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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is a clinically devastating disease of children and young adults. The cause of the stroke-like episodes is not known. We have sequenced the mitochondrial DNA (mtDNA) in archival paraffin-embedded material from two cases. In only one of these did the mitochondrial tRNA(Leu(UUR) gene contain the nucleotide 3243 A-to-G mutation that is most commonly responsible for MELAS. In this case, we determined the relative proportion of mutant:wild-type mtDNA in sections of the central nervous system and other tissues by PCR amplification, PalI digestion, DNA electrophoresis, and scanning densitometry of the ethidium bromide-stained gels. The technique allowed the proportion of mitochondria that contain the mutant genome to be compared with the histological findings in immediately adjacent sections of tissue. The mutant mtDNA was detectable in most tissues, the percentage of mtDNA ranging from barely detectable levels to 78 per cent. The relative amount of mutant mtDNA correlated poorly with the distribution of histological lesions, both within the central nervous system and in other tissues examined. The proportion was high in tissues such as liver, kidney, adrenal, and pancreas that appeared histologically normal. Relatively low levels were present in some regions of the central nervous system, such as the occipital lobe, which contained many of the characteristic infarct-like lesions. These observations do not support previous speculation that the distribution of these lesions reflects that of the defective mitochondria. The results emphasize the usefulness of the polymerase chain reaction in correlative histogenetic studies.
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PMID:Sequencing and quantitative assessment of mutant and wild-type mitochondrial DNA in paraffin sections from cases of MELAS. 832 63

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

The clinical manifestations of mitochondrial encephalomyopathy are described in four generations of a single kindred. The age of onset of major neurological disturbance varied from 3-70 years. In some patients, deafness was the only manifestation; in others, recurrent bouts of status epilepticus associated with focal neurological deficits and headache, caused severe disability or death. Examples of all three adult forms of mitochondrial encephalomyopathy: MELAS, MERFF and Kearns Sayre syndrome, were represented within the kindred. Associated features included deafness, short stature, non-insulin-dependent diabetes mellitus, migraine, peptic ulceration and severe constipation. The nt 3243 A-G MELAS mutation was detected in two members of the kindred. This study highlights the diversity of clinical expression of a mitochondrial mutation within a single kindred.
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PMID:Mitochondrial encephalomyopathy: variable clinical expression within a single kindred. 835 Jan 9

We studied multiple different postmortem tissue samples from a woman and two of her daughters with the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) tRNA(Leu(UUR)) mutation at nucleotide 3243 in mitochondrial DNA (mtDNA). All tissues examined were heteroplasmic for the mutation. The mean proportion of mutant mtDNAs in the mother's tissues (0.30 +/- 0.10) was significantly lower than that of each of her daughters' (0.76 +/- 0.11, p < 0.03, and 0.72 +/- 0.13, p < 0.001); there was no difference in the fraction of mutant mtDNAs between the daughters (p < 0.71). This difference in the mean proportion of mtDNA mutants between family members correlates with their clinical profiles; the mother had the latest onset of disease and lived longest, while the two daughters had a strikingly similar clinical course. In individual patients, the mean proportion of mutant mtDNAs was not different in tissues deriving from ectodermal, mesodermal, and endodermal germ layers. Variance in the mutant:wild-type mtDNA ratio was normally distributed about the mean, both when all tissues were considered together and when different regions of the CNS were considered separately. Thus, the proportion of mtDNAs carrying the tRNA(Leu(3243)) mutation was not uniform in members of this pedigree and did not undergo rapid mitotic segregation along germ-layer divisions. These findings are consistent with the hypothesis that the overall proportion of mtDNAs carrying this mutation is primarily determined by segregation during oogenesis or early embryologic development and that random replicative (mitotic) segregation, subsequent to the establishment of primary germ layers, is responsible for the variation between tissues.
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PMID:Variable distribution of mutant mitochondrial DNAs (tRNA(Leu[3243])) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation. 835 Oct 17

