Functional assessment of patients with mitochondrial myopathy caused by POLG and mtDNA deletions

Abstract

Background: Chronic Progressive External Ophthalmoplegia (CPEO) is a hallmark clinical manifestation of mitochondrial diseases, characterized by progressive weakness of the extraocular muscles and ptosis. Its genetic etiology is heterogeneous, commonly arising from either primary large-scale single mitochondrial DNA (mtDNA) deletions or nuclear DNA mutations (e.g., POLG) that lead to secondary multiple mtDNA deletions. Understanding the functional differences among phenptypes is crucial for tailoring clinical management, predicting disease progression, and establishing precise prognostic markers for patients with POLG-related versus single-deletion CPEO. Objective: To evaluate and analyze motor function scale (MFM) scores, respiratory function tests, performance measures, and timed functional tests in a sample of 14 patients with POLG- or MT‑single large deletion–related mitochondrial myopathy, in order to identify clinical characteristics and patterns of impairment. Methods: This was a observacional cross-sectional study including baseline assessment data from 14 patients with CPEO (4 POLG and 10 MT-del), evaluated from January 2024 to January 2026. Outcomes assessed: Motor Function Measure (MFM), forced vital capacity (FVC) and peak cough flow (PCF) sitting/supine, 6‑minute walk test (6MWT), five‑times sit‑to‑stand test (5XSTS), Timed Up and Go (TUG), time to ascend/descend four steps, and time to rise from the floor. Results: Total MFM scores were similar between groups (MT-del 90.8; POLG 90.3), however MT-del patients showed higher item variability while POLG patients demonstrated more homogeneous motor performance. The decline in FVC from sitting to supine was smaller in MT-del (81.3%→79.3%) and greater in POLG (76.5%→73.5%), indicating stronger positional respiratory impact in POLG. PCF values were higher in POLG (382.5 L/min) than MT-del (293 L/min), suggesting better cough effectiveness despite lower FVC. MT-del patients walked farther in the 6MWT (490.3 m vs. 439.2 m). The difference between the first and last laps was minimal (1.5 s vs. 1.1 s), indicating no significant fatigability. In most timed tests, MT-del patients had shorter mean times, except for rising from the floor. Conclusion: Although overall motor function (MFM) was similar, distinct functional profiles emerged. POLG patients exhibited more uniform motor involvement, greater positional respiratory decline and higher PCF suggests preserved expiratory effectiveness, while MT-del patients showed exhibited superior functional performance in most timed tasks and longer 6MWT distances, without evidence of significant fatigability. These findings support the importance of multimodal functional assessment and suggest genotype-specific patterns that may inform clinical monitoring and prognosis. Larger longitudinal studies are needed to expand these observations.