Bridging gaps in mitochondrial disease diagnosis : the role of advanced biomarker discovery

Abstract

Mitochondrial disease (MD) is associated with dysfunction of the oxidative phosphorylation (OXPHOS) system and represents one of the most frequently occurring inherited neuromuscular diseases. Like many rare diseases, MD is characterised by striking clinical heterogeneity, resulting from its unique bi-genomic aetiology and multi-system involvement of energy-dependent tissues. Despite four decades of genetic discoveries and the advent of omics-driven insights into genes, mutations, and phenotypes, achieving an early and accurate diagnosis remains challenging—even within advanced diagnostic settings. A reliable genetic diagnosis for MD requires specialised clinical expertise capable of recognising population-specific phenotypes, providing access to genomic diagnostic services, and interpreting local genotype–phenotype correlations. However, these resources remain unevenly distributed, limiting diagnostic yield and equity. Research output and diagnostic infrastructure for MD are disproportionately concentrated in high-income countries. This imbalance persists even though ~ 84% of the global population resides in low- and middle-income countries (LMICs), where access to MD diagnostics, research infrastructure, and specialised care remains limited. Recent World Health Organisation (WHO) and International Classification of Diseases (ICD-11) initiatives have acknowledged these disparities, emphasising the need for improved diagnostic access, laboratory capacity, and data-sharing mechanisms [4,5,6,7]. Nevertheless, the diagnostic capacity divide remains substantial. A major contributor to the diagnostic gap in MD is the absence of reliable biomarkers that enable early detection, disease monitoring, and assessment of therapeutic efficacy. The lack of validated biomarkers restricts both diagnostic precision and therapeutic development.