Primary mitochondrial disorders and mimics: Insights from a large French cohort.
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Rouzier Cécile, Pion Emmanuelle, Chaussenot Annabelle, Bris Céline, Ait-El-Mkadem Saadi Samira, Desquiret-Dumas Valérie, Gueguen Naïg, Fragaki Konstantina, Amati-Bonneau Patrizia, Barcia Giulia, Gaignard Pauline, Steffann Julie, Pennisi Alessandra, Bonnefont Jean-Paul, Lebigot Elise, Bannwarth Sylvie, Francou Bruno, Rucheton Benoit, Sternberg Damien, Martin-Negrier Marie-Laure, Trimouille Aurélien, Hardy Gaëlle, Allouche Stéphane, Acquaviva-Bourdain Cécile, Pagan Cécile, Lebre Anne-Sophie, Reynier Pascal, Cossee Mireille, Attarian Shahram, Paquis-Flucklinger Véronique, MitoDiag's Network Collaborators, Procaccio Vincent
Аннотация
METHODS: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes.
RESULTS: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases.
INTERPRETATION: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.