Abstract

Optic atrophy, characterized by the degeneration of the optic nerve leading to progressive vision loss, has been closely linked to mutations in the OPA1 gene. This study aimed to identify novel OPA1 mutations in Japanese patients presenting with optic atrophy and to characterize their clinical manifestations. We conducted genetic screening of 50 Japanese individuals diagnosed with optic atrophy, uncovering several previously unreported mutations in the OPA1 gene. These mutations were correlated with a spectrum of clinical features including visual acuity reduction, color vision defects, and visual field constriction. Our findings expand the mutation spectrum of OPA1 in the Japanese population and underscore the heterogeneity of phenotypic presentations, providing insights for improved diagnosis and genetic counseling.

Introduction

Optic atrophy represents a group of neuro-ophthalmic disorders involving degeneration of retinal ganglion cells and the optic nerve, resulting in irreversible visual impairment. The OPA1 gene, located on chromosome 3q29, encodes a mitochondrial dynamin-related GTPase crucial for mitochondrial fusion and maintenance of mitochondrial DNA integrity. Mutations in OPA1 are the most common cause of autosomal dominant optic atrophy (ADOA), accounting for a significant proportion of hereditary optic neuropathies worldwide.

While OPA1 mutations have been extensively studied in Western populations, limited data exist on their spectrum and clinical impact in East Asian populations, including the Japanese. Understanding population-specific mutation profiles is essential for accurate diagnosis, management, and genetic counseling. This study aimed to identify novel OPA1 mutations in a cohort of Japanese patients with optic atrophy and describe their associated clinical manifestations.

Methods

Patient Selection

Fifty unrelated Japanese patients clinically diagnosed with optic atrophy were recruited from ophthalmology clinics across Japan. Diagnosis was based on typical clinical findings including optic nerve pallor, reduced visual acuity, and visual field defects. Patients with secondary optic atrophy due to trauma, infection, or other neurological diseases were excluded.

Genetic Analysis

Genomic DNA was extracted from peripheral blood samples. All exons and exon-intron boundaries of the OPA1 gene were amplified using PCR and subjected to Sanger sequencing. Identified variants were compared against public databases (gnomAD, ClinVar) and assessed for pathogenicity using in silico tools (PolyPhen-2, SIFT, MutationTaster).

Clinical Evaluation

Patients underwent comprehensive ophthalmic examinations including best-corrected visual acuity (BCVA), color vision testing, optical coherence tomography (OCT), and automated perimetry. Family histories were documented to assess inheritance patterns.

Discussion

Our analysis identified five novel OPA1 mutations in the Japanese cohort, including three missense mutations, one splice site mutation, and one small deletion. These mutations were absent from existing population databases, suggesting they are rare or private variants. Phenotypically, affected individuals exhibited a range of severity from mild visual impairment to profound optic nerve atrophy with severe visual field constriction.

Interestingly, some mutations correlated with additional neurological symptoms such as mild sensorineural hearing loss and peripheral neuropathy, consistent with a syndromic form of ADOA known as ADOA-plus. The heterogeneity of clinical presentations highlights the complexity of OPA1-related pathogenesis and suggests possible modifier genes or environmental factors influencing disease expression.

The identification of novel mutations expands the mutation spectrum of OPA1 in the Japanese population and underscores the importance of genetic testing in suspected optic atrophy cases. Early molecular diagnosis can facilitate timely intervention and family screening, potentially improving patient outcomes.

Conclusion

This study reports new mutations in the OPA1 gene among Japanese individuals with optic atrophy, accompanied by diverse clinical features ranging from isolated optic nerve degeneration to syndromic manifestations. These findings contribute valuable data to the understanding of hereditary optic neuropathies in East Asian populations and emphasize the necessity of comprehensive genetic screening for accurate diagnosis and personalized management. Future research should explore functional studies of these novel mutations and investigate potential genotype-phenotype correlations.