Author response to the letter regarding the publication titled "Major cerebral vessels involvement in patients with MELAS syndrome: worth a scan? A systematic review"

We appreciate the interest in our systematic review, which revealed that dilatation or stenosis of major vessel caliber is present in 59% (27/46) of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) and underlined the importance of imaging intracranial vessels during prospective study protocols of patients with MELAS. We share the view that pathogenic mechanisms of (SLEs) are not fully understood and a variety of mechanisms has been proposed, including metabolically impaired mitochondrial energy production, as well as micro- and macrovascular angiopathy. A substantial degree of evidence has indicated that patients with MELAS have an inability to efficiently produce mitochondrial energy. In particular, a previous in vitro study of cybrid cell lines composed of cytoplasts from patients with MELAS bearing an A>G transition (nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome) fused with human cells lacking endogenous mitochondrial DNA (mtDNA) demonstrated impaired mitochondrial translation and protein synthesis. Consequently, the inability to efficiently produce mitochondrial energy is a biochemical feature of MELAS syndrome, which may periodically exacerbate during SLEs. Furthermore, microangiopathy of small blood vessels can occur in patients with MELAS that may show abnormal staining of succinate dehydrogenase, a mitochondrial enzyme, as well as mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels. Therefore, blood vessels’ impaired energy metabolism may intrinsically contribute to abnormal perfusion during SLEs. Notably, several studies have indicated increased perfusion in patients with MELAS using computed tomography (CT), magnetic resonance imaging (MRI) perfusion, and single photon emission computed tomography (SPECT) during SLEs. As suggested, we reviewed the possible influence of mtDNA mutations and pharmacological treatment on the vessel caliber alterations. It is well known that in patients harboring mtDNA mutations, both mutant and wild type mtDNA molecules may coexist within the same cell, defining a condition called heteroplasmy, which may vary widely among different tissues. Importantly, the skeletal muscle and blood heteroplasmy levels of the m.3243A>G mutation are correlated with disease severity in patients with MELAS. Interestingly, a recent study of our group identified a common diffuse pattern of brain biochemical alterations detected in vivo by proton magnetic resonance spectroscopy, which correlated with mtDNA heteroplasmy in patients with MELAS. Unfortunately, in the reviewed studies, the percentage of mutated mtDNA was reported in only one third of them (n = 8/23, 35%). Heteroplasmy ranged from 22% to 76%, and was measured in different tissues such as skeletal muscle, fibroblasts, and blood cells.