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:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epilepsia partialis continua (EPC) is a rare epileptic syndrome characterized by continuous focal seizures. We report on a 16-year-old girl who died of prolonged pharmacoresistant EPC in whom we identified a 7472insC mutation within the mitochondrial transfer ribonucleic acid (tRNA)(ser(UCN)). Additional symptoms included ataxia, lactic acidosis, myopathy, sensorineural hearing loss, severe headaches, and mental retardation. Quantification revealed 100% mutant mitochondrial DNA (mtDNA) in the patient, 4% in her mother, and none in her half-sister. This highly skewed mtDNA distribution is most improbable (approximately 3 x 10(-30)) if only explained by random genetic drift. Clustering of dysfunctional mitochondria and replicatory advantage of mutant mtDNA may play a role in the rapid segregation towards homoplasmy within one generation.
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PMID:Epilepsia partialis continua associated with a homoplasmic mitochondrial tRNA(Ser(UCN)) mutation. 977 73

Falciparum malaria remains a major killer in developing countries, particularly for African children. The sequestration of parasitized erythrocytes in the deep microvasculature is mostly mediated by their cytoadherence to activated endothelium. Proinflammatory cytokines and particularly tumor necrosis factor contribute to severe disease but the pathophysiology of coma remains poorly understood. In young children, features of severe malaria include severe anemia, hypoglycemia and cerebral malaria. Half of the children with neurological impairment actually have raised intracranial pressure, and seizures are extremely common. Clinical respiratory distress usually reflects severe lactic acidosis. In non immune adults, pictures of severe sepsis with shock, acute renal failure and respiratory distress syndrome are common and often associated with bacterial coinfection. Although chemotherapy of malaria is challenged by the continuing evolution of antimalarial resistance, quinine remains the first-line drug for severe disease. The optimization of symptomatic management of severe malaria remains a major concern in developing countries.
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PMID:[Severe malaria]. 978 Oct 74

A 55-year-old woman, who had two episodes of difficulty in putting a key into a keyhole probably due to optic ataxia at age 52 and 54 years old, developed speaking errors and was admitted to our hospital. She was 152.5 cm in height and 52.5 kg in weight. Neurological examination revealed right homonymous hemianopsia and sensory aphasia. A CSF examination revealed lymphocytic pleocytosis of 88/microliter. Serum lactate and pyruvate were remarkably increased after an aerobic exercise test. A few ragged-red fibers were present in the biopsied brachial biceps muscle. Brain MRI by FLAIR method showed scattered high signal lesions in the left temporal lobe, bilateral parieto-occipital lobes, left insular cortex and left thalamus. The left superficial temporal lesion was enhanced by gadolinium-DTPA. The proton MRS demonstrated the lactic acid peak as well as the decrease of NAA/choline ratio (0.38) in the left parieto-occipital region. Thus, she was diagnosed as a case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and successfully treated with ubidecarenone (150 mg/day). Six months later, she again developed seizure, right hemiparesis and deterioration of aphasia and presented again CSF lymphocytic pleocytoses of 15/microliter. Brain MRI demonstrated new lesions in the left temporoparietal lobes, left insular cortex and left corona radiata. Therefore, CSF pleocytosis appeared to be associated with stroke-like episodes in this case. Although the mechanism of CSF pleocytosis remains to be elucidated, it may involve the breakdown of blood-brain barrier caused by mitochondrial dysfunction. Otherwise, an inflammatory process similar to that in cases of Leber disease, who developed multiple sclerosis-like additional lesions in the central nervous system, may also take place in MELAS.
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PMID:[A case of MELAS showing CSF pleocytosis associated with stroke-like episodes]. 986 8

