Objective:

To assess whether combined functional tests on skin fibroblasts can help identify mitochondrial dysfunction, particularly when genomic sequencing is inconclusive.

Approach:

• Study samples: Researchers tested fibroblast cell lines from 204 patients with genetically confirmed mitochondrial disease, 51 healthy controls, and 53 patients with other diagnoses.
• Testing: The approach combined enzyme activity assays and tests of mitochondrial performance inside cells, with targeted protein measurements where appropriate.

Key Findings:

• The combined tests had 76% sensitivity and 93% specificity.
• Each of the three principal assays alone had sensitivity of 40% to 49%.
• Performance was strongest for disorders affecting individual respiratory chain complexes, mitochondrial protein production, and essential metabolic cofactors.
• Sensitivity was lower for some mitochondrial DNA disorders, particularly those affecting DNA maintenance.

Interpretation:

The findings support using complementary fibroblast functional tests alongside genomic sequencing when genetic results are uncertain or inconclusive. A normal fibroblast result does not exclude mitochondrial disease.

Limitations:

• The study tested samples from patients with established diagnoses rather than prospectively evaluating an undiagnosed population.
• Test performance varied by disease category.

Conclusion:

Comprehensive fibroblast analysis may strengthen interpretation of genetic findings and help direct further molecular investigations.

Sources:

• Article context; findings published in EMBO Molecular Medicine