA, Lo J, Chelva ES, Armstrong S, Pulido JS, et al. Retinal Dystrophies Associated With Peripherin–2: Genetic Spectrum and Novel Clinical Observations in 241 Patients. Invest Ophthalmol Vis Sci. 2024;65(5):22. Ba-Abbad R, Robson AG, Yap YC, Moore AT, Webster AR, Holder GE. Prph2 mutations as a cause of electronegative ERG. Retina. 2014;34(6):1235–43. Downes SM, Fitzke FW, Holder GE, Payne AM, Bessant DA, Bhattacharya SS, et al. Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families. Arch Ophthalmol. 1999;117(10):1373–83. Jacobson SG, Cideciyan AV, Maguire AM, Bennett J, Sheffield VC, Stone EM. Preferential rod and cone photoreceptor abnormalities in heterozygotes with point mutations in the RDS gene. Exp Eye Res. 1996;63(5):603–8. Ikelle L, Makia M, Lewis T, Crane R, Kakakhel M, Conley SM, et al. Comparative study of PRPH2 D2 loop mutants reveals divergent disease mechanism in rods and cones. Cell Mol Life Sci. 2023;80(8):214. El Mazouni D, Gros P. Cryo-EM structures of peripherin–2 and ROM1 suggest multiple roles in photoreceptor membrane morphogenesis. Sci Adv. 2022;8(45):eadd3677. Additional Declarations No competing interests reported. Supplementary Files TableS1ERGvalues1.docx FigureE1Pedigree.tif Figure E1:Pedigree of the affected family. FigE2Familyimages101025.tif Figure E2:Multimodal retinal imaging and electroretinography (ERG) for the affected family. Column A. Colour fundus photographs. Column B. Fundus autofluorescence. Column C. Optical coherence tomography. Column D. Dark-adapted bright flash ERG. N/A = not available. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 11 Feb, 2026 Reviewers invited by journal 11 Feb, 2026 Editor invited by journal 07 Feb, 2026 Editor assigned by journal 05 Feb, 2026 Submission checks completed at journal 05 Feb, 2026 First submitted to journal 02 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8765134","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":589655490,"identity":"6b212319-9518-4141-8ac9-b906d5ddbe30","order_by":0,"name":"Bridget Moran","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYBACAwbGBgk47wOUPkCEFgMwh3EGA4MEEVrAqiBamHmgWvACc+nDjTe/VPyJ5pc+/OyxbY5dHb/0AcYDH/BosexLbLaWOWOQO7Mvzdw4d1uyhGRfAsPBGfgcdoaxTVqyzSB3wxkGM+ncbcwSBmcYGA7zENTyD6SF/Zu05bZ6CXuQlj8EtEh+bABp4TGTZtx2WMIAaMNhfN637GFstmY4Zpw7s4enTLJ323HJGWcYGw724NFizsP+8OaPGrncfh72bRI/t1Xz8/cwH/7wA581DJDoQAaMDQQ0AJUQMnMUjIJRMApGOAAAkJdLQgwyFN8AAAAASUVORK5CYII=","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Bridget","middleName":"","lastName":"Moran","suffix":""},{"id":589655492,"identity":"6391ca20-4a4d-4ef4-9210-391c50c5bcd9","order_by":1,"name":"Kirk AJ Stephenson","email":"","orcid":"","institution":"Children’s Health Ireland","correspondingAuthor":false,"prefix":"","firstName":"Kirk","middleName":"AJ","lastName":"Stephenson","suffix":""},{"id":589655493,"identity":"18db04d8-1493-4524-8ea9-2c8660a15f45","order_by":2,"name":"Adrian Dockery","email":"","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Adrian","middleName":"","lastName":"Dockery","suffix":""},{"id":589655494,"identity":"f98daae8-a363-4a50-97de-da072df82311","order_by":3,"name":"Jacqueline Turner","email":"","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jacqueline","middleName":"","lastName":"Turner","suffix":""},{"id":589655495,"identity":"86ae2940-baec-4ff9-a733-ab2ed85b6f50","order_by":4,"name":"James J O’Byrne","email":"","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"J","lastName":"O’Byrne","suffix":""},{"id":589655496,"identity":"278cba54-a375-41c4-9934-24035074f7e0","order_by":5,"name":"Ian Flitcroft","email":"","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ian","middleName":"","lastName":"Flitcroft","suffix":""},{"id":589655497,"identity":"d7395e6c-3107-4e4a-8ff8-71b5e1aaadeb","order_by":6,"name":"Tomás Burke MB","email":"","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomás","middleName":"Burke","lastName":"MB","suffix":""},{"id":589655498,"identity":"3f836146-b587-4699-8f18-c8f011a4ef58","order_by":7,"name":"David J Keegan","email":"","orcid":"","institution":"Mater Misericordiae University Hospital","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"J","lastName":"Keegan","suffix":""}],"badges":[],"createdAt":"2026-02-02 