Ophthalmologic Manifestations Associated with Fukutin (FKTN) mutation subtypes in Korean Patients with Fukuyama Congenital Muscular Dystrophy: A Single-Center Retrospective Case Series

Ophthalmologic Manifestations Associated with Fukutin (FKTN) mutation subtypes in Korean Patients with Fukuyama Congenital Muscular Dystrophy: A Single-Center Retrospective Case Series | 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 Research Article Ophthalmologic Manifestations Associated with Fukutin (FKTN) mutation subtypes in Korean Patients with Fukuyama Congenital Muscular Dystrophy: A Single-Center Retrospective Case Series Seok Jae Lee, Hye Jun Joo, Dong Hyun Jo, Jae Ho Jung, Kihwang H. Lee, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7124555/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Nov, 2025 Read the published version in BMC Ophthalmology → Version 1 posted 11 You are reading this latest preprint version Abstract Background To evaluate phenotypes in Korean patients with Fukuyama congenital muscular dystrophy (FCMD), with a particular focus on ocular manifestations associated with specific Fukutin ( FKTN ) mutation subtypes. Methods We conducted a retrospective review of nine patients with genetically confirmed FCMD who were followed at a single tertiary referral center between 2005 and 2024. Comprehensive ophthalmologic evaluations were correlated with molecular genotyping, including detection of founder retrotransposon (RT) insertions and splice-disrupting variants in the FKTN gene. Results Seven of nine patients (77.8%) harbored compound heterozygous mutations comprising the RT insertion and deep intronic splice-site variants, while two patients carried non-founder mutations. The mean age at last ophthalmic evaluation was 7.59 ± 4.74 years. High myopia (44.4%), strabismus (22.2%), and nystagmus (11.1%) were frequently observed. Fundus examination revealed optic disc abnormalities in 77.8% of patients, including small discs (55.6%), pale discs (33.3%), and peripapillary fibrovascular membranes (33.3%). Additional retinal features included pigment without pressure (33.3%), tigroid fundus (33.3%), and peripheral retinal pigmentation (44.4%). Notably, rare but vision-threatening anomalies such as persistent fetal vasculature, and tractional retinal detachment were exclusively detected in patients with compound heterozygous mutations. Conclusion This study reveals a distinct ophthalmic phenotype in Korean patients with FCMD, characterized by optic nerve and retinal abnormalities. These findings suggest that patients with these genotypes may benefit from targeted and proactive ophthalmologic surveillance. Further studies in larger cohorts are warranted to validate these genotype-specific correlations. Fukuyama congenital muscular dystrophy FKTN gene Genotype–phenotype correlation Ocular phenotype Figures Figure 1 INTRODUCTION Fukuyama congenital muscular dystrophy (FCMD) is a severe autosomal recessive α-dystroglycanopathy first described by Fukuyama et al. in 1960 [ 1 ]. It is characterized by early-onset hypotonia, progressive muscular weakness, brain malformations, and distinct ophthalmic abnormalities. The disorder is caused by mutations in the Fukutin ( FKTN ) gene, located on chromosome 9q31, and is predominantly observed in East Asian populations, particularly in Japan and Korea [ 2 ]. In Japanese patients, a 3-kb retrotransposon (RT) insertion in the 3′ untranslated region (3′-UTR) of FKTN represents the ancestral founder mutation and accounts for approximately 80% of genetically confirmed cases, as demonstrated by large-scale registry-based analyses [ 3 ]. In contrast, Korean patients predominantly exhibit compound heterozygous mutations involving the RT insertion and deep intronic splice-disrupting variants such as c.647 + 2084G > T and c.346C > T, highlighting a distinct mutational landscape across East Asian populations [ 4 ]. Ocular abnormalities—including high myopia, cataracts, glaucoma, strabismus, optic nerve atrophy, and retinal detachment—have been well documented in Japanese cohorts [ 5 , 6 ]. However, the genotype–phenotype relationships underlying these ocular manifestations remain poorly defined, particularly in patients with compound heterozygous mutations prevalent outside of Japan. To address this knowledge gap, we present a detailed ophthalmologic evaluation of a Korean case series of genetically confirmed FCMD patients. METHODS Study population This retrospective study included patients with a confirmed diagnosis of FCMD who were evaluated at least twice by both pediatric neurology and ophthalmology specialists at a single tertiary care center—Seoul National University Children’s Hospital (Seoul, Republic of Korea)—between 2005 and 2024. The inclusion criteria were as follows: (1) histopathologic confirmation of hypoglycosylation of α-dystroglycan on skeletal muscle sections as demonstrated by immunohistochemical staining; (2) clinical evidence of early-onset hypotonia or generalized muscle weakness before the age of 2 years, in association with delayed developmental milestones and elevated serum creatine kinase (CK) levels; and (3) molecular confirmation of a pathogenic or likely pathogenic variant in the FKTN gene. A total of 28 patients with genetically confirmed FCMD harboring variants in the FKTN gene were initially identified. Among them, 19 patients were excluded due to insufficient ophthalmologic data: 14 patients had no ophthalmologic examinations, 2 patients had fewer than two ophthalmologic visits, and 3 patients lacked either anterior or posterior segment evaluation. The remaining 9 patients who underwent comprehensive ophthalmologic assessments, including both anterior and posterior segment examinations, were included in the final analysis (Table 1). FKTN mutational analysis Genetic analysis was conducted for all nine patients. FKTN variants were identified either directly from the proband or inferred from familial segregation analysis. All identified variants were confirmed by bidirectional Sanger sequencing. Nucleotide changes were annotated relative to the FKTN reference sequence (GenBank Accession No. NM_006731), and variant classification was performed according to ACMG/AMP guidelines. Clinical data collection Comprehensive clinical data were extracted from the electronic medical records. Parameters included age at diagnosis, age at most recent follow-up, presenting symptoms, developmental profile, seizure history, CK levels. Ophthalmologic variables