Combining several laboratory tests on skin cells can identify mitochondrial dysfunction with 76 percent sensitivity and 93 percent specificity, potentially improving diagnosis for patients whose genetic sequencing results are inconclusive.
The findings, published in EMBO Molecular Medicine, support the use of functional testing alongside genomic sequencing to investigate suspected primary mitochondrial disease.
Mitochondria produce much of the energy required for cells to function. Inherited defects affecting this process can cause disorders involving multiple organs, including the brain, muscles, heart, and liver. Their varied symptoms and genetic causes make diagnosis challenging.
Genomic sequencing is the recommended first-line investigation, but it leads to a diagnosis in only 50 to 65 percent of cases. Some patients have genetic variants whose clinical significance remains uncertain, while others receive no clear genetic findings.
To assess whether functional testing could address these gaps, researchers evaluated skin fibroblast cell lines from 204 patients with genetically confirmed mitochondrial disease, 51 healthy controls, and 53 patients with other diagnoses. Skin fibroblasts can be obtained through a minimally invasive biopsy, potentially reducing reliance on muscle or liver tissue sampling.
The testing combined measurements of enzyme activity with methods assessing the performance of mitochondria inside cells. Targeted protein measurements provided additional information where appropriate.
Individually, the three principal assays had sensitivities ranging from 40 to 49 percent. Combining their findings substantially improved detection while maintaining high specificity.
Performance varied across disease categories. The combined approach was particularly effective for disorders affecting individual respiratory chain complexes, mitochondrial protein production, and essential metabolic cofactors.
However, sensitivity was considerably lower for some disorders involving mitochondrial DNA, particularly those affecting its maintenance. A normal fibroblast result therefore cannot exclude mitochondrial disease.
The findings support a staged diagnostic approach in which genomic sequencing remains the first investigation, followed by functional testing when results are uncertain or inconclusive. The study also demonstrates the importance of selecting complementary assays rather than relying on enzyme measurements alone.
Although the study assessed samples from patients with established diagnoses, rather than prospectively testing an undiagnosed population, it provides evidence that comprehensive fibroblast analysis can strengthen the interpretation of genetic findings and help direct further molecular investigations.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
