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: EC:1.9.3.1 (cytochrome oxidase)
8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fourteen new cases of cytochrome oxidase (COX)-associated Leigh syndrome (LS) are combined with 20 reported cases to describe the clinical, laboratory, and radiological features of this devastating metabolic condition. Three clinical stages are identified. Most patients have normal neurological development during the first 8-12 months (stage I). Somatic complaints are common, including chronic diarrhea, recurrent vomiting, anorexia, and decelerating body and head growth. The second stage evolves during late infancy and early childhood when motor regression becomes evident. Eye signs, altered breathing patterns, pyramidal, extrapyramidal, and cerebellar signs emerge and sudden clinical deterioration occurs during intercurrent infectious or metabolic stress. The last stage may extend from 2 to 10 years and is manifested by extreme hypotonia, swallowing difficulties and undernutrition. Feeding assistance is necessary and seizures may occur. The CSF lactate concentration is consistently elevated and MRI abnormalities are seen in the subcortical structures. COX deficiency affects most tissues, but is not always generalized. For example, 3 patients with a cardiomyopathy had normal COX activity in cultured skin fibroblasts. Nearly normal amounts of cross-reacting material are present by ELISA and immunoblot analyses. Parental consanguinity has been found in several families, the hereditary pattern is recessive and males are affected more commonly (2:1). The biomolecular abnormality causing COX deficiency in LS is unknown, but the available evidence implicates a nuclear-encoded protein that affects the structure or the stability of the holoenzyme complex.
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PMID:Cytochrome c oxidase-associated Leigh syndrome: phenotypic features and pathogenetic speculations. 165 84

1H MRI permits detection of edema in the brain. In a middle cerebral artery stroke model in the cat, we found a significant correlation between an edema index based on MRI and a sensitive metabolic index of ischemia, the in vivo oxidation status of mitochondrial cytochrome aa3 determined by near-infrared reflectance spectrophotometry (r = -0.70, alpha = 0.001). This result suggests that a simple, noninvasive study using MRI can provide an index of the extent of ischemic damage in an experimental acute stroke model.
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PMID:MRI quantitation of edema in focal cerebral ischemia in cats: correlation with cytochrome aa3 oxidation state. 215 26

MELAS is a mitochondrial cytopathy characterized by encephalopathy with stroke-like episodes and lactic acidosis. Most patients exhibit an A-G transition mutation at np 3243 of mitochondrial DNA (tRNA(Leu)(UUR)). We present a family of four in which the mutation was discovered in blood and in muscle mt DNA. Two patients had the classic MELAS syndrome with multiple stroke-like episodes. Some episodes were precipitated by metabolic stress. The remaining two patients had an oligosymptomatic disease with mild chronic encephalopathy, small stature and hearing loss. MRI was followed over a period of 4-8 years, during which the MELAS patients showed progression from nonspecific multifocal signal change to typical extensive cortico-subcortical parieto-occipital lesions and progressive cerebral atrophy. MRI in the oligosymptomatic cases was normal, or showed non-progressive cerebellar atrophy. Biochemical findings were non-specific, indicating increased mitochondrial volume in all cases, and a relatively complex IV defect in one case. All patients were treated with coenzyme Q with varying clinical response. The percentage of mutant mt DNA in blood and muscle did not correlate with clinical severity. Pathogenetic theories based on molecular genetics, and the therapeutic regimen in terms of the underlying biochemical concepts are discussed.
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PMID:[MELAS syndrome. Clinical aspects, MRI, biochemistry and molecular genetics]. 801 33

The purpose of this paper is to investigate the origin of the signal changes in the blood oxygenation level dependent effect (BOLD) and the influence of oxygen metabolism by utilizing near-infrared spectrophotometry (NIRS), which can measure deoxyhemoglobin (deoxyHb) content in blood vessels and redox states of cytochrome oxidase in whole tissue. Simultaneous MRI and NIRS measurements of the rat head were performed by changing oxygen concentrations in the inhalant gas. The signal intensity based on the BOLD effect depended on the influence of both arterial and venous blood deoxygenation in the brain, whose relative contributions differed at various points. In this paper, it is noteworthy that the differential apparent transverse relaxation rate between two conditions in the brain areas was linearly correlated with deoxyHb content determined by NIRS, except in severe hypoxia, and that no reduction of cytochrome oxidase occurred under the same conditions. These results indicate that the influence of hemodynamic changes on the signal intensity of the BOLD effect, and therefore functional MRI, can be elucidated by the NIRS information to determine actual changes of blood deoxygenation and blood volume.
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PMID:Interpretation of BOLD MRI signals in rat brain using simultaneously measured near-infrared spectrophotometric information. 917 87