We describe a 42-year-old woman with overlapping syndrome of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonus epilepsy and ragged-red fibers). Clinically, she had episodic headache, stroke-like episode with left hemiparesis and lactic acidosis commonly found in MELAS syndrome. However, myoclonus seizure, and ataxia with dyssynergic gait characteristic of MERRF were also noted. Computed tomographic scans showed a right temporo-parietal hypodense lesion. The lesion disappeared 20 months later, even magnetic resonance images also failed to reveal this abnormality. A molecular analysis of mitochondrial DNA was conducted by using restriction endonucleases ApaI and NaeI. A transition from A to G was found at the nucleotide position 3243, but not found at the 8344th nucleotide pair. In this report, we document the fluctuating CT changes and emphasize the importance of molecular analysis in patients with overlapping syndrome of mitochondrial encephalomyopathies.
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PMID:Overlapping syndrome of MERRF and MELAS: molecular and neuroradiological studies. 835 81

Recent advances in molecular genetics have led to a better understanding of mitochondrially inherited diseases. Mitochondrial encephalomyopathy overlap syndrome is one such group of diseases in which ocular abnormalities are frequently manifest. The authors describe the clinical, molecular genetic, and pathologic findings of two patients with the mitochondrial encephalomyopathy overlap syndrome. The patients shared a similar clinical course with features overlapping the three traditionally distinct clinical phenotypes (the Kearns-Sayre syndrome; the syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke [MELAS], and the syndrome of myoclonus, epilepsy, and ragged red fibers [MERRF]). The patients had identical mitochondrial DNA mutations (at nucleotide position 3243) and had similar ultrastructural abnormalities, including abundant enlarged mitochondria with "whorled" and "tubular" cristae. These abnormal mitochondria appeared to be preferentially distributed in cells with high metabolic activity (retinal pigment epithelium, corneal endothelium, and extraocular muscles).
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PMID:Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes. 836 69

Single-photon emission computed tomography (SPECT) of the brain has been used to define functional abnormalities in two groups of childhood behavior disorders: (1) a "primary" category in which there is exclusive or predominant presentation with cognitive and/or behavioral dysfunction and (2) encephalopathies, often defined etiologically at the biochemical or molecular level, in which clinical expression includes, but is not confined to, neural dysfunction. Radiopharmaceuticals available for such studies are manifold, but those used to date have been predominantly perfusion agents, eg, Xenon-133 (133Xe) and technetium-99m (99mTc) hexamethylpropylene amine oxime, and studies with [99mTc]bicisate are eagerly awaited. Xenon-133 studies require that the patient be in the field of view of the detector while the tracer is administered. This renders it difficult for a subject to perform cognitive and other exercises while being imaged, because the environment is quite foreign. On the other hand, the 99mTc-labeled perfusion agents permit a scintigraphic "snapshot" of regional cerebral blood flow during a behavioral event without having to have the patient under the imaging instrument. Thus, one can separate the administration of the radiotracer, which can be done under more controlled and physiological conditions, from the actual imaging. In addition, greater spatial resolution is achieved with the technetium-based agents. Currently, multidetector or dedicated annular crystal-type cameras are the preferred brain SPECT devices, and they are essential to applications such as cortical "activation mapping" or tomographic detection of receptor systems. Close attention to technical detail and standardization of the child's behavioral environment during the investigation are critical to a successful study. The relative advantages and disadvantages of qualitative versus semiquantitative analysis of imaging date are reviewed. Among primary behavioral disorders, 133Xe SPECT studies in attention deficit disorder-hyperactivity (ADHD) have suggested a pattern of hypoperfusion of striatal and periventricular structures with sensorimotor cortical hyperperfusion. This pattern is consistent with some neurophysiological models of the disorder. In cerebral palsy, perfusional abnormalities have paralleled clinical deficits and may offer information to help predict outcome. The important field of childhood affective disorders (schizophrenia, juvenile autism, depression, etc) remains largely unstudied with SPECT. Finally, representative examples of the use of SPECT to study perfusion in encephalopathies with behavioral expression (phenylketonuria, MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome, Wilson's disease, etc) are given.
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PMID:Brain single-photon emission computed tomography for behavior disorders in children. 837 98