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. The authors describe a clinical case study of gastrointestinal manifestations in a pedigree with MELAS, in which all three children, ages 11, 8, and 6, demonstrated acute onset of intestinal obstruction. They unexpectedly showed severe abdominal distension and vomiting. Their parents had no clinical manifestation. The first female sibling underwent an emergent laparotomy because she was diagnosed to have intestinal strangulation. She had postoperative complications caused by progressive lactic acidosis and died the next day. The second and third sisters had similar onsets of the disease and were treated with gastrointestinal decompression and intravenous administration of lactate-free fluid and coenzyme Q10. Genetic testing using blood samples showed an A-to-G point mutation at nucleotide position 3243 in the tRNALeu(UUR) region in the mitochondrial DNA. In MELAS children who demonstrate acute onset of gastrointestinal manifestations, a careful review of family history and an elevation of serum lactate and pyruvate levels may enable a differential diagnosis to be made of acute abdomen to avoid unnecessary surgical intervention.
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PMID:Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). 986 67

An 11-year-old boy presented with seizure and cortical blindness. A T1 weighted magnetic resonance image of the brain showed high signal intensity in the bilateral corpus striatum and long T1 and T2 changes in the bilateral occipital and cerebellar hemispheric regions. Increased cerebrospinal fluid lactate concentration of 56.7 mg/dl and blood lactate concentration of 34.2 mg/dl were also noted. A muscle biopsy obtained from the quadriceps femoris muscle showed the presence of ragged red fibers and mitochondrial DNA (mtDNA) analysis showed an A-->G mutation at nucleotide position 3243. MtDNA analysis of the patient's mother revealed the same mutation. These findings indicated MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes).
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PMID:Childhood MELAS syndrome presenting with seizure and cortical blindness: a case report. 988 47

MELAS syndrome is typically characterized by normal early development and childhood-onset recurrent neurologic deficits (stroke-like episodes), seizures, short stature, lactic acidosis, and ragged red fibers on muscle biopsy specimens. It is usually, but not invariably, associated with the A3243G point mutation in the mitochondrial DNA tRNALeu(UUR) gene. We report 3 unrelated children with the A3243G mutation who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain magnetic resonance imaging (MRI). The second patient had generalized seizures refractory to treatment and bilateral occipital lesions on brain MRI. The third child had atypical retinal pigmentary changes, seizures, areflexia, and cerebral atrophy on brain MRI. All patients had several atypical features in addition to early onset: absence of an acute or focal neurologic deficit, variable serum and cerebrospinal fluid lactate levels, lack of ragged red fibers in muscle biopsy specimens. The proportion of mutant mtDNA in available tissues was relatively low (range, 5% to 51% in muscle; 4% to 39% in blood). These observations further extend the phenotypic expression of the A3243G "MELAS" mutation. Our findings confirm previous observations that there is poor correlation between abundance of mutant mtDNA in peripheral tissues and neurologic phenotype. This suggests that other factors contribute to the phenotypic expression of this mutation.
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PMID:Infantile encephalopathy associated with the MELAS A3243G mutation. 1035 36

We herein report a rare case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and diabetes mellitus with ketoacidosis. An 18-year-old female patient was diagnosed to have diabetes mellitus and insulin therapy was thereafter initiated. At 26 years of age, she was hospitalized for diabetic ketoacidosis, soon followed by a loss of consciousness, left-sided dysmetria, and ataxic speech. MELAS was diagnosed because of the presence of ragged red fibers in a muscle biopsy. At 33 years of age, she was admitted to our hospital because of ketoacidosis and partial status epilepticus. A blood gas examination revealed as follows; arterial pH, 6.88; bicarbonate, 2.1 mmol/l; base excess - 29.8 mmol/l. The serum level of glucose had also increased to 30 mmol/l. The serum levels of lactate and B-hydroxybutyrate were elevated to 11.4 mmol/l and 1,990 micromol/l, respectively. Ketoacidosis improved by fluid replacement and continuous intravenous insulin infusion. A brain MRI demonstrated hyperintensity areas on FLAIR images in the bilateral temporal lobes and the cerebellum. A proton MRS demonstrated the abnormal lactate accumulation in the bilateral temporal and occipital lobes. Since epileptic seizures are rare in patients with diabetic ketoacidosis, such seizures may indicate the existence of MELAS syndrome.
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PMID:Ketoacidosis accompanied by epileptic seizures in a patient with diabetes mellitus and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). 1111 21

