Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria are the principal site of generation of energy in form of adenosine triphosphate (ATP). They contain the enzymes of the Krebs and fatty acid cycles and the respiratory pathway. Ocular tissues with high energy consumption and dependence on oxidative energy production like the optic nerve, the retina, and the pigment epithelium are often involved in mitochondrial diseases. This article reviews the genetic mitochondrial diseases involving the visual system. Their most important ocular findings include: acute or slowly progressive bilateral visual loss and visual field loss due to an optic neuropathy or retinal degeneration, bilateral progressive decreased ocular motility, and bilateral upper lid ptosis. The following diseases are discussed: Leber's Hereditary Optic Neuropathy (LHON); Kearns-Sayre Syndrom (KSS); Chronic Progressive External Ophthalmoplegia (CPEO); Autosomal Recessive Cardiomyopathy, Ophthalmoplegia (ARCO); Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-Like Episodes (MELAS); Neuropathy, Ataxia, Retinitis Pigmentosa (NARP); Mitochondrial Neuropathy, Gastro-Intestinal Encephalomyopathy (MNGIE); Myoclonus Epilepsy, Ragged-Red-Fibers (MERRF); Wilson's disease; Friedreich's ataxia. Diagnosis of mitochondrial encephalomyopathies is established by screening for mutations in blood or muscle biopsy samples. No specific therapies which influence the course of mitochondrial encephalomyopathies are known. Drugs interacting with the mitochondria function, alcohol consumption and smoking should be avoided.
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PMID:[Eye diseases in mitochondrial encephalomyopathies]. 1121 87

We report three members of a family, who exhibited a phenotype similar to 'myoclonus epilepsy with ragged-red fibers' but had a genotype usually associated with 'mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes'. The patients, a 48-year-old female, and her two sons, aged 21 and 19 respectively, presented with photo-reactive syncopal episodes, disturbances of gait and writing, dysarthria and finger tremor since the 3rd and 2nd decade of life, respectively, that were accompanied also by numbness and weakness of the extremities. Subsequently, cerebellar ataxia and myoclonus were also noted. Electromyography revealed both myogenic and neurogenic muscular changes, and nerve conduction studies demonstrated a sensory-motor neuropathy. Biopsy showed ragged-red fibers with strongly stained SDH-positive vessels in skeletal muscles, and a marked loss of myelinated fibers of the sural nerves. Mitochondrial (mt) DNA analyses of peripheral blood, muscles and nerves revealed that all members had a heteroplasmic np3271 (T-C) point mutation in the mitochondrial tRNA-Leu gene (UUR). This family is unique, in that all patients presented with a myoclonus epilepsy with ragged-red fibers-like phenotype and had a distinctive peripheral neuropathy, while the detected mtDNA 327l (T-C) mutation has been reported to date only in rare cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
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PMID:A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA. 1140 19

We report on a unique patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting optic atrophy, cardiomyopathy, and bilateral striatal necrosis before stoke-like episodes became apparent. Skeletal muscle total mitochondrial DNA analysis identified a heteroplasmic A to G point mutation in the tRNA(Lys) gene at position 8296. Skeletal muscle pathology revealed typical MELAS findings, including ragged-red fibers cytochrome c oxidase positive strongly succinate dehydrogenase-reactive blood vessels. Recent reports describe the 8296 mutation identified in patients with diabetes mellitus or myoclonus epilepsy with ragged-red fibers, not MELAS. We conclude that the 8296 mutation is likely to be pathogenic and that it may be not only a mutation responsible for diabetes mellitus or myoclonus epilepsy with ragged-red fibers but also for MELAS.
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PMID:Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation. 1250 10

Point mutations in mitochondrial tRNAs can cause severe multisystemic disorders such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Some of these mutations impair one or more steps of tRNA maturation and protein biosynthesis including 5'-end-processing, post-transcriptional base modification, structural stability, aminoacylation, and formation of tRNA-ribosomal complexes. tRNALeu(UUR), an etiologic hot spot for such diseases, harbors 20 of more than 90 disease-associated mutations described to date. Here, the pathogenesis-associated base substitutions A3243G, T3250C, T3271C, A3302G and C3303T within this tRNA were tested for their effects on endonucleolytic 3'-end processing and CCA addition at the tRNA 3'-terminus. Whereas mutations A3243G, A3302G and C3303T reduced the efficiency of 3'-end cleavage, only the C3303T substitution was a less efficient substrate for CCA addition. These results support the view that pathogenesis may be elicited through cumulative effects of tRNA mutations: a mutation can impede several pre-tRNA processing steps, with each such reduction contributing to the overall impairment of tRNA function.
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PMID:A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3'-end processing and CCA addition. 1501 75

Disease-causing mutations in mitochondrial DNA (mtDNA) are typically heteroplasmic and therefore interpretation of genetic tests for mitochondrial disorders can be problematic. Detection of low level heteroplasmy is technically demanding and it is often difficult to discriminate between the absence of a mutation or the failure of a technique to detect the mutation in a particular tissue. The reliable measurement of heteroplasmy in different tissues may help identify individuals who are at risk of developing specific complications and allow improved prognostic advice for patients and family members. We have evaluated Pyrosequencing technology for the detection and estimation of heteroplasmy for six mitochondrial point mutations associated with the following diseases: Leber's hereditary optical neuropathy (LHON), G3460A, G11778A, and T14484C; mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), A3243G; myoclonus epilepsy with ragged red fibers (MERRF), A8344G, and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)/Leighs: T8993G/C. Results obtained from the Pyrosequencing assays for 50 patients with presumptive mitochondrial disease were compared to those obtained using the commonly used diagnostic technique of polymerase chain reaction (PCR) and restriction enzyme digestion. The Pyrosequencing assays provided accurate genotyping and quantitative determination of mutational load with a sensitivity and specificity of 100%. The MELAS A3243G mutation was detected reliably at a level of 1% heteroplasmy. We conclude that Pyrosequencing is a rapid and robust method for detecting heteroplasmic mitochondrial point mutations.
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PMID:Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing. 1622 98

Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase gamma. Furthermore, processed OPA1 was observed in heart tissue derived from heart-specific TFAM knock-out mice suffering from mitochondrial cardiomyopathy and in skeletal muscles from patients suffering from mitochondrial myopathies such as myopathy encephalopathy lactic acidosis and stroke-like episodes. Dissipation of the mitochondrial membrane potential leads to fast induction of proteolytic processing of OPA1 and concomitant fragmentation of mitochondria. Recovery of mitochondrial fusion depended on protein synthesis and was accompanied by resynthesis of large isoforms of OPA1. Fragmentation of mitochondria was prevented by overexpressing OPA1. Taken together, our data indicate that proteolytic processing of OPA1 has a key role in inducing fragmentation of energetically compromised mitochondria. We present the hypothesis that this pathway regulates mitochondrial morphology and serves as an early response to prevent fusion of dysfunctional mitochondria with the functional mitochondrial network.
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PMID:Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. 1700 40

We developed an oligonucleotide biochip for synchronous multiplex detection of 31 known mitochondrial DNA mutations associated with MELAS (Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MERRF (Myoclonic epilepsy with ragged red fibers). Allele-specific oligonucleotide probes were covalently immobilized on aldehyde modified glass slides, and then hybridized with Cy5-labled DNA fragments amplified from sample DNAs by a multiplex asymmetric PCR (MAP) method. Five patients with MELAS, 5 patients with MERRF and 20 healthy controls were investigated using the oligonucleotide biochip. The results showed that all the cases with MELAS had an A3243G mutation in the MT-TL1 gene. In the MERRF group, 4 cases were found to be an A8344G mutation and 1 case was a T8356C mutation, and both mutations were in the MT-TK gene. In the healthy controls, none of the 31 related mutations was found. The results of the DNA biochip were consistent with those by DNA sequencing. Clearly, the DNA biochip combined with MAP method would become a valuable tool in multiplex detecting of the point mutations in mtDNA leading to MELAS and/or MERRF syndrome. Moreover, this biochip format could be modified to extend to the screening scope of SNPs for any other human mitochondrial diseases.
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PMID:[Development of a DNA biochip for detection of known mtDNA mutations associated with MELAS and MERRF syndromes.]. 1893 Aug 87

Identifying mitochondrial DNA (mtDNA) sequence variants in human diseases is complicated. Many pathological mutations are heteroplasmic, with the mutant allele represented at highly variable percentages. High-resolution melt (HRM or HRMA) profiling was applied to comprehensive assessment of the mitochondrial genome and targeted assessment of recognized pathological mutations. The assay panel providing comprehensive coverage of the mitochondrial genome utilizes 36 overlapping fragments (301-658 bp) that employ a common PCR protocol. The comprehensive assay identified heteroplasmic mutation in 33 out of 33 patient specimens tested. Allele fraction among the specimens ranged from 1 to 100%. The comprehensive assay panel was also used to assess 125 mtDNA specimens from healthy donors, which identified 431 unique sequence variants. Utilizing the comprehensive mtDNA panel, the mitochondrial genome of a patient specimen may be assessed in less than 1 day using a single 384-well plate or two 96-well plates. Specific assays were used to identify the myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) mutation m.3243A>G, myoclonus epilepsy, ragged red fibers (MERRF) mutation m.8344A>G, and m.1555A>G associated with aminoglycoside hearing loss. These assays employ a calibrated, amplicon-based strategy that is exceedingly simple in design, utilization, and interpretation, yet provides sensitivity to detect variants at and below 10% heteroplasmy. Turnaround time for the genotyping tests is about 1 hr.
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PMID:Identifying sequence variants in the human mitochondrial genome using high-resolution melt (HRM) profiling. 1937 Jul 63

The objective of this study is to report cases of unexpected deaths in Unverricht-Lundborg disease (ULD) patients, a comparatively benign form of progressive myoclonus epilepsy. We performed a multicentric study of the circumstances of death in ULD patients seen in the last 16 years. We assessed age, sex, severity and duration of disease, antiepileptic drugs, circumstances and presumed cause of death. Nineteen observations (12 females, 7 males) were collected from four centers (Tunis, Marseille, Milan, Belgrade). The most common causes of death are (1) SUDEP (six cases, all female), with 4/6 on phenobarbital alone, and (2) complications of severe ULD (six cases). Two patients committed suicide. Only one death was clearly unrelated to ULD (car accident), while four patients died of stroke, drowning, complications of chronic alcoholism and Wernicke encephalopathy, respectively. In conclusion, although the prognosis of ULD has progressed, there are still spontaneously severe forms and high risk of early death, including SUDEP.
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PMID:Death in Unverricht-Lundborg disease. 1949 78

There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents.
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PMID:Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. 2016 67


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