Objective: To report a Taiwanese family with a heterozygous missense mutation of OPA1 gene (NM_130836, p.Ser582Arg) presenting with optic atrophy and parkinsonism and establish an induced pluripotent stem cell (iPSC)-based model of OPA1 mutation.

Background: Mounting evidence links Parkinson’s disease with mitochondrial dysfunction. Mutations in OPA1, a dynamin-related GTPase involved in the maintenance of mitochondrial structure and function, have been linked to pure optic atrophy or plus variable disorders (e.g. parkinsonism). It is intriguing to study the impact of OPA1 halploinsufficiency on the mitochondria using iPSC-derived cells in case presenting with optic atrophy and parkinsonism.

Method: A 3 generation family was studied. Optic atrophy was identified by clinical features and visual evoked potential study. Brain MRI and SPECT/DaT scan were conducted. We performed trio-based exome sequencing to detect mutation, and validated by Sanger sequencing. Bioinformatics prediction tool was used to predict the pathogenic role of gene. iPSCs were generated from the blood of a patient with OPA1 and parkinsonism.

Results: Six members were affected by autosomal dominant optic atrophy in which one affected member also developed parkinsonism. This patient with parkinsonism is a 48-year-old male who suffered from visual impairment since childhood and developed asymmetry upper limb tremor, slowness in motion and festinating gait at 46 years. The result of brain MRI was unremarkable and SPECT/DaT scan showed a dopaminergic defect. Exome sequencing identified a novel heterozygous p.Ser582Arg mutation of OPA1 in all affected patients with optic atrophy. The pathogenic role of OPA1 mutation was supported by conservation analysis of amino acid residues after alignment of sequence from different eukaryotic species and by in silico analysis using prediction tools (SIFT, PolyPhen-2, Mutation Taster and CADD score).

Conclusion: Further functional studies would be warranted to establish the link between the OPA1 mutation in mitochondrial function and neurodegeneration with parkinsonism using iPSC-based disease modelling.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/optic-atrophy-and-parkinsonism-in-a-family-associated-with-opa1-mutation/