Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 19-year-old woman with long-standing sensorineural deafness, bilateral cataracts and mild clumsiness, presented with acute focal edema in the left temperoparieto-occipital area which required surgical decompression as a life-saving measure. Investigation revealed a persistent lactic acidemia and evidence of many ragged red fibres in a skeletal muscle biopsy specimen, suggesting a diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. The patient developed two further stroke-like episodes over a short period. One sibling died at the age of 14 years with a progressive neurological illness characterised by seizures, bilateral optic atrophy, ataxia, myoclonus and progressive dementia. The diagnosis of MELAS syndrome should be considered in young people presenting with stroke-like episodes that fail to conform to a given vascular territory, particularly if they have long-standing minor neurological abnormalities or a family history of obscure early onset neurological disease. The different clinical pictures in the two affected siblings in this family suggest that MELAS syndrome is part of a spectrum of inherited mitochondrial cytopathies rather than a discrete disease entity.
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PMID:Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): adolescent onset with severe cerebral edema. 339 2

Patients with several inherited human encephalomyopathies exhibit systemic and neurological symptoms in association with specific mitochondrial mutations. The mechanisms by which these mitochondrial mutations result in cellular injury have not been elucidated. One potential cause of neuronal vulnerability is an inability to effectively buffer intracellular calcium. We report that fibroblasts from patients with one specific inherited encephalomyopathy, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome, have elevated levels of ionized calcium and cannot normally sequester calcium influxes. Quantitative fluorescence imaging demonstrated that this abnormality was associated with a relative decrease in mitochondrial membrane potential compared to control fibroblasts. This documentation of pathological calcium homeostasis in a genetic neurological disease extends the calcium hypothesis of toxic cell injury to human mitochondrial encephalomyopathies.
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PMID:Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. 784 43

Though mitochondria have been a major source of energy production in eukaryotae since 15-20 billion years previously, existence of disorders due to primary abnormalities of their DNA has not been known until very recent years. In 1962, Luft et al reported the first case of such myopathy, and another case reported in 1967 by Shy et al was also the first case of generalized disorder with mitochondrial abnormalities. Since then, many case reports have followed including MELAS and other encephalomyopathies. Finally, in 1989, deletion of mitochondria DNA was found by Folt et al. Today, these disorders were able to be classified as follows: 1) LHON and A1555G type deafness as strictly limited non-syndromic type, 2) encephalomyopathies and their incomplete forms due to common and other deletions of mitochondria DNA, 3) encephalomyopathies and their incomplete forms including MIDD, diabetes mellituis, cardiomyopathy, deafness due to point mutations of mitochondria DNA related MELAS and others, 4) Neurodegenerative types including Parkinson's disease, Alzheimer's disease, cerebellar degeneration, and amyotrophic lateral sclerosis, or neurologic disorders mimic to such diseases, 5) Mitochondrial involvement not due to primary abnormalities of mitochondria DNA. Possible mechanisms were discussed, but sufficient knowledge is lacking so far to clarify pathophysiology of these disorders and the role of deleterious DNA in aging. Possible effective therapeutic strategies were also discussed, but further development of research works on these disorders in the 21st century are needed to answer these questions.
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PMID:[Current and future aspects of mitochondrial diseases]. 1079 Oct 75

Migraine headache is a heterogenous group of neurologic disorders with high prevalence in the general population and strong familial aggregation. Epidemiologic evidence for frequent maternal transmission has long suggested a role for an altered mitochondrial genetic background. This is supported by the observation of impaired energy metabolism and mitochondrial function in migraine patients as well as by the frequent association of migraine headache in MELAS. In the literature, some patients having migraine headache are reported to have mitochondrial DNA abnormalities, however, systematic screening studies have failed to demonstrate the clear relationship between migraine headache and mitochondrial DNA abnormalities. Migraine may be associated with mutations of nuclear genes which encode respiratory chain enzymes.
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PMID:[Migraine headache and mitochondrial DNA abnormality]. 1621 81

Mutations in gene products expressed in the mitochondrion cause a nuclear transcriptional response that leads to neurological disease. To examine the extent to which the transcriptional profile was shared among 5 mitochondrial diseases (LHON, FRDA, MELAS, KSS, and NARP), we microarrayed mutant and control groups in N-tera2, SH-SY5Y, lymphoblasts, fibroblasts, myoblasts, muscle, and osteosarcoma cybrids. Many more transcripts were observed to be significantly altered and shared among these 5 mitochondrial diseases and cell types than expected on the basis of random chance, and these genes are significantly clustered with respect to biochemical pathways. Mitochondrial disease activated multiple transcripts of the unfolded protein response (UPR), and of the cell cycle pathway, and low doses of the mitochondrial inhibitor rotenone induced UPR transcripts in the absence of cell death. By contrast, functional clusters inhibited by mitochondrial disease included: vesicular secretion, protein synthesis, and oligodendrogenesis. As it is known that UPR activation specifically inhibits vesicular secretion and protein synthesis, these data support the view that mitochondrial disease and dysfunction triggers the UPR, which in turn causes secretory defects which inhibit cellular migratory, synaptic, and oligodendrocytic functions, providing a testable hypothesis for how mitochondrial dysfunction causes disease. Since ischemic hypoxia, chemical hypoxia, and mitochondrial genetic disease (which could be considered 'genetic hypoxia') produce an overlapping induction of UPR and cell cycle genes which appears to have negative consequences, the modulation of these responses might be of benefit to patients with mitochondrial disease.
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PMID:Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts. 1681 2

Though inherited mitochondrial disorders (MIDs) are most well known for their syndromic forms, for which widely known acronyms (MELAS, MERRF, NARP, LHON etc.) have been coined, the vast majority of inherited MIDs presents in a non-syndromic form. Since MIDs are most frequently multisystem disorders already at onset or during the disease course, a MID should be suspected if there is a combination of neurological and non-neurological abnormalities. Neurological abnormalities occurring as a part of a MID include stroke-like episodes, epilepsy, migraine-like headache, movement disorders, cerebellar ataxia, visual impairment, encephalopathy, cognitive impairment, dementia, psychosis, hypopituitarism, aneurysms, or peripheral nervous system disease, such as myopathy, neuropathy, or neuronopathy. Non-neurological manifestations concern the ears, the endocrine organs, the heart, the gastrointestinal tract, the kidneys, the bone marrow, and the skin. Whenever there is an unexplained combination of neurological and non-neurological disease in a patient or kindred, a MID should be suspected and appropriate diagnostic measures initiated. Genetic testing should be guided by the phenotype, the biopsy findings, and the biochemical results.
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PMID:Inherited mitochondrial disorders. 2239 23

Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.
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PMID:Transfer RNA and human disease. 2491 79