Two siblings (one man, one woman), presenting with diarrhea, severe weight loss peripheral neuropathy, ophthalmoparesis, asymptomatic leukoencephalopathy were diagnosed as a new cases of Mitochondrial Neuro Gastro Intestinal Encephalomyopathy syndrome (MNGIE). Hirano (1994) defined four criteria for the diagnostic: peripheral neuropathy, ophthalmoparesis, gastro intestinal dysmotility, muscle biopsy with histologic features of mitochondrial myopathy (ragged-red fibers, muscle fibers with increased succinate deshydrogenase stain or ultra structurally abnormal mitochondria). In a review of the literature, we found 31 cases with MNGIE. With our two cases, we study this group of 33 patients. First symptoms begin about 13.5 years with a median of 10 years and extremes for 1 to 32 years. The first signs are gastro intestinal symptoms (recurrent nausea, vomiting or diarrhea with intestinal dysmotility) in 22 cases, an ophthalmoparesia in 4 cases, intestinal and ocular signs in 1 case, gait ataxia or peripheral neuropathy in 3 cases, hearing loss in 1 case, gait ataxia or peripheral neuropathy in 3 cases, hearing loss in 1 case. During the evolution, besides the cardinal signs, the following features have been observed with a variable frequency: hearing loss, short stature, facial palsy, dysphonia, dysarthria, sweating, orthostatic hypotension, bladder dysfunction, hepatomegalia, The laboratory features are: abnormal Nerve Condition Studies/EMG compatible with a sensory motor neuropathy, lactic acidosis, mitochondrial respiratory chain defect (essentially complex IV deficiency, complex I deficiency or multiple complex defect), MRI leukodystrophy, elevated CSF protein, heart block, ragged-red fibers or increased SDH stain. The prognosis is poor, due to a severe weight loss bordering on cachexia 13 patients died with a mean age of 28.5 years (median 24 years, extreme 3 years to 51 years). The prognosis seems to be worsened by a young age of onset. The 33 patients belong to 19 families with 7 cases of consanguinity. 25 patients had a brother, a sister or a cousin affected. The study of these families is compatible with an autosomic recessive transmission, suggesting a pathology of the nuclear genomi, probably impliying the control of the mitochondrial DNA replication. In fact, in 13 cases, a study of the mt DNA was realized: multiple deletions were founded in 6 cases, multiples mutations in one case, unique mutation in 1 case. In 5 cases ther was no evidence of abnormality. These precise etiology and pathophysiologic significance of the mt DNA deletions, and the heterogeneity of the modifications of the mt DNA remain unknown. However, the possibility of various phenotypes for a same genotype or inversely is known in mitochondriopathies.
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PMID:[MNGIE syndrome in 2 siblings]. 968 18

Spontaneous, low frequency (4-12 cpm) fluctuations, independent of the cardiac and respiratory cycles, in human and animal brains were first recorded with the O2 polarographic technique in the late 1950s. They were seen in NADH and cytochrome oxidase and associated with spontaneous vasomotion pial and large cerebral arteries. Renewed interest in spontaneous fluctuations was generated by studies with laser-Doppler flowmetry (LDF), reflectance oximetry and functional MRI. Spontaneous fluctuations were consistently produced when cerebral perfusion was challenged by systemic or local manipulations; the fluctuation amplitude reached 30-40% of the mean. The most potent stimuli are hypotension, hyperventilation, cerebral artery occlusion and cerebral vasoconstriction elicited, for example, by a nitric oxide synthase inhibitor but not by indomethacin. The fluctuations are suspended by CO2 and halothane at concentrations that produce hyperemia. Recently, spontaneous fluctuations were recorded by LDF microprobes in areas as small as 130 microns and by video-microscopy in single capillaries. The fluctuations were absent in severe, focally ischemic brain territories. The dependence of spontaneous fluctuations on intravascular pressure argues for the importance of a myogenic mechanism, however, neuronal modulation may also play a role. Coherence of small vessel vasomotion may be required for the emergence of regional flow fluctuations. There is a need to elucidate the spatial and frequency domains in which fluctuations are present under normal physiological conditions and those in which they may reflect brain injury and pathologies of diagnostic or prognostic value.
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PMID:Spontaneous fluctuations in cerebral oxygen supply. An introduction. 988 35

