Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement

Abstract

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients.

Epilepsy in adults with mitochondrial disease: A cohort study

“…The m.8344A>G mutation shows a largely homogeneous distribution within the body,28 including in neuronal tissues, and it may be for this reason that the commonest seizure type is generalized. In contrast, the m.3243A>G mutation shows large differences in mutation load between and within tissues,29 with a particularly high mutation load in cerebral vascular smooth muscle cells 30. Energy failure is one plausible mechanism whereby neuronal dysfunction develops in mitochondrial disease,31 and it may be that localized perfusion deficits predispose to focal seizures.…”

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNAGlu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

“…Sequential COX/SDH histochemistry was performed on frozen tissue sections as previously described (12). Sections were mounted on glass slides for quantitation of percentage COX-deficiency.…”

“…The findings reveal diverse changes according to the mt-tRNA defect and variability within patient populations harboring the same mutated mt-tRNA. In patients with m.3243A9G, there typically are multiple ischemic-like lesions in posterior cerebral regions, including the occipital, temporal, and parietal cortices, and the cerebellum and abnormalities of the cerebral vasculature (12,13). Patients with the m.8344A9G mutation associated with myoclonic epilepsy ragged red fibers (MERRF) show severe degenerative CNS changes with neuronal cell loss and astrogliosis in the cerebellum, inferior olives, red nucleus, and substantia nigra (14,15).…”

Strokes in mitochondrial diseases

“…При исследовании серого вещества в зонах «инфарктов» установлено, что повреждение происхо-дит скорее на клеточном уровне, нежели на сосудистом [49], но выявляются и сосудистые поражения [50].…”