Genotype-Phenotype Correlation in Progressive External Ophthalmoplegia: Insights From a Retrospective Analysis.

Background: Progressive external ophthalmoplegia (PEO) is a classic manifestation of mitochondrial disease. However, the link between its genetic characteristics and clinical presentations remains poorly investigated.

Methods: We analysed the clinical, pathological and genetic characteristics of a large cohort of patients with PEO, based on the type of their mtDNA variations. Eighty-two PEO patients were enrolled and grouped into three categories: mtDNA single large-scale deletions (SLDs), multiple deletions (MulDs) and the m.3243A > G point variant. Patients in the SLD category were further divided into 'common deletion' and 'noncommon deletion' groups based on the presence or absence of a 4977-bp deletion. The mutational load of deleted mtDNA of these patients was comprehensively detected by real-time polymerase chain reaction (RT-PCR).

Results: SLD Patients showed the highest proportion of cytochrome C oxidase-negative (COX-n) fibres on muscle biopsy. The mutational load of deleted mtDNA exhibited an inverse relationship with deletion length and a direct relationship with the COX-n fibre ratio. Compared with patients having noncommon deletions, those with common deletions tend to have other muscle involvement, lower body mass index (BMI) scores (17 ± 3 vs. 22 ± 4 kg/m), higher mutational load in muscle (63% ± 22% vs. 46% ± 24%), more COX-n fibres (26% vs. 9%, interquartile range [IQR]: 15%-32% vs. 6%-26%) and higher growth and differentiation factor 15 (GDF15) levels (2583 vs. 1472, IQR: 1746-4081 vs. 924-2155 pg/mL). MulDs patients displayed milder symptoms, especially compared to patients with m.3243A > G variant, as indicated by their later age of onset (31 vs. 13, IQR: 27-49 vs. 6-29 years), higher BMI scores (24.0 ± 4 vs. 16.5 ± 3.4 kg/m), lower lactate (1.6 ± 1.1 vs. 6.3 ± 6.0 mmol/L) levels and lower proportion of ragged-blue fibres (RBFs) (3 vs. 16, IQR: 1%-9% vs. 7%-27%).

Conclusion: The m.3243A > G variant group exhibits more severe symptoms compared to other subgroups, particularly MulDs patients. In the SLD group, those with common deletions experience more severe clinical and pathological manifestations. These findings enhance our understanding of PEO, facilitating its diagnosis, prognosis and genetic counselling.