Tolomeo Deborah, Orsucci Daniele, Nesti Claudia, Baldacci Jacopo, Battini Roberta, Bruno Claudio, Bruno Giorgia, Cassandrini Denise, Doccini Stefano, Donati M Alice, Ferrari Annarita, Fiori Simona, Fiorillo Chiara, Guerrini Renzo, Mari Francesco, Montomoli Martino, Pochiero Francesca, Procopio Elena, Ruggiero Lucia, Sampaolo Simone, Sicca Federico, Ticci Chiara, Rubegni Anna, Santorelli Filippo M
Department of Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy.
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy.
J Clin Med. 2021 Jul 22;10(15):3222. doi: 10.3390/jcm10153222.
Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new "genotype first" approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.
线粒体疾病（MDs）是一大类由基因决定的多系统疾病，其特征为显著的表型异质性，部分归因于线粒体蛋白质组的双重基因组控制（核DNA和线粒体DNA）。在过去二十年中，新一代测序技术的进展给临床医生带来了一项挑战：即在大量提供的数据中筛选出可能致病的变异。不幸的是，现有的支持基因解读的临床工具仍缺乏特异性和敏感性。因此，MDs的诊断仍然困难，新的“基因型优先”方法仍无法诊断出很大一部分患者。为了研究临床和/或生化表型与明确的分子诊断之间可能存在的关系，我们对111例临床怀疑患有MD的儿科患者进行了一项回顾性多中心研究。在这个队列中，MD分子诊断（特别是与线粒体DNA相关的诊断）的最强预测因素是基底神经节（BG）受累的神经影像学证据。回归分析证实，BG影像学正常预示着MD的基因研究结果为阴性。精神运动发育倒退被确认为MD明确诊断的独立预测因素。本研究结果证实了先前的数据，支持神经影像学在MD诊断方法中的作用，并强化了至少在特定儿童群体中应将线粒体DNA测序作为一线检测手段的观点。