Nucleoside analogues represent the cornerstones of antiretroviral regimens. A range of drug- or tissue-specific toxicities, such as peripheral neuropathy, myopathy, pancreatitis and lactic acidosis with hepatic steatosis, has been documented with these agents. The fat atrophy seen on long term antiretroviral therapy may also be related to nucleoside analogues. The mechanisms by which nucleoside analogues cause toxicity are not clearly established. In vitro, the triphosphates of these agents are weak to modest substrates for human DNA polymerases, showing the greatest affinity for mitochondrial DNA polymerase gamma. Short term exposure in vitro to some nucleoside analogues has been demonstrated to cause increased lactate production or falls in mitochondrial DNA suggestive of mitochondrial toxicity. However, stavudine and to a lesser extent zidovudine are poor substrates for mitochondrial thymidine kinase type 2, the predominant form in cells that are not actively mitotic such as neurons, myocytes and adipocytes. These are the cell types where the proposed mitochondrial toxicities neuropathy, myopathy and lipoatrophy are observed. Thus, active concentrations of phosphorylated products of stavudine and zidovudine may not be present in mitochondria. The familial mitochondrial diseases do not have identical presentations to nucleoside analogue toxicities. These disorders most commonly involve the CNS, typically with seizures or dementia, and occasionally the kidneys. Although nucleoside analogues are known to penetrate the CNS and are commonly renally excreted unchanged, mitochondrial toxicities at these sites have not been documented. Furthermore, toxicity caused by nucleoside or nucleotide analogues does not always appear to arise through the mitochondrial route. Cidofovir appears to cause renal tubular dysfunction via a toxic intracellular metabolite, and zidovudine-related anaemia appears to be related to decreased globin RNA synthesis. In vitro or animal models suggest that zidovudine myopathy, stavudine-related (but not zalcitabine- or didanosine-related) neuropathy and didanosine-related pancreatitis may all be not related, or not exclusively related, to mitochondrial dysfunction. The integration of nucleoside analogues into nuclear DNA, best documented with zidovudine but likely to occur with other agents, represents an alternative but potentially delayed pathway to cytotoxicity and cell apoptosis. This is the mechanism of cell death during therapy with antineoplastic nucleoside analogues, and may have contributed to the multisystem toxicities observed with the anti-hepatitis B drug fialuridine. New research evaluating the effects of long term exposure of cell lines is required to address the possibility that nuclear genotoxicity plays a role in long term nucleoside analogue toxicity.
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PMID:Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism? 1114 57

We report the clinical and MR manifestations of an 18 year-old girl with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Recurrent status epilepticus caused reversible cytotoxic edema on diffusion-weighted images (DWI). Initial and one month follow-up MR spectroscopy, after seizure control, showed some discrepancies in the ratio of metabolites. N-acetylaspartate (NAA) partially recovered (NAA/creatine (Cr) ratio: 1.27-->1.84). This was because of a normalization of decreased NAA due to cellular dysfunction as a result of status epilepticus. A low ratio of NAA/Cr due to abnormal mitochondria remained in the decreased state. Reversible NAA/Cr ratios in the acute lesion suggested that NAA reflects the neuronal function as well as the level of neuronal structural damage. The altered NAA/Cr ratio better correlated with the abnormal signal intensity area of T2-weighted images (T2WI) and DWI than the lactate (Lac)/Cr ratio. With conservative treatment with anti-epileptics not accompanied by coenzyme Q or sodium dichloroacetate, lactate persistently increased (Lac/Cr ratio: 1.01-->1.21) because of the continued production of lactate in cells with respiratory deficiency, which is the main pathology of MELAS.
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PMID:Diffusion-weighted image and MR spectroscopic analysis of a case of MELAS with repeated attacks. 1129 91

Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on respiratory chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to respiratory chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the respiratory chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for respiratory chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.
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PMID:Respiratory chain deficiency in Alpers syndrome. 1152 Dec 12


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