12:53:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8765134/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8765134/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102807075,"identity":"6eaeb9d7-092a-4401-8c4f-eac1b1d2c76b","added_by":"auto","created_at":"2026-02-17 00:53:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5159332,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal retinal imaging of the proband, 33F. A,B: Colour fundus photographs of the right and left eyes, respectively, demonstrating central pigment mottling (white box) and arteriolar attenuation (black arrow). Inset images depict a magnified view of the central macula. C,D: Fundus autofluorescence showing innumerable hypoautofluorescent foci on a background of generally increased autofluorescence. There are also a few hyperautofluorescent foci. E,F: Optical coherence tomography horizontal scans through the central fovea demonstrating thickening of the EZ and RPE layers with focal areas of atrophy and hyperreflective material in the ONL.\u003c/p\u003e","description":"","filename":"Fig1Fundusimages11025.png","url":"https://assets-eu.researchsquare.com/files/rs-8765134/v1/5e11f44981b68e1a78b39d00.png"},{"id":102807148,"identity":"d098a1c9-0a9b-4fa7-b0ac-4206010d43fb","added_by":"auto","created_at":"2026-02-17 00:53:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":229115,"visible":true,"origin":"","legend":"\u003cp\u003eA: ISCEV standard full field ERG of the right eye showing an electronegative DA 3.0 and reduced b:a ratio for the LA 3.0. DA = dark adapted. LA = light adapted. All stimuli are in candela seconds per metre squared (cdsm\u003csup\u003e-2\u003c/sup\u003e). B: Pattern ERG of the right eye showing reduced P50 amplitude suggestive of macular dysfunction.\u003c/p\u003e","description":"","filename":"Figure2ERGPERGgreyscale3.png","url":"https://assets-eu.researchsquare.com/files/rs-8765134/v1/ee23eefd13a1ed7e42dce414.png"},{"id":105751664,"identity":"b78071b9-e0f9-49ca-8824-45d840393240","added_by":"auto","created_at":"2026-03-30 15:35:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6684286,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8765134/v1/fe8a72e9-cd0e-4f03-a8a1-0a84f2b9f0bf.pdf"},{"id":102807074,"identity":"a0745796-71e6-4ff5-97c5-a70b824a6ce4","added_by":"auto","created_at":"2026-02-17 00:53:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24385,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1ERGvalues1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8765134/v1/655c24b85efe1afe80c7dcf7.docx"},{"id":102807077,"identity":"686a0d0d-2fb1-48f7-97d7-04052d933a87","added_by":"auto","created_at":"2026-02-17 00:53:51","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":122308,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure E1:\u003c/strong\u003ePedigree of the affected family.\u003c/p\u003e","description":"","filename":"FigureE1Pedigree.tif","url":"https://assets-eu.researchsquare.com/files/rs-8765134/v1/bc9d1bbcb1b7364d0a435c59.tif"},{"id":102807145,"identity":"84d34191-4ffb-4c7c-bace-c56f827a545a","added_by":"auto","created_at":"2026-02-17 00:53:53","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":6793630,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure E2:\u003c/strong\u003eMultimodal retinal imaging and electroretinography (ERG) for the affected family. Column A. Colour fundus photographs. Column B. Fundus autofluorescence. Column C. Optical coherence tomography. Column D. Dark-adapted bright flash ERG. N/A = not available.\u003c/p\u003e","description":"","filename":"FigE2Familyimages101025.tif","url":"https://assets-eu.researchsquare.com/files/rs-8765134/v1/b137e3da0d7ed743a917e68b.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Case of PRPH2-associated Retinal Dystrophy as a Rare Cause of Electronegative ERG","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe \u003cem\u003ePRPH2\u003c/em\u003e gene (peripherin-2, chromosome 6p) encodes a transmembrane protein expressed in rod and cone photoreceptor outer segments (1). Deleterious \u003cem\u003ePRPH2\u003c/em\u003e variants are implicated in 3–5% of inherited retinal diseases (IRD) (2, 3). \u003cem\u003ePRPH2\u003c/em\u003e phenotypes are heterogeneous including restricted macular or diffuse pan-retinal disease and can be congenital or adult-onset, typically with autosomal dominant inheritance. Functional impact ranges from severe visual impairment to asymptomatic maculopathy.