Clinical Heterogeneity and Candidate Biomarkers in

Background and Objectives: Methods: We analyzed a cohort of 34 patients with confirmed pathogenic Results: Thirty four patients (0.6-71 years) from 33 families were included. Juvenile/adult onset (12-40 years) was the most common presentation (62%). The predominant phenotypic categories were ataxia-neuropathy spectrum ([ANS], 44%), autosomal recessive PEO-plus (arPEO-plus, 26%), and autosomal dominant PEO-plus ([adPEO-plus], 15%), with frequent phenotypic overlap. Recessive inheritance accounted for 74% of cases, with the most common variants being p.([Thr251Ile; Pro587Leu]) paired on 1 allele, p.(Ala467Thr), and p.(Trp748Ser). Dominant variants were associated with milder, primarily myopathic phenotypes. The most common dominant variant was p.(Tyr955Cys). No clear genotype-phenotype correlations were identified among recessive variants. Compared with previously reported cohorts, our patients exhibited a lower prevalence of seizures, hepatopathy, and stroke-like episodes. GDF15 was elevated in 87.5% of patients, with a mean level of 3,315 pg/mL (±1,559.79), showing no significant differences between myopathic and ANS phenotypes, supporting its role as a general biomarker of mitochondrial dysfunction. NF-L was elevated in 78.6% of tested individuals but did not correlate with phenotype or clinical severity (as per Newcastle Mitochondrial Disease Adult Scale score).On average, muscle mtDNA copy number in patients was 76% of that observed in controls, with no differences by phenotype or inheritance pattern. All but 1 patient exhibited multiple mtDNA deletions, likely representing the primary mechanism of oxidative phosphorylation dysfunction rather than mtDNA depletion. Discussion: