MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study

Abstract

We performed a neuropathological examination of the central nervous system from seven autopsied patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Five of the seven cases were confirmed to have the mitochondrial DNA (mtDNA) 3243 point mutation. In addition to the changes reported previously, diffuse atrophy of the cerebral and cerebellar cortices, diffuse gliosis of cerebral and cerebellar white matter, and cactus formation of Purkinje cells were observed. Electron microscopy revealed accumulation of mitochondria in the cactus formations. These lesions are common in MELAS with the mtDNA 3243 point mutation, but cannot be explained solely by mitochondrial angiopathy, and suggest that intrinsic mitochondrial malfunction contributes to neuronal damage in MELAS pathology. Moreover, the pathological changes observed in the cerebellum suggest that cerebellar function should be evaluated more carefully at the clinical level.

Apparent Diffusion Coefficients of Metabolites in Patients with MELAS Using Diffusion-Weighted MR Spectroscopy

“…41 Compared with healthy controls, the ADC increases in the lesions were 35% for Cho, 55% for Cr, and 38% for NAA as seen in Table 2. Because the old ischemia-like lesions of MELAS are characterized by laminar necrosis and extensive neuronal loss, [42][43][44] some of the metabolites can leak into the extracellular space and the neuronal loss can lead to the expansion of the extracellular space, which augments the ADCs of the metabolites. As discussed above, there also may be disruption of intracellular organelles, which can increase the ADCs of the metabolites.…”

Voxelwise Analysis of Diffusion Tensor Imaging and Structural MR Imaging in Patients with the m.3243A>G Mutation in Mitochondrial DNA

“…The most commonly described neuropathologic features of the MELAS syndrome are multifocal necrotic foci in the cerebral cortex and predominantly subcortical white matter gliosis. 8,9 However, the classic MELAS syndrome is relatively rare, and most patients with m.3243AϾG mutation present with other symptoms of mitochondrial disease, such as sensorineural hearing impairment, diabetes mellitus, myopathy, or cognitive impairment. 10 The large variation in the clinical phenotypes is at least partly due to heteroplasmy of the mutation (ie, the co-occurrence of the 2 alleles within mitochondria, cells, and tissues).…”

A3243G mitochondrial mutation associated with polymicrogyria

“…In MELAS syndrome, the most common pathology reported is basal ganglia calcification (Sue et al 1998), as well as transient infarct-like lesions (Valanne et al 1998). Cerebral and cerebellar atrophy and gliosis, and even Alzheimer-like lesions have also been reported (Kaido et al 1996, Tanahashi et al 2000. Sue and colleagues (1999) described cerebral atrophy and increased T 2 signals, but not cortical malformation/polymicrogyria in patients who presented with developmental delay.…”