\u003c/p\u003e\n\u003cp\u003eElectroretinography (ERG) is a useful tool to measure objective retinal function and monitor progression of degenerative conditions. When the ERG b-wave (post-phototransduction origin) is of lower amplitude than the preserved a-wave (photoreceptor origin), it is termed electronegative ERG, which suggests dysfunction of the inner retina (4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHerein, we report a case of \u003cem\u003ePRPH2\u003c/em\u003e-IRD with an electronegative ERG, despite the assumption of photoreceptor-level dysfunction.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 37-year-old woman presented with progressive nyctalopia, delayed dark adaptation and scotopic visual field loss for the past 7-years. She had amblyopia treatment as a child but had no nystagmus. She had no significant medical history but there was a strong family history of \u003cem\u003ePRPH2\u003c/em\u003e-associated IRD (Figures E1/2, proband is patient III-2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn examination, best corrected visual acuity (BCVA) was 6/7.5 in each eye (RE +4.00D/-4.00Dx160\u003csup\u003eo\u003c/sup\u003e, LE +3.75/-4.25x5\u003csup\u003eo\u003c/sup\u003e) and Goldmann visual fields were full. Anterior segment examination was unremarkable. Her fundal exam (Figure 1A,B) revealed multiple discrete focal hyperpigmented deep retinal lesions in the fovea and diffuse arteriolar attenuation. Fundus autofluorescence (FAF) demonstrated symmetrical innumerable hypoautofluorescent lesions throughout the posterior pole extending beyond the vascular arcades and few hyperautofluorescent foci in the central macula (Figure 1C,D). Optical coherence tomography showed evidence of ellipsoid zone (EZ) and retinal pigment epithelial thickening suggesting deposition (Figure 1E,F). There were focal areas of EZ atrophy and migration of hyperreflective material into the outer nuclear layer. Clinically, this was consistent with a Stargardt-like maculopathy.\u003c/p\u003e\n\u003cp\u003eERG (Figure 2A, Table S1) demonstrated reduced DA0.01 b-wave amplitudes and normal DA3.0/10.0 a-waves suggesting preserved rod photoreceptor function (i.e., phototransduction). The DA 3.0 and 10.0 b-waves were disproportionately reduced in amplitude, suggestive of a post-phototransduction defect. The b:a ratios were reduced at RE 1.02, LE 1.07 for DA 3.0 (normal mean 1.83\u0026nbsp;±0.30) and RE 0.68, LE 0.90 for DA10.0 (normal mean 1.60\u0026nbsp;±0.23). Light adapted (LA) single flash 3.0 2Hz and 30Hz stimuli responses were within the normal range for amplitude and latency. LA b:a ratio was 2.66 and 2.97 for right and left eyes, respectively (normal mean 4.34\u0026nbsp;±0.70). (Table S2) These disproportionately abnormal b-waves were suggestive of generalized rod \u0026amp; cone postsynaptic dysfunction. Pattern ERG (15\u003csup\u003eo\u003c/sup\u003e field) showed reduction of both P50 and N95 amplitudes though N95:P50 ratio was preserved, suggesting macular dysfunction (Figure 2B, Table S3).\u003c/p\u003e\n\u003cp\u003ePanel-based genetic testing identified a pathogenic missense variant in \u003cem\u003ePRPH2\u003c/em\u003e:c.457A\u0026gt;G,p.(Lys153Glu) and no other candidate variants. Her father (Figure E1, II-1), brother (III-1) and uncle (II-3) and cousins (III-6, III-7) also carried this variant. Her father had more advanced retinal degeneration with a similar distribution but ERG was extinguished at 65-years-old. Her uncle had a moderate maculopathy phenotype but intact cone responses, mildly reduced rod responses and normal b:a ratio (RE 3.0, LE 2.77) at 62-years-old. This family highlights the significant clinical and electrophysiological heterogeneity of \u003cem\u003ePRPH2\u003c/em\u003e-IRD.