Abstract
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.
Highlights
Mitochondrial diseases (MDs) are a large and heterogeneous group of genetically determined multisystem disorders mainly related to the oxidative phosphorylation (OXPHOS) system [1,2]
Our study is the first attempt to define features potentially influencing a definitive diagnosis of MD, and it allows us to highlight a series of aspects of the diagnostic process
We demonstrated that careful imaging assessment is crucial in children with a suspected diagnosis of MD and that basal ganglia (BG)
Summary
Mitochondrial diseases (MDs) are a large and heterogeneous group of genetically determined multisystem disorders mainly related to the oxidative phosphorylation (OXPHOS) system [1,2]. They are caused by the most common inborn errors of metabolism [3]. The significant clinical variability of MDs is related to the extreme genetic heterogeneity of these conditions, linked to mutations in both nuclear (nDNA) and mitochondrial DNA (mtDNA). The unpredictable role of tissue heteroplasmy in cases with defects in the mitochondrial genome, and that of genetic modifiers [10], may further influence the phenotype and the extent of intrafamilial variability
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