Disease relevance of MELAS

• A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies [1].
• The mutation was present in 26 out of 31 independent MELAS patients and 1 out of 29 CPEO patients, but absent in the 5 MERRF and 50 controls tested [1].
• Mitochondrial encephalomyopathies are usually divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibres (MERRF); and (3) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome [1].
• The molecular lesions in two patients exhibiting classical clinical manifestations of MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) syndrome have been investigated [2].
• METHODS AND RESULTS: We studied mitochondrial mutations and cardiac changes in 17 patients with Kearns-Sayre syndrome; ocular myopathy; myoclonus epilepsy with ragged red fibers (MERRF); and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) [3].

Psychiatry related information on MELAS

• HMPAO-SPECT imaging resembling Alzheimer-type dementia in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [4].
• The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is an uncommon neuromuscular disorder caused by mitochondrial dysfunctions that result in headaches, seizures, and progressive dementia [5].
• Therapeutic effect of sodium dichloroacetate on visual and auditory hallucinations in a patient with MELAS [6].
• Aggressive confusional state as a clinical manifestation of status epilepticus in MELAS [7].
• Because patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) sometimes show organic mental disorder, 'atypical psychosis' may be caused by mutations of mitochondrial DNA (mtDNA) in some patients [8].

High impact information on MELAS

• Individuals with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) carry a common A-to-G substitution in a highly conserved portion of the gene for transfer RNA(Leu(UUR)) [9].
• Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies [9].
• Although the MELAS mutation may be comparable to the defect in the tRNA(Lys) gene associated with MERRF (myoclonus epilepsy associated with ragged-red fibres), it is also embedded in the middle of a tridecamer sequence necessary for the formation of the 3' ends of 16S ribosomal RNA in vitro [9].
• This suggests that the molecular defect in MELAS is the inability to produce the correct type and quantity of rRNA relative to other mitochondrial gene products [9].
• The presence of carcinogenic and mutagenic chemical(s) in the effluent of a wastewater treatment plant was indicated by papillomas developing on caged black bullheads (Ictalurus melas), hepatic enzyme induction in exposed fish, and Ames test mutagenicity of organic extracts of the wastewater [10].

Chemical compound and disease context of MELAS

• Combined alteration of the pyruvate dehydrogenase complex and respiratory chain function is described in a 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome [11].
• Intramuscular blood vessels were examined with succinate dehydrogenase stain in skeletal muscle biopsy specimens from 6 patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) [12].
• We present the clinical and laboratory effects of dichloroacetate (DCA) in three children with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) who had not responded to other medications [13].
• In order to obtain some insight into the cellular mechanisms of neurodegeneration, we examined cultured fibroblasts from patients with the MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome, which is most frequently caused by a mutation in the mitochondrial tRNA for leucine [14].
• CONCLUSIONS: We observed generalized cerebral hyperemia and fluctuating CO2 reactivity in MELAS, possibly a consequence of local lactic acid production [15].

Biological context of MELAS

• Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells) [16].
• Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a maternally inherited disorder, is usually associated with a point mutation in mitochondrial DNA (mtDNA) at position 3,243 in the tRNA Leu(UUR) gene [17].
• We report on 4 male patients with clinical, radiological, and muscle biopsy findings typical of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype [18].
• Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations [19]?
• The expression of nuclear and mitochondrial oxidative phosphorylation (OXPHOS) genes was examined in the skeletal muscle of patients with Kearns-Sayre syndrome (KSS), myoclonic epilepsy associated with ragged red fibers (MERRF), and myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and compared with controls [20].

Anatomical context of MELAS

• We investigated whole blood cell DNA of 14 patients with MELAS-related mitochondriopathy and two patients with the LHON-associated G11778A mutation of the mitochondrial genome [21].
• An increase of the number of mitochondria was noted in smooth muscle and endothelial cells of epineurial arterioles in three cases of mitochondrial encephalomyopathy (two cases with Kearns Sayre syndrome, and one with mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes, i.e., "MELAS") [22].
• In myoblasts from the patients with MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and KSS (Kearns-Sayre) syndromes, both methodologies revealed an increase of mtDNA transcript levels [23].
• RESULTS: All patients with MELAS showed focal hypoperfusion in the parietal and/or occipital lobes [24].
• We report a novel G13513A mutation in the mitochondrial ND5 gene in a patient who had morphologically and biochemically abnormal muscle mitochondria and died at age 45 with a diagnosis of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) [25].

Associations of MELAS with chemical compounds

• Yet another pattern of regional metabolic abnormality was present in the MELAS syndrome, where proton spectroscopic imaging demonstrated focal localization of abnormally increased lactate/creatine and decreased N-acetylaspartate/creatine to the regions of the stroke-like lesions on conventional MR images [26].
• Cerebral perfusion reserve was obtained from 6 patients (3 MELAS, 1 MERRF, 1 KSS, 1 CCOD) for a comparative analysis using the split-dose 123I-IMP SPECT method before and after the injection of acetazolamide [24].
• Treatment of MELAS, LHON, and MERRF cells with cyclosporin A caused significant rescue from oxidant exposure, and in each case significantly greater rescue of mutant than control cells [27].
• Pyruvate dehydrogenase complex deficiency and altered respiratory chain function in a patient with Kearns-Sayre/MELAS overlap syndrome and A3243G mtDNA mutation [11].
• The patients with this mutation did not have cerebro-muscular symptoms as were observed in MELAS [28].

Physical interactions of MELAS

• A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients [29].
• We report a novel point mutation in the gene for the mitochondrially encoded ND6 subunit of the NADH:ubiquinone oxidoreductase (complex I of the respiratory chain) in a patient with MELAS syndrome [30].
• The MELAS mutation occurs within the mtDNA binding site for a protein factor (mTERF) that promotes termination of transcription at the 16S rRNA/tRNA(LeuUUR) gene boundary [31].

Other interactions of MELAS

• A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I [2].
• A novel combination of mitochondrial tRNA and ND1 gene mutations in a syndrome with MELAS, cardiomyopathy, and diabetes mellitus [32].
• No association of ALDH2 genotype in MELAS [33].
• An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome [30].
• We believe that MELAS represents a distinctive syndrome and that it can be differentiated from two other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns-Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome [34].

Analytical, diagnostic and therapeutic context of MELAS

• The decreased cerebral perfusion reserve in patients with MELAS may represent an important feature of the pathogenesis of the strokelike episodes [24].
• In spite of the small number of cases in each group, in Alpers, MERRF and MELAS syndromes we found sequential EEG patterns which seemed to be typical of the respective syndromes [35].
• We here report Southern blot analyses in the cases of CPEO we have seen and describe the search for point mutations in MELAS and MERRF [36].
• CONCLUSION: These data suggest that a prenatal diagnosis for MELAS syndrome might be helpful for at-risk families [37].
• Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study [38].

References