included best-corrected visual acuity (BCVA), presence of strabismus or nystagmus, refractive error, cataract status, and detailed retinal findings based on dilated fundus examination and, when available, ocular imaging (fundus photography or B-scan ultrasonography). A small optic disc was defined as a disc-to-macula (DM) to disc diameter (DD) ratio greater than 3.0, measured using fundus photography. DM was defined as the distance from the center of the fovea to the temporal margin of the optic disc, and DD as the horizontal (nasal-to-temporal) diameter of the optic disc. Optic disc pallor was assessed qualitatively, based on diffuse or sectoral pallor and reduced neuroretinal rim coloration, as evaluated by two independent pediatric ophthalmologists (S.J. Lee and H.J. Joo). Statistical analysis Descriptive statistics were used to summarize clinical and ophthalmologic features. Continuous variables were expressed as means with standard deviations (SD) or medians with interquartile ranges (IQR), as appropriate. Categorical variables were reported as counts and percentages. Due to the small sample size and the descriptive nature of this study, formal inferential statistical testing was not performed. RESULTS Demographics and genetic characteristics Nine Korean patients with genetically and clinically confirmed FCMD were included in the study cohort (Table 2). The group consisted of 6 males (66.7%) and 3 females (33.3%). The mean age at diagnosis was 0.78 ± 0.34 years, and the median age was 0.42 years (IQR, 0.58–1.00; range, 0.25–1.13 years), reflecting early disease onset during infancy. Five distinct combinations of FKTN variants were identified. The most prevalent genotype was RT/c.648-1243G>T, observed in 3 patients (33.3%), followed by RT/c.165+835T>G and RT/c.647+2084G>T, each present in 2 patients (22.2%). The remaining two combinations—c.165+835T>G/c.647+2084G>T and c.1170_1171delCG/c.1136G>C—were observed in one patient each (11.1%). Notably, the RT insertion, a hallmark mutation in East Asian populations, was present in 7 out of 9 patients (77.8%) as part of a compound heterozygous configuration. This mutation spectrum aligns with previous epidemiologic observations suggesting a predominance of RT insertion and splice-site disrupting variants in Korean FCMD cohorts, in contrast to the RT homozygosity typically reported in Japanese populations [4, 5]. Ophthalmologic features and genotype correlations Ocular assessments were available for all 9 genetically confirmed patients (Table 3 and Figure 1). The mean age at the most recent ophthalmic examination was 7.59 ± 4.74 years, with a median of 6.33 years (IQR, 4.17–10.17; range, 2.58–17.50 years). Best-corrected visual acuity (BCVA) could be reliably assessed in only one patient (Case 2). Strabismus was documented in 2 patients (22.2%): Case 6 had 30 prism diopters of esotropia and Case 7 had 10 prism diopters of esotropia. Nystagmus was noted in Case 7 (11.1%). Refractive error analysis revealed astigmatism of 1.5 D or greater (absolute value) in 4 patients (44.4%) (Cases 4, 6, 8 and 9). High myopia (spherical equivalent ≤ –6.00 D) was present in 4 patients (44.4%) (Cases 4–6 and 9). Fundoscopic examination revealed optic disc abnormalities in 7 of the 9 patients (77.8%), with the exception of Case 1 and 2. Among these, small optic discs were present in 5 patients (55.6%) and optic disc pallor in 3 patients (33.3%), with one patient (Case 5) exhibiting both features. These structural findings suggest that optic nerve hypoplasia or atrophy is a common and possibly defining feature of FCMD-related ocular pathology. In addition to optic nerve anomalies, peripheral retinal abnormalities were also frequently encountered. Pigment without pressure (PWOP)—defined as pigmentary changes in the peripheral retina occurring independently of elevated intraocular pressure or intraocular inflammation—was seen in 3 patients (33.3%). A tigroid fundus pattern, characterized by enhanced visibility of the choroidal vasculature due to attenuation or thinning of the retinal pigment epithelium (RPE), was noted in another 3 patients (33.3%). Moreover, peripheral retinal pigmentation, likely reflective of RPE migration or proliferation in the peripheral retina, was documented in 4 patients (44.4%). Importantly, all patients exhibiting optic disc pallor (Cases 4–6) shared a distinctive set of overlapping retinal findings, including high myopia, peripapillary fibrovascular membrane, tigroid fundus appearance, and peripheral pigmentation. The co-occurrence of these features suggests a characteristic structural retinal phenotype associated with optic nerve atrophy in FCMD and may serve as a recognizable clinical endophenotype. In a subset of patients harboring compound heterozygous FKTN mutations involving the founder RT insertion and splice-site disrupting variants, more severe and complex retinal pathologies were observed. These included a tractional retinal detachment (TRD) in Case 6, and persistent fetal vasculature (PFV) with cataract in Case 7. Notably, these severe retinal findings were exclusive to individuals with RT-associated compound heterozygous FKTN mutations. DISCUSSION This study offers a comprehensive ophthalmologic characterization of nine genetically confirmed Korean patients with FCMD. Our cohort was predominantly composed of individuals harboring compound heterozygous mutations involving the founder RT insertion and deep intronic splice-disrupting variants. Notably, our data possibly suggest a genotype–phenotype correlation in FCMD, wherein RT-associated compound heterozygous FKTN mutations predispose patients to more severe ocular involvement. All patients demonstrated early-onset hypotonia, elevated CK levels, and delayed developmental milestones—hallmark features of dystroglycanopathy (Supplementary Table 1). In this cohort of 9 genetically confirmed FCMD patients, a total of six distinct FKTN variants were identified (Supplementary table 2 ), including the well-known 3-kb RT insertion, multiple deep intronic splice-disrupting mutations (c.165 + 835T > G, c.647 + 2084G > T, c.648-1243G > T), missense substitutions (c.1136G > C), and a previously unreported frameshift variant (c.1170_1171delCG). The most common variant was the RT insertion in intron 1, which appeared in 7 of 9 patients (77.8%) and is recognized as a founder mutation in Japanese and Korean populations [ 2 , 4 ]. However, the majority of Japanese FCMD patients are homozygous for the RT insertion, with a reported frequency of approximately 80% in a national registry-based analysis, most Korean patients carry compound heterozygous mutations comprising this RT insertion and additional deep intronic splice-site variants. This highlights a notable difference in the mutational spectrum between Japanese and Korean FCMD cohorts [ 2 , 4 , 5 , 7 ]. In a large-scale Japanese cross-sectional analysis of the database from the registry of patients with FCMD, myopia was the most frequently detected ocular abnormality (8.6%), followed by strabismus (5.3%), cataract (1.9%), glaucoma (1.0%), retinal detachment (1.0%), and optic disc atrophy (1.0%).