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Researchers evaluated multiple functional tests in fibroblasts from 204 patients with primary mitochondrial disease to determine their diagnostic accuracy. The combined battery of tests (respiratory chain enzyme assays, BN-PAGE, complex I assembly assay, and protein abundance measurements) achieved 76% sensitivity and 93% specificity, with 96% positive predictive value. Different test types showed varying effectiveness across disease subtypes, with isolated complex deficiencies and protein synthesis defects showing high sensitivity, while mitochondrial DNA mutations were poorly detected.
Why it matters
This study provides evidence-based guidance for clinicians ordering functional tests to diagnose mitochondrial disorders when genetic testing is inconclusive or reveals variants of uncertain significance. The comprehensive analysis of 204 patients establishes benchmarks for test performance and identifies which disease categories are most reliably detected through fibroblast testing.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.
Source: The clinical utility of functional testing in fibroblasts to diagnose primary mitochondrial disease