\u003c/p\u003e\n\n"},{"header":"Outcome and Follow-Up","content":"\u003cp\u003eThough her nyctalopia was unchanged, she had evidence of gradual macular atrophic changes in keeping with the historical\u0026nbsp;‘retinal degeneration slow’\u0026nbsp;(\u003cem\u003eRDS\u003c/em\u003e) nomenclature for\u0026nbsp;\u003cem\u003ePRPH2\u003c/em\u003e. Thus, her diagnosis was refined to macular dystrophy with panretinal post-phototransduction dysfunction. As no disease-modifying therapies are approved for \u003cem\u003ePRPH2\u003c/em\u003e-retinopathy, the mainstays of treatment are refractive correction, reduction of oxidative stress (e.g., diet, exercise, UV protection, smoking avoidance) and provision of supports (e.g., mobility, low vision).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report a case of \u003cem\u003ePRPH2\u003c/em\u003e-IRD with a Stargardt-like maculopathy phenotype, though with unexpected pan-retinal involvement and post-synaptic dysfunction on ERG. This case highlights a discordance between disease severity (largely restricted to posterior pole), fundal appearance (macular dystrophy) and electrophysiology (electronegative ERG) which is characteristic of \u003cem\u003ePRPH2\u003c/em\u003e-IRD. The pedigree is also typical of the significant intrafamilial clinical heterogeneity.\u003c/p\u003e\n\u003cp\u003eStructure-function mismatch is described in \u003cem\u003ePRPH2\u003c/em\u003e-IRD, particularly between FAF and ERG (5). Concomitant rod and cone photoreceptor dysfunction has also been noted, regardless of FAF appearance, likely due to expression of the PRPH2 transmembrane channel in both rod and cone outer segment disc membranes. However, variants affecting different protein domains may have preferential effects on either rods (e.g., p.Lys153Arg) or cones (e.g., p.Arg172Trp) (5). A series by Ba-Abbad et al. reported 6 patients with \u003cem\u003ePRPH2\u003c/em\u003e-IRD and electronegative ERG, 4 of whom carried the c.514C\u0026gt;T,p.Arg172Trp allele (6). A related publication reported a 44-year-old female (also \u003cem\u003ePRPH2\u003c/em\u003e:c.514C\u0026gt;T variant) with an electronegative ERG suggesting a variant-specific effect on post-synaptic function (7). These patients predominantly had a macular dystrophy phenotype but ERG suggested generalized post-phototransduction dysfunction for DA-maximal (4/6), LA-single flash (3/6) and long flash (3/5) stimuli. Heath-Jeffery et al. found that had an electronegative waveform was more common for photopic (31%) than scotopic (8%) ERG (5).\u003c/p\u003e\n\u003cp\u003eMost \u003cem\u003ePRPH2\u003c/em\u003e variants causing a macular dystrophy phenotype (or sometimes RP) are located on the large extracellular D1 loop [amino acid (aa)123–264] of the PRPH2 protein, including the current (c.457A\u0026gt;G, aa153) and previous (c.514C\u0026gt;T, aa172) missense variants associated with electronegative ERG (1). A different mutation at aa153 (p.Lys153Arg) has been reported, with greater reduction of rod maximal amplitudes, though no comment was made regarding b:a ratio (8). However, the identification of another deleterious variant at the same position (aa153) supports the critical nature of this residue for normal photoreceptor outer segment function (meeting American College of Medical Genetics and Genomics PM5 criteria) (8). The lysine residue at this position is critical in the formation of a hydrophobic pocket domain which influences dimerization with aa221 (serine) of \u003cem\u003eROM1\u003c/em\u003e (9, 10). Lysine chains play prominent roles in both membrane stability and cell signalling, thus loss of a lysine residue at this position may explain both the expected photoreceptor membrane instability and the unexpected post-phototransduction disorder.\u003c/p\u003e\n\u003cp\u003eThe mechanism underlying an electronegative ERG in a condition primarily affecting photoreceptor outer segments is unknown, however we discuss four possibilities. 1) Although a\u0026nbsp;‘pseudo-electronegative ERG’\u0026nbsp;for DA stimulation may be caused by\u0026nbsp;‘mid-stage’\u0026nbsp;rod-cone dystrophy (i.e. photopic hill phenomenon in the dark), the reported electronegative \u003cem\u003ePRPH2\u003c/em\u003e-IRD cases (c.457A\u0026gt;G and c.514C\u0026gt;T) had normal photoreceptor function (ERG a-wave) but b:a ratio was reduced for photopic and scotopic stimuli suggesting a post-phototransduction impairment for both rod and cone systems (6). 