MERRF/MELAS overlap syndrome associated with 3243 tRNALeu(UUR) mutation of mitochondrial DNA

We report a case of myoclonus epilepsy associated with ragged-red fibers (MERRF)/mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) overlap syndrome with hearing loss, external ophthalmoplegia, and myoclonus epilepsy in addition to stroke-like episode and diabetes mellitus. Pathologically, there was degeneration in the dentate nuclei, substantia nigra, red nucleus, and subthalamic nucleus which has been reported as characteristic of MERRF, as well as necrotic lesions of various stages in the cerebral cortex, characteristic of MELAS. The gene study disclosed 3243 mutation in the tRNA^Leu(UUR) gene of mitochondrial DNA. This case is the first neuropathological report of MERRF/MELAS overlap syndrome verified by gene analyses.     

Novel heteroplasmic mutation in the anticodon stem of mitochondrial tRNALys associated with dystonia and stroke‐like episodes

Gal A, Pentelenyi K, Remenyi V, Pal Z, Csanyi B, Tomory G, Rasko I, Molnar MJ. Novel heteroplasmic mutation in the anticodon stem of mitochondrial tRNA^Lys associated with dystonia and stroke‐like episodes.
Acta Neurol Scand: 2010: 122: 252–256.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – We report a novel heteroplasmic mitochondrial tRNA^Lys mutation associated with dystonia, stroke‐like episodes, sensorineural hearing loss and epilepsy in a Hungarian family. Material and methods – A 16‐year‐old boy, his brother and mother were investigated. Thorough clinical investigation as well as electrophysiological, neuroradiological and myopathological examinations were performed. Molecular studies included the analysis of the DYT1, DDP1/TIMM8A (deafness‐dystonia peptid‐1) genes and mitochondrial DNA (mtDNA). Results –  The mtDNA analysis of the proband revealed a heteroplasmic A8332G substitution in the anticodon stem of the tRNA^Lys gene. The mutation segregated in all affected family members. Besides this mutation 16 further mtDNA polymorphisms were detected. Complex I activity of the patient’s fibroblast cultures showed decreased activity confirming mitochondrial dysfunction. Conclusion –  The novel A8332G heteroplasmic mutation is most likely a new cause of dystonia and stroke‐like episodes due to mitochondrial encephalopathy. The synergistic effect of the G8697A, A11812G and T10463C single nucleotide polymorphisms may modify the phenotype.     

Increased number of mitochondria in capillaries distributed in stroke‐like lesions of two patients with MELAS

We investigated two autopsy cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) using immunohistochemical staining with an anti‐mitochondrial antibody against translocase of the outer membrane 20 (TOMM20). In case 1, the patient was a 42‐year‐old man with a disease duration of 53 days, and in case 2, the patient was a 62‐year‐old woman with a disease duration of 27 months. In both the cases autopsy revealed moderate atrophy of the cerebrum and cerebellum and multifocal necrotizing lesions, irrespective of the vascular territory. Case 1 showed multiple areas with total necrosis in the cortex, accompanied by increases in number of protoplasmic astrocytes and acidophilic neurons as well as axonal swelling, suggestive of acute or subacute stage stroke‐like lesions (SLLs). In case 2, most of the SLLs displayed laminar spongy change in a rarefied cortex, and were considered to be at the chronic stage. In both the cases, capillary proliferation was noted within the SLLs, particularly in the acute phase. Endothelial cells of proliferating capillaries were strongly positive for TOMM20. In the cortex outside the SLLs, microvessels displayed only a fine granular immunoreactivity, as is seen in the controls. Although smooth muscle cells and endothelial cells in pial arteries and arterioles were also strongly positive for TOMM20, the territories of the affected pial arteries and arterioles did not correlate with the distribution of the SLLs. Although MELAS is characterized by recurrent stroke‐like episodes (SLEs), the pathogenetic relationship between SLEs and mitochondrial angiopathy remains unknown. An aberrant increase of mitochondria in the capillary endothelial cells of SLLs may disturb endothelial function, thus playing a role in the formation or development of SLLs.     