[ 5 ] Ophthalmologic features in this cohort, however, were not stratified by genotype including homozygous for the RT insertion as well as compound heterozygous mutations. In this study, patients harboring compound heterozygous RT insertions in combination with splice-site variants—such as c.165 + 835T > G, c.647 + 2084G > T, and c.648-1243G > T—exhibited more complex ocular phenotypes characterized by multiple concurrent abnormalities, including optic disc abnormalities (small disc in 55.6%, pallor in 33.3%), high myopia (44.4%), and peripheral retinal pigmentary changes (44.4%). These features frequently co-occurred in the same individuals, indicating a broader extent of structural retinal involvement. In contrast, Case 2, who carried a novel frameshift mutation (c.1170_1171delCG), did not exhibit any of these retinal or optic nerve abnormalities, suggesting phenotypic variability even among patients with disruptive FKTN variants. One particularly novel and noteworthy finding in this study is the identification of DWOP in 33.3% of patients. This term refers to peripheral pigmentary changes all of whom exhibited in the absence of external pressure applied to the globe. Recent studies, particularly in retinal imaging, suggest that such findings may represent early signs of outer retinal or RPE dysfunction, possibly arising from developmental disorganization or metabolic dysregulation [ 8 , 9 ]. Beyond DWOP, the presence of peripapillary fibrovascular membranes (33.3%) is notable, as this has not been extensively documented in previous FCMD literature. These membranes may represent reactive gliosis or abnormal neovascular remodeling, further implicating defective dystroglycan-mediated signaling pathways in ocular vascular homeostasis. Furthermore, another notable retinal feature in FCMD was the presence of a consistent constellation of findings among patients exhibiting optic disc pallor (Cases 4–6), including high myopia, peripapillary fibrovascular membranes, tigroid fundus appearance, and peripheral retinal pigmentation. In addition to more commonly observed findings such as optic disc pallor and pigmentary retinal changes, several rare but clinically significant retinal pathologies were identified in the patients harbored compound RT and splice-disrupting variants. These included PFV, and TRD, each confirmed through clinical examination. There have been previous reports that associate compound heterozygosity involving RT insertion and deep intronic mutations with a more severe clinical phenotype, including greater motor impairment and more extensive brain MRI abnormalities [ 4 , 5 , 7 , 10 , 11 ]. In terms of ocular phenotypes, this notion is further supported by Japanese autopsy data, where an atypical FCMD case exhibited PFV, extensive retinal folding, TRD, and a persistent hyaloid artery.[ 12 ] Similarly, another case with compound heterozygous FKTN mutations—an insertion in the 3′ UTR and a nonsense variant (c.250C > T, p.R47X)—also exhibited TRD, linking severe FKTN mutations to complex retinal dysgenesis in FCMD [ 13 ]. Taken together, these rare yet clinically significant retinal findings emphasize the importance of incorporating detailed retinal imaging and/or ocular ultrasonography into the routine ophthalmic evaluation of FCMD patients—particularly those harboring RT insertions in combination with splice-site or missense variants—as such anomalies may critically influence visual prognosis and therapeutic decision-making. Our findings might suggest genotype-dependent variability in the ophthalmologic manifestations of FCMD, with compound RT and splice-site FKTN mutations potentially associated with more severe neuroretinal and vascular phenotypes. Further validation in larger cohorts is essential to clarify the full extent of genotype–phenotype correlations and their implications for clinical care. Declarations Acknowledgements We thank all the participants included in the cohorts analyzed in this study, as well as all the team members of the pediatric ophthalmology department at Seoul National University Children’s Hospital. Funding This research was supported by the Seoul National University Hospital Research Grant (04-2024-0420 to K.H. Lee and 04-2025-0520 to S.J. Lee). Author Contributions Conception and design: Kihwang Lee Draft writing: Seok Jae Lee, Kihwang Lee Analysis and interpretation: Seok Jae Lee, Hye Jun Joo, Kihwang Lee Data collection: Dong Hyun Jo, Jae Ho Jung, Jeong Hun Kim, Seong-Joon Kim, Jong Hee Chae Overall responsibilit y: Kihwang Lee Ethics declarations Ethics approval and consent to participate The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2506-082-1649), and all procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. Given the retrospective nature of the study and use of de-identified data, the requirement for written informed consent was waived by the IRB. Consent to publish declaration Not Applicable. Competing interests All the authors have declared no conflicts of interest in connection with this article. Data availability The authors declare that all data supporting the findings of this study are available within the paper and its extended data and supplemental information files. The datasets generated during or analyzed in the current study are available from the corresponding author upon reasonable request. References Toda T, Kobayashi K, Kondo-Iida E, Sasaki J, Nakamura Y. The Fukuyama congenital muscular dystrophy story. Neuromuscul Disord. 2000;10(3):153–9. Kobayashi K, Kato R, Kondo-Iida E, Taniguchi-Ikeda M, Osawa M, Saito K, Toda T. Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan. J Hum Genet. 2017;62(11):945–8. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998;394(6691):388–92. Lim BC, Ki CS, Kim JW, Cho A, Kim MJ, Hwang H, Kim KJ, Hwang YS, Park WY, Lim YJ, et al. Fukutin mutations in congenital muscular dystrophies with defective glycosylation of dystroglycan in Korea. Neuromuscul Disord. 