POLG1-related levodopa-responsive parkinsonism.

Area of Science:

• Genetics
• Neurology
• Mitochondrial Biology

Background:

• Mutations in the POLG1 gene, encoding the catalytic subunit of mitochondrial DNA polymerase, are associated with various neurodegenerative disorders.
• Parkinsonian features have been reported in POLG1 mutation carriers, but clinical heterogeneity and treatment responses remain poorly understood.

Observation:

• This study describes three unrelated patients with neurodegenerative parkinsonism, preceded by progressive external ophthalmoplegia (PEO) and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndromes.
• All patients harbored POLG1 mutations, including two novel mutations, and exhibited reduced striatal dopamine uptake.

Findings:

• A sustained positive response to levodopa treatment was observed in the parkinsonian syndrome over 3 and 8 years of follow-up.
• The genotypic and phenotypic spectrum of POLG1-related parkinsonism was reviewed, highlighting the variability in clinical presentation.

Implications:

• These findings suggest that POLG1 mutations can cause a treatable form of parkinsonism with a sustained response to dopaminergic therapy.
• The study contributes to the ongoing debate on the role of mitochondrial DNA defects in the pathogenesis of neurodegenerative parkinsonism, emphasizing the importance of considering genetic testing in such cases.