Clinical Heterogeneity and Candidate Biomarkers in POLG-Related Mitochondrial Disease

Mitochondrial disease, long misunderstood as primarily pediatric, is now recognized as a major adult neurological disorder with a prevalence of 1 in 4,000 — yet it remains underdiagnosed due to clinical heterogeneity and reliance on outdated diagnostic frameworks. In this episode, Cristina Dominguez Gonzalez from Madrid’s 12th of October University Hospital reveals that POLG-related mitochondrial disease, the most common nuclear gene cause, presents with a wide spectrum of phenotypes — from isolated ophthalmoplegia to ataxia-neuropathy syndromes — often mimicking more common conditions like myasthenia or ALS. The key breakthrough lies in rethinking biomarkers: while lactate is unreliable, growth differentiation factor 15 (GDF15) emerges as a highly sensitive and clinically actionable signal of mitochondrial dysfunction, capable of guiding genetic testing and monitoring treatment response. Despite advances, the field remains hampered by a lack of natural history data and validated biomarkers, making clinical trial design nearly impossible — a critical barrier to developing therapies for these rare, complex disorders. The episode challenges neurologists to shift from rigid syndrome-based thinking to a phenotype-driven approach, emphasizing that muscle biopsy still holds diagnostic value, especially in adults with inconclusive genetic results.