The pathophysiological significance of the mitochondrial microangiopathy in MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) syndrome was evaluated in an autopsy study of a nearly 13-year-old girl who had suffered from multiple infarctlike lesions in the brain, a mitochondrial myopathy-cardiomyopathy, and a generalized mitochondrial microangiopathy. Cytochemically, defects of cytochrome c oxidase (complex IV) were visualized by light and electron microscopy in the skeletal and heart muscle and in the altered vessels, as well as in single bile duct cells, with the activity of the hepatocytes being diffusely reduced, whereas in the brain, the cytochemical activity was only slightly diminished. Biochemical studies revealed a 50% reduction of both NADH (the reduced from of nicotinamide-adenine dinucleotide) dehydrogenase (complex I) and complex IV in the skeletal muscle. In the brain, complex I was diminished to 20%, whereas complex IV was only slightly below the low-normal range. Immunohistochemical studies with the use of subunit-specific antiserum samples against cytochrome c oxidase showed a varying protein profile, with loss of both mitochondrially and nuclearly derived subunits being most pronounced in the heart muscle and lesser in the skeletal muscle. In the brain, liver, bile ducts, and especially the vessels, no loss of enzyme protein content was observed. The results illustrate heterogeneous tissue expression of respiratory chain defects in MELAS syndrome and indicate that vascular cytochrome c oxidase deficiency may be involved in the cerebral manifestation of the disease, whereas in other organs like the heart, a similar pathogenetic importance of the microangiopathy cannot be verified.
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PMID:Generalized mitochondrial microangiopathy and vascular cytochrome c oxidase deficiency. Occurrence in a case of MELAS syndrome with mitochondrial cardiomyopathy-myopathy and combined complex I/IV deficiency. 838 Dec 71

A family with maternally-transmitted deafness and diabetes mellitus is described. Although the proband clinically exhibited MELAS-like symptoms such as sudden-onset cerebellar ataxia and weakness of the proximal portion of the limbs in addition to deafness and diabetes mellitus, the other three members of the family had only deafness and diabetes mellitus and no neurological manifestations. The analysis of mitochondrial DNA of the two members revealed an A-->G mutation of tRNA(leu(UUR)), a mutation commonly seen in patients with MELAS. According to the clinical histories and endocrinological investigations, the type of the diabetes mellitus in this family was considered to be IDDM, which may be attributed to the dysfunction of mitochondrial of the pancreas islet cells, resulting from the mutation of the mitochondrial DNA.
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PMID:[A family with MELAS whose main manifestations are maternally-transmitted deafness and diabetes mellitus]. 840 88

Recent studies analyzing mtDNA have established to elucidate the molecular pathology of mitochondrial encephalomyopathies. The human mitochondrial genome is 16,569 bp circular double-stranded molecule that is maternally inherited. Since the first report on large deletions of mtDNA in patients with progressive external ophthalmoplegia (PEO) by Holt et al in 1988, various mtDNA mutations were found. On the basis of the recent findings of mtDNA mutations, genetic classification of mitochondrial diseases has been proposed by S DiMauro in 1991. (1) large deletions or duplications of mtDNA were found in PEO and Pearson disease. (2) A single base substitution were reported in several mitochondrial encephalomyopathies as follows: (a) At nucleotide position 11778, 4136 or 4160......Leber's hereditary optic neuritis, (b) 8344......MERRF, (c) 3243 or 3271......MELAS, (d) 8993......Holt's disease.
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PMID:[Mitochondrial encephalomyopathies: pleomorphism of the mitochondrial DNA mutations and clinical features]. 841 14


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