Objective: To describe a patient with a pathogenic POLG mutation presenting with sensory neuropathy, ataxia, recurrent falls, and supranuclear gaze palsy initially misdiagnosed as progressive supranuclear palsy (PSP), highlighting phenotypic overlap with atypical parkinsonism.

Background: Mutations in the POLG gene are the most common cause of inherited mitochondrial disease and produce a multisystem phenotype with prominent neurological involvement. Age at onset ranges from neonatal to late adulthood; genotype-phenotype correlations remain limited. Movement disorders, most often parkinsonism, are increasingly recognized. Oculomotor involvement typically presents with diplopia and multidirectional gaze limitation, whereas selective vertical gaze restriction, as seen in PSP, is atypical and may result in misdiagnosis

Method: A 67-year-old woman presented for a second opinion after a PSP diagnosis. Six years earlier, she developed vertigo and diplopia, followed by progressive imbalance and recurrent falls unresponsive to levodopa. Distal lower-extremity numbness began at 56 and progressed bilaterally, with left sensorineural hearing loss at 60. Examination showed restricted upgaze, hypometric vertical saccades, mild asymmetric bradykinesia, distal vibration loss, and ataxic gait; vertical gaze was not improved by vestibulo-ocular reflex. Extensive metabolic, autoimmune, and vascular evaluation was unrevealing

Results: Brain MRI demonstrated progressive confluent supratentorial and brainstem white matter hyperintensities with generalized atrophy, evolving over serial studies from 2017 to 2025. DAT scan was normal. CSF showed type III oligoclonal bands. A leukodystrophy panel identified a heterozygous pathogenic POLG variant (c.2209G>C; p.Gly737Arg), establishing a mitochondrial etiology

Conclusion: This case expands the phenotypic spectrum of POLG-related disease, demonstrating that mitochondrial disorders may present with supranuclear gaze palsy and parkinsonian features mimicking PSP. Unlike the classic sensory ataxic neuropathy, dysarthria, and ophthalmoparesis phenotype, this patient lacked dysarthria and exhibited selective vertical gaze restriction rather than diffuse ophthalmoparesis or ptosis. Recognition may prevent misdiagnosis and prompt genetic evaluation in atypical PSP

References: 1. Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019 Jan;15(1):40-52. doi: 10.1038/s41582-018-0101-0. PMID: 30451971; PMCID: PMC8796686.
2. Li LX, Jiang LT, Pan YG, Zhang XL, Pan LZ, Nie ZY, Chen YH, Jin LJ. Clinical and Molecular Features of POLG-Related Sensory Ataxic Neuropathy with Dysarthria and Ophthalmoparesis. J Mol Neurosci. 2021 Dec;71(12):2462-2467. doi: 10.1007/s12031-021-01831-9. Epub 2021 Apr 1. PMID: 33791913

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MDS Abstracts - https://www.mdsabstracts.org/abstract/polg-related-disease-mimicking-progressive-supranuclear-palsy-with-selective-vertical-gaze-restriction/