2010;20(8):524–30. Ishigaki K, Ihara C, Nakamura H, Mori-Yoshimura M, Maruo K, Taniguchi-Ikeda M, Kimura E, Murakami T, Sato T, Toda T, et al. National registry of patients with Fukuyama congenital muscular dystrophy in Japan. Neuromuscul Disord. 2018;28(10):885–93. Yoshioka M, Kuroki S, Kondo T. Ocular manifestations in Fukuyama type congenital muscular dystrophy. Brain Dev. 1990;12(4):423–6. Lee J, Lee BL, Lee M, Kim JH, Kim JW, Ki CS. Clinical and genetic analysis of a Korean patient with Fukuyama congenital muscular dystrophy. J Neurol Sci. 2009;281(1–2):122–4. Guo Q, Jin X, Xin X, Guo X, Ming S, Li Y, Lei B. Multimodal imaging of dark without pressure in high myopia reveals evidence that photoreceptor microscopic lesions may be reversible. Sci Rep. 2025;15(1):18803. Yu H, Luo H, Zhang X, Sun J, Zhong Z, Sun X. Analysis of White and Dark without Pressure in a Young Myopic Group Based on Ultra-Wide Swept-Source Optical Coherence Tomography Angiography. J Clin Med 2022, 11(16). Kondo-Iida E, Kobayashi K, Watanabe M, Sasaki J, Kumagai T, Koide H, Saito K, Osawa M, Nakamura Y, Toda T. Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet. 1999;8(12):2303–9. Yoshioka M, Higuchi Y, Fujii T, Aiba H, Toda T. Seizure-genotype relationship in Fukuyama-type congenital muscular dystrophy. Brain Dev. 2008;30(1):59–67. Hino N, Kobayashi M, Shibata N, Yamamoto T, Saito K, Osawa M. Clinicopathological study on eyes from cases of Fukuyama type congenital muscular dystrophy. Brain Dev. 2001;23(2):97–107. Kondo H, Saito K, Urano M, Sagara Y, Uchio E, Kondo M. A case of Fukuyama congenital muscular dystrophy associated with negative electroretinograms. Jpn J Ophthalmol. 2010;54(6):622–4. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files 4.SupplementaryTable1.docx 4.Supplementarytable2.docx Tables.docx Cite Share Download PDF Status: Published Journal Publication published 04 Nov, 2025 Read the published version in BMC Ophthalmology → Version 1 posted Editorial decision: Revision requested 16 Sep, 2025 Reviews received at journal 15 Sep, 2025 Reviews received at journal 14 Sep, 2025 Reviews received at journal 10 Sep, 2025 Reviewers agreed at journal 04 Sep, 2025 Reviewers agreed at journal 31 Aug, 2025 Reviewers agreed at journal 28 Aug, 2025 Reviewers invited by journal 27 Jul, 2025 Editor assigned by journal 22 Jul, 2025 Submission checks completed at journal 17 Jul, 2025 First submitted to journal 17 Jul, 2025 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. 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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-7124555","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":491665620,"identity":"42f08d43-5d5d-4f21-bb45-eeccf7da8e98","order_by":0,"name":"Seok Jae Lee","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seok","middleName":"Jae","lastName":"Lee","suffix":""},{"id":491665621,"identity":"60c8f090-878e-4539-93a9-154fcf15a4f8","order_by":1,"name":"Hye Jun Joo","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hye","middleName":"Jun","lastName":"Joo","suffix":""},{"id":491665622,"identity":"60f4480c-19b6-49bc-a3f1-cc4f427153d8","order_by":2,"name":"Dong Hyun Jo","email":"","orcid":"","institution":"Seoul National University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"Hyun","lastName":"Jo","suffix":""},{"id":491665623,"identity":"27c07151-e14d-42c6-9178-eba1fa87ce97","order_by":3,"name":"Jae Ho Jung","email":"","orcid":"","institution":"Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jae","middleName":"Ho","lastName":"Jung","suffix":""},{"id":491665624,"identity":"8be12920-fe73-4c39-943f-ffb7b420eced","order_by":4,"name":"Kihwang H. 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(B, Case 4) Fundus photograph revealing a tigroid-patterned retina with optic disc pallor and a peripapillary fibrovascular membrane (red arrow) (C, Case 9) Fundus photograph demonstrating a small optic disc with a disc-to-macula (DM: distance from the macular center to the temporal margin of the optic disc; blue dashed line) to disc diameter (DD: horizontal [nasal-to-temporal] optic disc diameter; red dashed line) ratio of approximately 3.3 (DM:DD ratio \u0026gt;3.0). (D–E, Case 7) Anterior segment and fundus images showing combined-type persistent hyperplastic primary vitreous, characterized by elongated ciliary processes and a fibrovascular stalk (red arrow) extending from the lens to the optic disc. (F–G, Case 6) Fundus photograph and corresponding B-scan ultrasonography depicting tractional retinal detachment with distorted retinal folds and associated vitreous hemorrhage.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7124555/v1/393365279cc64ad053105100.png"},{"id":95564072,"identity":"e9f0b902-0617-4eda-a27a-9b55440fb653","added_by":"auto","created_at":"2025-11-10 16:07:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2518813,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7124555/v1/d17ca5aa-de06-4f9d-8c90-c41d061d44e5.pdf"},{"id":88101412,"identity":"21091a95-c90c-4277-ab9d-8829e24ed47a","added_by":"auto","created_at":"2025-08-01 11:30:48","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":24597,"visible":true,"origin":"","legend":"","description":"","filename":"4.SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7124555/v1/50b5111300f591b37c80896a.docx"},{"id":88099237,"identity":"aae86a82-ec58-41e0-9d83-6e4c17c1fa5f","added_by":"auto","created_at":"2025-08-01 11:14:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21712,"visible":true,"origin":"","legend":"","description":"","filename":"4.Supplementarytable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7124555/v1/531f11b3c543ebf1ebdb2236.docx"},{"id":88099241,"identity":"3f2f9007-8c6d-4a0e-b2f8-3c02c6ec657f","added_by":"auto","created_at":"2025-08-01 11:14:48","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":141732,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7124555/v1/c6c59eb9907615994ba29581.