Clinical Report: Mitochondrial Diagnoses From Skin Tests

Overview

A study of skin fibroblasts from 204 patients with genetically confirmed mitochondrial disease and 104 controls found that combining functional assays detected disease with 76% sensitivity and 93% specificity. The findings support using complementary fibroblast tests alongside genomic sequencing when genetic results are uncertain or inconclusive, while a normal result does not exclude mitochondrial disease.

Background

Primary mitochondrial diseases arise from inherited defects in cellular energy production and can affect multiple organs, including the brain, muscles, heart, and liver. Their varied clinical presentations and genetic causes make diagnosis challenging. Genomic sequencing is the recommended first-line investigation, but the supplied article reports a diagnosis in only 50% to 65% of cases, with some results remaining uncertain or inconclusive. Functional testing of skin fibroblasts offers a way to assess mitochondrial performance in cells obtained through a minimally invasive biopsy.

Data Highlights

Key Findings

• The study evaluated skin fibroblast cell lines from 204 patients with genetically confirmed mitochondrial disease, 51 healthy controls, and 53 patients with other diagnoses.
• Combining enzyme activity measurements with tests of mitochondrial performance inside cells achieved 76% sensitivity and 93% specificity.
• The three principal assays had individual sensitivities of 40% to 49%, indicating higher detection when findings were combined.
• Performance was particularly effective for disorders affecting individual respiratory chain complexes, mitochondrial protein production, and essential metabolic cofactors.
• Sensitivity was considerably lower for some mitochondrial DNA disorders, particularly those affecting mitochondrial DNA maintenance; a normal fibroblast result therefore cannot exclude mitochondrial disease.
• The study assessed samples from patients with established diagnoses, not a prospectively tested undiagnosed population.

Clinical Implications

The article supports genomic sequencing as the first investigation for suspected primary mitochondrial disease, with complementary fibroblast functional testing when sequencing is uncertain or inconclusive. Results should be interpreted in light of disease-specific differences in assay sensitivity; a normal fibroblast result does not rule out mitochondrial disease.

Conclusion

Combined functional testing of skin fibroblasts showed higher sensitivity than the individual principal assays while retaining high specificity in the studied samples. The findings support its use as a complement to genomic investigation, with limitations for some mitochondrial DNA disorders and for extrapolation to undiagnosed populations.

Related Resources & Content

1. Authors not specified, EMBO Molecular Medicine, 2026 — Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease
2. Mavraki et al., European Journal of Human Genetics, 2023 — Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines
3. new retinal physician — Syndromic Pattern Dystrophy due to a Mitochondrial DNA Variant
4. the pathologist — What Can Skin Reveal About Dementia?
5. ASCO Publications — Mitochondrial therapy can inhibit melanoma development.
6. ASCO Publications — Mitochondrial therapy can inhibit melanoma development.
7. Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease
8. Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines
9. Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines
10. Diagnostic Criteria and Management of MELAS and Stroke‐Like Episodes: Consensus‐Based Statements - Mancuso - 2026 - European Journal of Neurology - Wiley Online Library