Sporadic MERRF/MELAS overlap syndrome associated with the 3243 tRNALeu(UUR) mutation of mitochondrial DNA

We studied a patient with a mitochondrial encephalomyopathy characterized by the presence of all the cardinal features of both myoclonic epilepsy and ragged-red fibers (MERRF) and mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndromes. Muscle biopsy showed ragged-red fibers (RRF). Some RRF were cytochrome c oxidase (COX)-negative, while some others stained positive for COX. Muscle biochemistry revealed defects of complexes I and IV of the respiratory chain. Both muscle and blood mitochondrial DNA from the patient showed the presence of the mutation at nucleotide position 3243 in the tRNA^Leu(UUR) gene and the absence of point mutations related to MERRF syndrome. The proportions of mutant mtDNA were 70% in muscle and 30% in blood. The mutation was absent in blood from all maternal relatives, in hair follicles from the mother, and in muscle from one sister of the proband. Therefore, there was no evidence of maternal inheritance. © 1996 John Wiley & Sons, Inc.     

Clinicopathological findings of a mitochondrial encephalopathy,lactic acidosis,and stroke‐like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT‐ND1

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke‐like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT‐ND1. A 41‐year‐old woman had experienced multiple stroke‐like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid‐attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase‐reactive blood vessels. L‐arginine therapy improved her consciousness and prevented further stroke‐like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct‐like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L‐arginine treatment.     

Phenotypic patterns of MELAS/LS overlap syndrome associated with m.13513G>A mutation,and neuropathological findings in one autopsy case

The 13513G>A mutation in the ND5 gene of mitochondrial DNA (mtDNA) is usually associated with mitochondrial encephalomyopathy with lactate acidosis and stroke‐like episodes (MELAS), or Leigh syndrome (LS). In this study, we describe three young Chinese patients with MELAS/LS overlap syndrome who carried the m.13513G>A mutation. Clinical and MRI features were characteristic of both MELAS and LS. Interestingly, the clinical presentation of this overlap syndrome could be variable depending on the degree of relative contribution of MELAS and LS, that is, MELAS as the initial presenting syndrome, LS as the predominant syndrome, or both MELAS and LS appearing at the same time. The final brain MRI showed findings characteristic of both MELAS and LS, with asymmetrical lesions in the cortex and subcortical white matter of the occipital, temporal, and frontal lobes (MELAS), and bilateral and symmetrical lesions in the basal ganglia and brainstem (LS). Brain autopsy in one case revealed infarct‐like lesions in the cerebral cortex, basal ganglia and brainstem, providing further insight into the distribution of the pathological lesions in MELAS/LS overlap syndrome. This is the first report of the brain pathological changes in a patient with m.13513G>A mutation. The spatial distribution of infarct‐like lesions in the brain could explain the symptoms in MELAS/LS overlap syndrome.     

Afferent and efferent connections of the dorsolateral precentral gyrus (area 4, hand/arm region) in the macaque monkey, with comparisons to area 8

The afferent and efferent connections of the dorsolateral precentral gyrus, the primary motor cortex for control of the upper extremity, were studied by using the retrograde and anterograde capabilities of the horseradish peroxidase (HRP) technique in three adult macaque monkeys that had received HRP gel implants in this cortical region. Reciprocal corticocortical connections were observed primarily with the supplementary motor area (SMA) in medial premotor area 6 and dorsal bank of the cingulate sulcus, postarcuate area 6 cortex, dorsal cingulate cortex (area 24), superior parietal lobule (area 5, PE/PEa), and inferior parietal lobule (area 7b, PF/PFop, including the secondary somatosensory SII region). In these heavily labeled regions, the associational intrahemispheric afferents originated primarily from small and medium sized pyramidal cells in layer III, but also from layer V. The SMA projections were columnar in organization. Intrahemispheric afferents from contralateral homologous and nonhomologous frontal and cingulate cortices also originated predominantly from layer III, but the connections from contralateral area 4 were almost exclusively from layer III. The bilateral connections with premotor frontal area 6 and cingulate cortices were not observed with parietal regions; i.e., only ipsilateral intrahemispheric parietal corticocortical connections were observed. There were no significant connections with prearcuate area 8 or the granular frontal (prefrontal) cortex. Subcortical afferents originated primarily from the nucleus basalis of Meynert, dorsal claustrum, ventral lateral (VLo and VLc), area X, ventral posterolateral pars oralis (VPLo), central lateral and centromedian thalamic nuclei, lateral hypothalamus, pedunculopontine nucleus, locus ceruleus and subceruleus, and superior central and dorsal raphe nuclei. Lesser numbers of retrogradely labeled neurons were observed in the nucleus of the diagonal band, mediodorsal (MD), paracentral, and central superior lateral thalamic nuclei, nucleus limitans, nucleus annularis, and the mesencephalic and pontine reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)