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ophthalmologic Manifestations Associated with Fukutin (FKTN) mutation subtypes in Korean Patients with Fukuyama Congenital Muscular Dystrophy: A Single-Center Retrospective Case Series","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eFukuyama congenital muscular dystrophy (FCMD) is a severe autosomal recessive α-dystroglycanopathy first described by Fukuyama et al. in 1960 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is characterized by early-onset hypotonia, progressive muscular weakness, brain malformations, and distinct ophthalmic abnormalities. The disorder is caused by mutations in the \u003cem\u003eFukutin\u003c/em\u003e (\u003cem\u003eFKTN\u003c/em\u003e) gene, located on chromosome 9q31, and is predominantly observed in East Asian populations, particularly in Japan and Korea [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn Japanese patients, a 3-kb retrotransposon (RT) insertion in the 3\u0026prime; untranslated region (3\u0026prime;-UTR) of \u003cem\u003eFKTN\u003c/em\u003e represents the ancestral founder mutation and accounts for approximately 80% of genetically confirmed cases, as demonstrated by large-scale registry-based analyses [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, Korean patients predominantly exhibit compound heterozygous mutations involving the RT insertion and deep intronic splice-disrupting variants such as c.647\u0026thinsp;+\u0026thinsp;2084G\u0026thinsp;\u0026gt;\u0026thinsp;T and c.346C\u0026thinsp;\u0026gt;\u0026thinsp;T, highlighting a distinct mutational landscape across East Asian populations [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOcular abnormalities\u0026mdash;including high myopia, cataracts, glaucoma, strabismus, optic nerve atrophy, and retinal detachment\u0026mdash;have been well documented in Japanese cohorts [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, the genotype\u0026ndash;phenotype relationships underlying these ocular manifestations remain poorly defined, particularly in patients with compound heterozygous mutations prevalent outside of Japan. To address this knowledge gap, we present a detailed ophthalmologic evaluation of a Korean case series of genetically confirmed FCMD patients.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included patients with a confirmed diagnosis of FCMD who were evaluated at least twice by both pediatric neurology and ophthalmology specialists at a single tertiary care center—Seoul National University Children’s Hospital (Seoul, Republic of Korea)—between 2005 and 2024. The inclusion criteria were as follows: (1) histopathologic confirmation of hypoglycosylation of α-dystroglycan on skeletal muscle sections as demonstrated by immunohistochemical staining; (2) clinical evidence of early-onset hypotonia or generalized muscle weakness before the age of 2 years, in association with delayed developmental milestones and elevated serum creatine kinase (CK) levels; and (3) molecular confirmation of a pathogenic or likely pathogenic variant in the \u003cem\u003eFKTN\u003c/em\u003e gene.\u0026nbsp;A total of 28 patients with genetically confirmed FCMD harboring variants in the \u003cem\u003eFKTN\u003c/em\u003e gene were initially identified. Among them, 19 patients were excluded due to insufficient ophthalmologic data: 14 patients had no ophthalmologic examinations, 2 patients had fewer than two ophthalmologic visits, and 3 patients lacked either anterior or posterior segment evaluation. The remaining 9 patients who underwent comprehensive ophthalmologic assessments, including both anterior and posterior segment examinations, were included in the final analysis (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFKTN\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003emutational analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenetic analysis was conducted for all nine patients. \u003cem\u003eFKTN\u003c/em\u003e variants were identified either directly from the proband or inferred from familial segregation analysis. All identified variants were confirmed by bidirectional Sanger sequencing. Nucleotide changes were annotated relative to the \u003cem\u003eFKTN\u003c/em\u003e reference sequence (GenBank Accession No. NM_006731), and variant classification was performed according to ACMG/AMP guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical data collection\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComprehensive clinical data were extracted from the electronic medical records. Parameters included age at diagnosis, age at most recent follow-up, presenting symptoms, developmental profile, seizure history, CK levels. Ophthalmologic variables included best-corrected visual acuity (BCVA), presence of strabismus or nystagmus, refractive error, cataract status, and detailed retinal findings based on dilated fundus examination and, when available, ocular imaging (fundus photography or B-scan ultrasonography). A small optic disc was defined as a disc-to-macula (DM) to disc diameter (DD) ratio greater than 3.0, measured using fundus photography. DM was defined as the distance from the center of the fovea to the temporal margin of the optic disc, and DD as the horizontal (nasal-to-temporal) diameter of the optic disc. Optic disc pallor was assessed qualitatively, based on diffuse or sectoral pallor and reduced neuroretinal rim coloration, as evaluated by two independent pediatric ophthalmologists (S.J. Lee and H.J. Joo).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive statistics were used to summarize clinical and ophthalmologic features. Continuous variables were expressed as means with standard deviations (SD) or medians with interquartile ranges (IQR), as appropriate. Categorical variables were reported as counts and percentages. Due to the small sample size and the descriptive nature of this study, formal inferential statistical testing was not performed.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eDemographics and genetic characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNine Korean patients with genetically and clinically confirmed FCMD were included in the study cohort (Table 2). The group consisted of 6 males (66.7%) and 3 females (33.3%). The mean age at diagnosis was 0.78 \u0026plusmn; 0.34 years, and the median age was 0.42 years (IQR, 0.58\u0026ndash;1.00; range, 0.25\u0026ndash;1.13 years), reflecting early disease onset during infancy. Five distinct combinations of \u003cem\u003eFKTN\u003c/em\u003e variants were identified. The most prevalent genotype was RT/c.648-1243G\u0026gt;T, observed in 3 patients (33.3%), followed by RT/c.165+835T\u0026gt;G and RT/c.647+2084G\u0026gt;T, each present in 2 patients (22.2%). The remaining two combinations\u0026mdash;c.165+835T\u0026gt;G/c.647+2084G\u0026gt;T and c.1170_1171delCG/c.1136G\u0026gt;C\u0026mdash;were observed in one patient each (11.1%). Notably, the RT insertion, a hallmark mutation in East Asian populations, was present in 7 out of 9 patients (77.8%) as part of a compound heterozygous configuration. This mutation spectrum aligns with previous epidemiologic observations suggesting a predominance of RT insertion and splice-site disrupting variants in Korean FCMD cohorts, in contrast to the RT homozygosity typically reported in Japanese populations [4, 5].