2) Altered/absent PRPH2 protein may directly or indirectly influence pre-synaptic or post-synaptic membrane activity via interaction with other molecules (e.g., \u003cem\u003eROM1\u003c/em\u003e) though the exact mechanism is unknown (8). 3) This patient could be affected by two separate IRDs; however, no other disease-causing variants were detected on a comprehensive testing platform and she lacks many of the other features of conditions with an electronegative ERG (e.g., macular schisis in males, nystagmus). 4) There could be an acquired cause for electronegative ERG but the patient had no active illnesses, history of malignant melanoma or vasculopathic features to explain selective inner retinal dysfunction.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe current case is the youngest patient yet reported with an electronegative ERG related to \u003cem\u003ePRPH2\u003c/em\u003e-IRD, and the first instance of the variant [\u003cem\u003ePRPH2\u003c/em\u003e:c.457A\u0026gt;G, p.(Lys153Glu)] being linked to this phenotype. This case also demonstrates that significant intra-familial variability can manifest despite a shared variant.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eDeclaration of Interest:\u003c/u\u003e The authors have no conflicting interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eDeclaration of Generative AI use:\u003c/u\u003e No AI was used in any part of the creation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eData availability declaration:\u003c/u\u003e All data underlying the results are available as part of the publication and no additional source data are required\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding statement:\u003c/u\u003e No funding was provided for the completion of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEthical statement:\u003c/u\u003e This case report was part of a study approved by the local institutional ethics review board (1.378.1358).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent to Participate declaration:\u003c/u\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent to Publish declaration:\u003c/u\u003e The patient provided written informed consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthor contributions:\u003c/u\u003e IF conceived the original idea. IF, JT, JO’B and AD supplied study materials. BM drafted the initial manuscript. BM, KS, TB and DK further refined the manuscript. All authors approved the submitted version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBoon CJ, den Hollander AI, Hoyng CB, Cremers FP, Klevering BJ, Keunen JE. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res. 2008;27(2):213\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePontikos N, Arno G, Jurkute N, Schiff E, Ba-Abbad R, Malka S, et al. Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom. Ophthalmology. 2020;127(10):1384\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoetz KE, Reeves MJ, Gagadam S, Blain D, Bender C, Lwin C, et al. Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network. Am J Med Genet C Semin Med Genet. 2020;184(3):828\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang X, Mahroo OA. Negative electroretinograms: genetic and acquired causes, diagnostic approaches and physiological insights. Eye (Lond). 2021;35(9):2419\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeath Jeffery RC, Thompson JA, Lo J, Chelva ES, Armstrong S, Pulido JS, et al. Retinal Dystrophies Associated With Peripherin\u0026ndash;2: Genetic Spectrum and Novel Clinical Observations in 241 Patients. Invest Ophthalmol Vis Sci. 2024;65(5):22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBa-Abbad R, Robson AG, Yap YC, Moore AT, Webster AR, Holder GE. Prph2 mutations as a cause of electronegative ERG. Retina. 2014;34(6):1235\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDownes SM, Fitzke FW, Holder GE, Payne AM, Bessant DA, Bhattacharya SS, et al. Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families. Arch Ophthalmol. 