Objective: To define the genetic background of a case affected by parkinsonism with optic atrophy.

Background: Mutations in SLC25A46 have been recently described as causative of a wide spectrum of neurodegenerative disorders including early-onset cerebellar ataxia, optic atrophy, axonal neuropathy and a lethal pontocerebellar hypoplasia. SLC25A46 encodes a protein which is involved in mitochondrial dynamics and is recruited to the outer mitochondrial membrane.

Method: Clinical evaluation was performed by a team of neurologists specialized in movement disorders. Neuro-ophthalmological evaluation and Visual Evoked Potential were conducted. Genetic analysis was performed using an NGS panel followed by whole exome sequencing and Sanger confirmation of the identified mutations.

Results: A patient affected by optic atrophy since the age of 16 developed asymmetrical resting tremor and foot dystonia at the age of 40, followed by bradykinesia. Marked constipation and RBD were present. Family history was unremarkable. MRI of the brain showed external capsule with matter T2 hyperintensity. The parkinsonian symptoms were slowly progressive. There was an excellent response to levodopa. Genetic analysis excluded mutations in mtDNA, OPA1, POLG1, PEO1 and known genes related to autosomal dominant and recessive PD. Exome sequencing revealed two novel heterozygous mutations in SLC25A46, a frameshift c.1198_1199insC and a missense p.H137R. Both mutations were predicted to be pathogenetic by predictive tools.

Conclusion: This is the first association of mutations in SLC25A46 and parkinsonism with optic atrophy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-onset-parkinsonism-and-optic-atrophy-due-to-slc25a46-mutations/