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOphthalmologic features and genotype correlations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOcular assessments were available for all 9 genetically confirmed patients (Table 3 and Figure 1). The mean age at the most recent ophthalmic examination was 7.59 \u0026plusmn; 4.74 years, with a median of 6.33 years (IQR, 4.17\u0026ndash;10.17; range, 2.58\u0026ndash;17.50 years). Best-corrected visual acuity (BCVA) could be reliably assessed in only one patient (Case 2). Strabismus was documented in 2 patients (22.2%): Case 6 had 30 prism diopters of esotropia and Case 7 had 10 prism diopters of esotropia. Nystagmus was noted in Case 7 (11.1%). Refractive error analysis revealed astigmatism of 1.5 D or greater (absolute value) in 4 patients (44.4%) (Cases 4, 6, 8 and 9). High myopia (spherical equivalent \u0026le; \u0026ndash;6.00 D) was present in 4 patients (44.4%) (Cases 4\u0026ndash;6 and 9).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFundoscopic examination revealed optic disc abnormalities in 7 of the 9 patients (77.8%), with the exception of Case 1 and 2. Among these, small optic discs were present in 5 patients (55.6%) and optic disc pallor in 3 patients (33.3%), with one patient (Case 5) exhibiting both features. These structural findings suggest that optic nerve hypoplasia or atrophy is a common and possibly defining feature of FCMD-related ocular pathology. In addition to optic nerve anomalies, peripheral retinal abnormalities were also frequently encountered. Pigment without pressure (PWOP)\u0026mdash;defined as pigmentary changes in the peripheral retina occurring independently of elevated intraocular pressure or intraocular inflammation\u0026mdash;was seen in 3 patients (33.3%). A tigroid fundus pattern, characterized by enhanced visibility of the choroidal vasculature due to attenuation or thinning of the retinal pigment epithelium (RPE), was noted in another 3 patients (33.3%). Moreover, peripheral retinal pigmentation, likely reflective of RPE migration or proliferation in the peripheral retina, was documented in 4 patients (44.4%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eImportantly, all patients exhibiting optic disc pallor (Cases 4\u0026ndash;6) shared a distinctive set of overlapping retinal findings, including high myopia, peripapillary fibrovascular membrane, tigroid fundus appearance, and peripheral pigmentation. The co-occurrence of these features suggests a characteristic structural retinal phenotype associated with optic nerve atrophy in FCMD and may serve as a recognizable clinical endophenotype.\u003c/p\u003e\n\u003cp\u003eIn a subset of patients harboring compound heterozygous \u003cem\u003eFKTN\u003c/em\u003e mutations involving the founder RT insertion and splice-site disrupting variants, more severe and complex retinal pathologies were observed. These included a tractional retinal detachment (TRD) in Case 6, and persistent fetal vasculature (PFV) with cataract in Case 7. Notably, these severe retinal findings were exclusive to individuals with RT-associated compound heterozygous \u003cem\u003eFKTN\u003c/em\u003e mutations.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study offers a comprehensive ophthalmologic characterization of nine genetically confirmed Korean patients with FCMD. Our cohort was predominantly composed of individuals harboring compound heterozygous mutations involving the founder RT insertion and deep intronic splice-disrupting variants. Notably, our data possibly suggest a genotype\u0026ndash;phenotype correlation in FCMD, wherein RT-associated compound heterozygous \u003cem\u003eFKTN\u003c/em\u003e mutations predispose patients to more severe ocular involvement.\u003c/p\u003e\u003cp\u003eAll patients demonstrated early-onset hypotonia, elevated CK levels, and delayed developmental milestones\u0026mdash;hallmark features of dystroglycanopathy (Supplementary Table\u0026nbsp;1). In this cohort of 9 genetically confirmed FCMD patients, a total of six distinct \u003cem\u003eFKTN\u003c/em\u003e variants were identified (Supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), including the well-known 3-kb RT insertion, multiple deep intronic splice-disrupting mutations (c.165\u0026thinsp;+\u0026thinsp;835T\u0026thinsp;\u0026gt;\u0026thinsp;G, c.647\u0026thinsp;+\u0026thinsp;2084G\u0026thinsp;\u0026gt;\u0026thinsp;T, c.648-1243G\u0026thinsp;\u0026gt;\u0026thinsp;T), missense substitutions (c.1136G\u0026thinsp;\u0026gt;\u0026thinsp;C), and a previously unreported frameshift variant (c.1170_1171delCG). The most common variant was the RT insertion in intron 1, which appeared in 7 of 9 patients (77.8%) and is recognized as a founder mutation in Japanese and Korean populations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, the majority of Japanese FCMD patients are homozygous for the RT insertion, with a reported frequency of approximately 80% in a national registry-based analysis, most Korean patients carry compound heterozygous mutations comprising this RT insertion and additional deep intronic splice-site variants. This highlights a notable difference in the mutational spectrum between Japanese and Korean FCMD cohorts [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn a large-scale Japanese cross-sectional analysis of the database from the registry of patients with FCMD, myopia was the most frequently detected ocular abnormality (8.6%), followed by strabismus (5.3%), cataract (1.9%), glaucoma (1.0%), retinal detachment (1.0%), and optic disc atrophy (1.0%).