Single Large-Scale Mitochondrial DNA Deletions: Literature Review, Genetic Analysis and Considerations on Central Nervous System Involvement

Background: Single large-scale mitochondrial DNA deletions (SLSMDs) are a significant cause of mitochondrial diseases affecting cell energy production and contributing to a spectrum of clinical symptoms, including neurological manifestations, such as cerebellar ataxia. Two of the main diseases involved are Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome (KSS). The conflicting genotype-phenotype evidence in recent literature highlights the importance of further investigation in this field. Aims: The main objective is to provide a detailed genetic analysis of single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) with a specific focus on the implications of these deletions on the central nervous system (CNS). Methods: After an accurate review of the literature published about SLSMDs, a cohort of 19 patients diagnosed with SLSMDs were retrospectively enrolled and included in the study. For the patients with available samples, we used long-range PCR and mitochondrial DNA sequencing to characterize different genotypic features, after DNA extraction from the provided specimens (blood, urine and muscle tissue). Data about phenotypical manifestations were collected and analyzed along with the genotypic features and then tested statistically for potential correlations. Results: The obtained genetic information included, where available, deletion length, heteroplasmy levels and deletion break points, while the considered clinical outcomes were age at onset, disease severity measured by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score, and CNS involvement. Our analysis revealed several correlations among those data, supporting findings from previous studies. Remarkably, a strong inverse relationship was observed between age at onset and deletion midpoints (deletion central position), suggesting that higher deletion midpoints may correspond to earlier age at onset. Additionally, our findings highlighted the influence of Cytochrome b gene (CYB) gene deletion in CNS involvement. Conclusions: This study emphasizes the role of deletion location in CNS involvement, demonstrating their potential influence on mitochondrial disease outcomes. However, the small sample size limits the generalizability of these findings. Future research with larger datasets and integrated genetic analyses is essential to validate these trends and uncover the mechanisms underlying CNS pathology in SLSMD.