Less invasive approach to diagnosing mitochondrial disease 

Researchers have published one of the largest studies to date evaluating advanced laboratory testing for mitochondrial disease, providing new evidence that a small skin biopsy can often help diagnose these rare and complex conditions without the need for more invasive procedures.

The study, recently accepted for publication in EMBO Molecular Medicine, evaluated the clinical utility of a comprehensive set of functional diagnostic tests used to identify primary mitochondrial diseases, a group of genetic disorders that impair the body's ability to produce energy. Mitochondrial diseases affect approximately 1 in 5,000 people and can impact multiple organs throughout the body.

"Diagnosing mitochondrial disease can be incredibly challenging for patients, families and clinicians," said one of the corresponding authors. "While advances in genetic testing have transformed our ability to identify many of these conditions, a significant number of patients still do not receive clear answers. This study shows that functional testing can play a critical role in closing that gap."

Genetic testing, including whole genome sequencing, is often the first step in evaluating patients with suspected mitochondrial disease. However, many patients receive inconclusive results because genetic testing identifies variants whose significance is uncertain. In addition, current genetic testing methods identify a definitive genetic cause in only about 50% to 65% of cases.

To help address this challenge, researchers evaluated a broad range of functional tests that measure how well mitochondria perform inside cells. The study assessed how effectively these tests identify mitochondrial disease and distinguish affected patients from those without the condition.

The research included samples from more than 30 medical centers across North America, Europe and Australia/New Zealand, making it one of the most comprehensive evaluations of mitochondrial functional testing conducted to date.

Among the study's most significant findings, researchers demonstrated that cells grown from a small skin biopsy, known as fibroblasts, can often provide the information needed for diagnosis.

The researchers evaluated respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses.

Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%.

Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging.

The findings suggest that more invasive diagnostic procedures, such as muscle or liver biopsies, may not be necessary in many cases.

"For patients and families, reducing the need for invasive procedures is a meaningful advance," said the author. "Being able to obtain critical diagnostic information from a simple skin biopsy has the potential to make the diagnostic process more accessible and less burdensome."

The study builds upon years of research and clinical translation. Nearly all of the functional tests examined in the publication are now available through the Mitochondrial Diagnostic Laboratory within the Department of Pathology and Laboratory Medicine at Children's Colorado.

The publication also represents the first comprehensive evaluation of the clinical performance of these tests, including how often they successfully contribute to a diagnosis and how accurately they identify mitochondrial disease.

https://link.springer.com/article/10.1038/s44321-026-00497-3

https://sciencemission.com/functional-testing-in-fibroblasts