[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Ophthalmologic features in this cohort, however, were not stratified by genotype including homozygous for the RT insertion as well as compound heterozygous mutations. In this study, patients harboring compound heterozygous RT insertions in combination with splice-site variants\u0026mdash;such as c.165\u0026thinsp;+\u0026thinsp;835T\u0026thinsp;\u0026gt;\u0026thinsp;G, c.647\u0026thinsp;+\u0026thinsp;2084G\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.648-1243G\u0026thinsp;\u0026gt;\u0026thinsp;T\u0026mdash;exhibited more complex ocular phenotypes characterized by multiple concurrent abnormalities, including optic disc abnormalities (small disc in 55.6%, pallor in 33.3%), high myopia (44.4%), and peripheral retinal pigmentary changes (44.4%). These features frequently co-occurred in the same individuals, indicating a broader extent of structural retinal involvement. In contrast, Case 2, who carried a novel frameshift mutation (c.1170_1171delCG), did not exhibit any of these retinal or optic nerve abnormalities, suggesting phenotypic variability even among patients with disruptive \u003cem\u003eFKTN\u003c/em\u003e variants.\u003c/p\u003e\u003cp\u003eOne particularly novel and noteworthy finding in this study is the identification of DWOP in 33.3% of patients. This term refers to peripheral pigmentary changes all of whom exhibited in the absence of external pressure applied to the globe. Recent studies, particularly in retinal imaging, suggest that such findings may represent early signs of outer retinal or RPE dysfunction, possibly arising from developmental disorganization or metabolic dysregulation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Beyond DWOP, the presence of peripapillary fibrovascular membranes (33.3%) is notable, as this has not been extensively documented in previous FCMD literature. These membranes may represent reactive gliosis or abnormal neovascular remodeling, further implicating defective dystroglycan-mediated signaling pathways in ocular vascular homeostasis. Furthermore, another notable retinal feature in FCMD was the presence of a consistent constellation of findings among patients exhibiting optic disc pallor (Cases 4\u0026ndash;6), including high myopia, peripapillary fibrovascular membranes, tigroid fundus appearance, and peripheral retinal pigmentation.\u003c/p\u003e\u003cp\u003eIn addition to more commonly observed findings such as optic disc pallor and pigmentary retinal changes, several rare but clinically significant retinal pathologies were identified in the patients harbored compound RT and splice-disrupting variants. These included PFV, and TRD, each confirmed through clinical examination. There have been previous reports that associate compound heterozygosity involving RT insertion and deep intronic mutations with a more severe clinical phenotype, including greater motor impairment and more extensive brain MRI abnormalities [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In terms of ocular phenotypes, this notion is further supported by Japanese autopsy data, where an atypical FCMD case exhibited PFV, extensive retinal folding, TRD, and a persistent hyaloid artery.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Similarly, another case with compound heterozygous \u003cem\u003eFKTN\u003c/em\u003e mutations\u0026mdash;an insertion in the 3\u0026prime; UTR and a nonsense variant (c.250C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.R47X)\u0026mdash;also exhibited TRD, linking severe \u003cem\u003eFKTN\u003c/em\u003e mutations to complex retinal dysgenesis in FCMD [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTaken together, these rare yet clinically significant retinal findings emphasize the importance of incorporating detailed retinal imaging and/or ocular ultrasonography into the routine ophthalmic evaluation of FCMD patients\u0026mdash;particularly those harboring RT insertions in combination with splice-site or missense variants\u0026mdash;as such anomalies may critically influence visual prognosis and therapeutic decision-making. Our findings might suggest genotype-dependent variability in the ophthalmologic manifestations of FCMD, with compound RT and splice-site \u003cem\u003eFKTN\u003c/em\u003e mutations potentially associated with more severe neuroretinal and vascular phenotypes. Further validation in larger cohorts is essential to clarify the full extent of genotype\u0026ndash;phenotype correlations and their implications for clinical care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants included in the cohorts analyzed in this study, as well as all the team members of the pediatric ophthalmology department at Seoul National University Children\u0026rsquo;s Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Seoul National University Hospital Research Grant (04-2024-0420 to K.H. Lee and 04-2025-0520 to S.J. Lee).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConception and design:\u003c/strong\u003e Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDraft writing:\u003c/strong\u003e Seok Jae Lee, Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis and interpretation:\u003c/strong\u003e Seok Jae Lee, Hye Jun Joo, Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection:\u003c/strong\u003e Dong Hyun Jo, Jae Ho Jung, Jeong Hun Kim, Seong-Joon Kim, Jong Hee Chae\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall responsibilit\u003c/strong\u003ey:\u0026nbsp;Kihwang Lee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2506-082-1649), and all procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. Given the retrospective nature of the study and use of de-identified data, the requirement for written informed consent was waived by the IRB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish declaration\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have declared no conflicts of interest in connection with this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that all data supporting the findings of this study are available within the paper and its extended data and supplemental information files. The datasets generated during or analyzed in the current study are available from the corresponding author upon reasonable request.\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eToda T, Kobayashi K, Kondo-Iida E, Sasaki J, Nakamura Y. The Fukuyama congenital muscular dystrophy story. Neuromuscul Disord. 2000;10(3):153\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKobayashi K, Kato R, Kondo-Iida E, Taniguchi-Ikeda M, Osawa M, Saito K, Toda T. Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan. J Hum Genet. 2017;62(11):945\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998;394(6691):388\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLim BC, Ki CS, Kim JW, Cho A, Kim MJ, Hwang H, Kim KJ, Hwang YS, Park WY, Lim YJ, et al. Fukutin mutations in congenital muscular dystrophies with defective glycosylation of dystroglycan in Korea. Neuromuscul Disord. 