A Scoping Review of POLG-Related Cerebellar Ataxia: Insights and Clinical Perspectives

Background: Cerebellar ataxia is one of the most common movement disorders in mitochondrial disease, with POLG mutations being a frequent cause. This scoping review aimed to summarize current knowledge regarding cerebellar ataxia due to POLG mutations, focusing on epidemiological, clinical, radiological features and genotype-phenotype correlations.

Methods: We searched PubMed and Web of Science databases for all articles published in English till September 2025 describing cases of POLG-related cerebellar ataxia.

Results: In homozygous or compound heterozygous POLG mutation carriers, cerebellar ataxia seems to be progressive, and can initiate from either the bulbar muscles, trunk, or limbs. Age at onset varies greatly, ranging from birth to the early 70s. The most common variants in POLG-related cerebellar ataxia are W748S and A476T, localized in the linker region of POLG gene. Cerebellar ataxia due to POLG mutations can present in combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy (including status epilepticus), headache, other hyperkinetic movement disorders such as myoclonus and tremor, cognitive or affective disorders. Brain imaging commonly reveals atrophy of the vermis or cerebellar hemispheres, cortical atrophy, and/or bilateral T2/FLAIR lesions in both white matter and deep brain nuclei, including inferior olivary nuclei.

Conclusion: POLG-related ataxia should be included in the differential diagnosis of slowly progressive cerebellar ataxias. POLG-related disease comprises a continuum of clinical features; the combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy, hyperkinetic movement disorders, as well as characteristic imaging findings, can aid the diagnosis of this underdiagnosed entity. These findings contribute to a better characterization of the phenotype-genotype relationship in the extended pool of POLG-related mitochondrial diseases.

Highlights

This review summarizes current knowledge regarding cerebellar ataxia due to POLG mutations. A slowly progressive cerebellar ataxia in combination with sensory neuropathy, progressive external ophthalmoplegia, epilepsy, myoclonus, and characteristic imaging findings, including cerebellar atrophy, bilateral lesions in deep brain nuclei (thalami, olivary nuclei) should raise suspicion for POLG-related disease.