1999;117(10):1373\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacobson SG, Cideciyan AV, Maguire AM, Bennett J, Sheffield VC, Stone EM. Preferential rod and cone photoreceptor abnormalities in heterozygotes with point mutations in the RDS gene. Exp Eye Res. 1996;63(5):603\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIkelle L, Makia M, Lewis T, Crane R, Kakakhel M, Conley SM, et al. Comparative study of PRPH2 D2 loop mutants reveals divergent disease mechanism in rods and cones. Cell Mol Life Sci. 2023;80(8):214.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Mazouni D, Gros P. Cryo-EM structures of peripherin\u0026ndash;2 and ROM1 suggest multiple roles in photoreceptor membrane morphogenesis. Sci Adv. 2022;8(45):eadd3677.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"PRPH2, electronegative ERG, inherited retinal disease, electroretinogram","lastPublishedDoi":"10.21203/rs.3.rs-8765134/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8765134/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cspan type=\"BoldSmallCaps\" class=\"BoldSmallCaps\" name=\"Emphasis\"\u003eA 37-year-old female presented with approximately 7 years of nyctalopia but had no central vision complaints. She was found to have a predominantly macular dystrophy with flecks and visual acuity of 20/25 in each eye. However, her full-field electroretinogram (ERG) showed an electronegative configuration (or reduced b:a ratio) under both scotopic and photopic conditions suggestive of inner retinal dysfunction of both the rod and cone systems. This phenomenon has\u003c/span\u003e \u003cb\u003eonly once\u003c/b\u003e \u003cspan type=\"BoldSmallCaps\" class=\"BoldSmallCaps\" name=\"Emphasis\"\u003ebeen described with\u003c/span\u003e \u003cspan type=\"BoldItalicSmallCaps\" class=\"BoldItalicSmallCaps\" name=\"Emphasis\"\u003ePRPH2\u003c/span\u003e\u003cspan type=\"BoldSmallCaps\" class=\"BoldSmallCaps\" name=\"Emphasis\"\u003e-related retinopathy and the mechanism of dysfunction is particularly interesting, considering that\u003c/span\u003e \u003cspan type=\"BoldItalicSmallCaps\" class=\"BoldItalicSmallCaps\" name=\"Emphasis\"\u003ePRPH2\u003c/span\u003e \u003cspan type=\"BoldSmallCaps\" class=\"BoldSmallCaps\" name=\"Emphasis\"\u003eis expressed in rod and cone photoreceptor outer segments, not in the photoreceptor inner segments or bipolar cells where post-phototransduction activity occurs. Thus, unknown downstream post-phototransduction effects are possible. Four paternal relatives also affected by\u003c/span\u003e \u003cspan type=\"BoldItalicSmallCaps\" class=\"BoldItalicSmallCaps\" name=\"Emphasis\"\u003ePRPH2\u003c/span\u003e\u003cspan type=\"BoldSmallCaps\" class=\"BoldSmallCaps\" name=\"Emphasis\"\u003e-retinopathy are presented, all of whom have a similar fundus appearance, though none have the electronegative ERG, highlighting the remarkable intrafamilial variability phenotype associated with pathogenic\u003c/span\u003e \u003cspan type=\"BoldItalicSmallCaps\" class=\"BoldItalicSmallCaps\" name=\"Emphasis\"\u003ePRPH2\u003c/span\u003e \u003cspan type=\"BoldSmallCaps\" class=\"BoldSmallCaps\" name=\"Emphasis\"\u003evariants.\u003c/span\u003e\u003c/p\u003e","manuscriptTitle":"A Case of PRPH2-associated Retinal Dystrophy as a Rare Cause of Electronegative ERG","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-17 00:53:13","doi":"10.21203/rs.3.rs-8765134/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"32240833480464844569673724554855855457","date":"2026-02-11T13:36:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-11T06:40:18+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-07T06:58:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T03:39:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-06T03:39:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2026-02-02T12:17:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e3f4aa38-067f-49d4-b5db-f890b5c69a37","owner":[],"postedDate":"February 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T00:53:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-17 00:53:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8765134","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8765134","identity":"rs-8765134","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}