2010;20(8):524\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIshigaki K, Ihara C, Nakamura H, Mori-Yoshimura M, Maruo K, Taniguchi-Ikeda M, Kimura E, Murakami T, Sato T, Toda T, et al. National registry of patients with Fukuyama congenital muscular dystrophy in Japan. Neuromuscul Disord. 2018;28(10):885\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshioka M, Kuroki S, Kondo T. Ocular manifestations in Fukuyama type congenital muscular dystrophy. Brain Dev. 1990;12(4):423\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee J, Lee BL, Lee M, Kim JH, Kim JW, Ki CS. Clinical and genetic analysis of a Korean patient with Fukuyama congenital muscular dystrophy. J Neurol Sci. 2009;281(1\u0026ndash;2):122\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuo Q, Jin X, Xin X, Guo X, Ming S, Li Y, Lei B. Multimodal imaging of dark without pressure in high myopia reveals evidence that photoreceptor microscopic lesions may be reversible. Sci Rep. 2025;15(1):18803.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu H, Luo H, Zhang X, Sun J, Zhong Z, Sun X. Analysis of White and Dark without Pressure in a Young Myopic Group Based on Ultra-Wide Swept-Source Optical Coherence Tomography Angiography. J Clin Med 2022, 11(16).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKondo-Iida E, Kobayashi K, Watanabe M, Sasaki J, Kumagai T, Koide H, Saito K, Osawa M, Nakamura Y, Toda T. Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet. 1999;8(12):2303\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshioka M, Higuchi Y, Fujii T, Aiba H, Toda T. Seizure-genotype relationship in Fukuyama-type congenital muscular dystrophy. Brain Dev. 2008;30(1):59\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHino N, Kobayashi M, Shibata N, Yamamoto T, Saito K, Osawa M. Clinicopathological study on eyes from cases of Fukuyama type congenital muscular dystrophy. Brain Dev. 2001;23(2):97\u0026ndash;107.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKondo H, Saito K, Urano M, Sagara Y, Uchio E, Kondo M. A case of Fukuyama congenital muscular dystrophy associated with negative electroretinograms. Jpn J Ophthalmol. 2010;54(6):622\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Fukuyama congenital muscular dystrophy, FKTN gene, Genotype–phenotype correlation, Ocular phenotype","lastPublishedDoi":"10.21203/rs.3.rs-7124555/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7124555/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTo evaluate phenotypes in Korean patients with Fukuyama congenital muscular dystrophy (FCMD), with a particular focus on ocular manifestations associated with specific \u003cem\u003eFukutin\u003c/em\u003e (\u003cem\u003eFKTN\u003c/em\u003e) mutation subtypes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e We conducted a retrospective review of nine patients with genetically confirmed FCMD who were followed at a single tertiary referral center between 2005 and 2024. Comprehensive ophthalmologic evaluations were correlated with molecular genotyping, including detection of founder retrotransposon (RT) insertions and splice-disrupting variants in the \u003cem\u003eFKTN\u003c/em\u003e gene.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSeven of nine patients (77.8%) harbored compound heterozygous mutations comprising the RT insertion and deep intronic splice-site variants, while two patients carried non-founder mutations. The mean age at last ophthalmic evaluation was 7.59\u0026thinsp;\u0026plusmn;\u0026thinsp;4.74 years. High myopia (44.4%), strabismus (22.2%), and nystagmus (11.1%) were frequently observed. Fundus examination revealed optic disc abnormalities in 77.8% of patients, including small discs (55.6%), pale discs (33.3%), and peripapillary fibrovascular membranes (33.3%). Additional retinal features included pigment without pressure (33.3%), tigroid fundus (33.3%), and peripheral retinal pigmentation (44.4%). Notably, rare but vision-threatening anomalies such as persistent fetal vasculature, and tractional retinal detachment were exclusively detected in patients with compound heterozygous mutations.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study reveals a distinct ophthalmic phenotype in Korean patients with FCMD, characterized by optic nerve and retinal abnormalities. These findings suggest that patients with these genotypes may benefit from targeted and proactive ophthalmologic surveillance. Further studies in larger cohorts are warranted to validate these genotype-specific correlations.\u003c/p\u003e","manuscriptTitle":"Ophthalmologic Manifestations Associated with Fukutin (FKTN) mutation subtypes in Korean Patients with Fukuyama Congenital Muscular Dystrophy: A Single-Center Retrospective Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-01 11:14:43","doi":"10.21203/rs.3.rs-7124555/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-16T16:44:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-15T10:52:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-14T14:56:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-10T08:18:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31005526415277656035235172431322060095","date":"2025-09-04T15:08:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220376171548112050286434972285236082086","date":"2025-08-31T11:41:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188616589439835974157349037981391621998","date":"2025-08-28T07:54:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-27T16:16:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-22T07:23:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-18T02:05:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-07-18T02:03:00+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":"ee99dd52-c883-4aff-b0ec-5fb402f1cac7","owner":[],"postedDate":"August 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T16:02:38+00:00","versionOfRecord":{"articleIdentity":"rs-7124555","link":"https://doi.org/10.1186/s12886-025-04432-x","journal":{"identity":"bmc-ophthalmology","isVorOnly":false,"title":"BMC Ophthalmology"},"publishedOn":"2025-11-04 15:57:51","publishedOnDateReadable":"November 4th, 2025"},"versionCreatedAt":"2025-08-01 11:14:43","video":"","vorDoi":"10.1186/s12886-025-04432-x","vorDoiUrl":"https://doi.org/10.1186/s12886-025-04432-x","workflowStages":[]},"version":"v1","identity":"rs-7124555","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7124555","identity":"rs-7124555","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}