Hypoxic-ischaemic encephalopathy (HIE) was diagnosed in an infant with acidosis. At 7 weeks of age further investigations revealed abnormal neuroimaging (CT and MRI scans) and a raised plasma and CSF lactate. A skeletal-muscle biopsy at 2 months of age confirmed the diagnosis of cytochrome oxidase deficiency. The course of the patient's disorder has taken that of a static encephalopathy (cerebral palsy). Inborn disorders of the respiratory chain should be considered in the differential diagnosis of HIE.
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PMID:Cytochrome oxidase deficiency presenting as birth asphyxia. 1087 29

We report an infant with intermittent urinary excretion of D-2-hydroxyglutaric (D-2-OHG) acid who died at the age of 10 months from cardiogenic shock due to cardiomyopathy. High urinary concentrations of D-2-OHG and succinic acid, as well as increased levels of lactic acid were detected on three different occasions, whereas a normal urinary profile of organic acids was found on one occasion. The clinical findings of our patient consisted of generalized hypotonia, irritability, developmental delay, generalized tonic seizures, lethargy, cardiomyopathy, and respiratory distress. Cerebral MRI revealed bilateral lesions in the substantia nigra, the periaqueductal area, the medial part of the thalamus, the hypothalamus, the caudate nucleus, putamen and globus pallidus. This pattern is suggestive of a mitochondriopathy. However, respiratory chain enzyme activities were normal in fibroblasts. Exogenous supplementation of D-2-OHG acid strongly inhibited cytochrome-c oxidase activity in fibroblasts from the patient and from normal controls in vitro. The results suggest that our patient has an unusual form of D-2-hydroxyglutaric aciduria (D-2-OHGA), different from the patients published so far, and that the increase of lactic acid and some citric acid cycle intermediates encountered in some patients with D-2-OHGA may be due to a functional defect of the respiratory chain caused by D-2-OHG acid.
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PMID:D-2-Hydroxyglutaric aciduria in a patient with a severe clinical phenotype and unusual MRI findings. 1199 77

In childhood mitochondrial encephalopathies the common MRI features are bilateral symmetric abnormalities in basal nuclei and brainstem. The presence of diffuse white matter abnormality has been described only in a few cases. Among a series of 110 children with mitochondrial encephalopathies, 8 patients with MR imaging consistent with a leukoencephalopathy were retrospectively evaluated. Diagnosis was based on the recognition of the biochemical defect in muscle homogenate. H-MR spectroscopic imaging was performed in six of them. Biochemical analysis demonstrated a defect of respiratory chain complexes in six patients: complex I in two cases, complex II in two, complex IV in one, multiple complexes defect in one. Pyruvate dehydrogenase deficiency was demonstrated in two patients. MRI showed severe involvement of the brain white matter without significant basal nuclei or brainstem abnormalities. Two patients developed large cystic areas since onset; in two others progressive vacuolisation of affected white matter was seen later in the course of the disease. One patient with pyruvate dehydrogenase deficiency also presented with a diffuse cortical polymicrogyria. H-MR spectroscopic imaging showed a decrease of N-acetylaspartate, choline and creatine with lactate accumulation in five patients, and was normal in one. These findings suggest that mitochondrial disorders should be included in the differential diagnosis of white matter disorders.
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PMID:Cerebral white matter involvement in children with mitochondrial encephalopathies. 1207 88

Mutations in SURF1, a gene involved in cytochrome-c oxidase (COX) assembly, cause COX deficiency and Leigh Syndrome (LS). Typical presentation is in the first year of life, with failure to thrive, psychomotor regression, ataxia, signs of brainstem dysfunction, and peripheral neuropathy. Progression is rapid and patients usually die of respiratory failure before 2 years of age. LS is characterized by symmetrical bilateral lesions in the brainstem and basal ganglia, revealed premortem as signal hyperintensities in T2-weighted MRI imaging. Here, we describe a 10-year-old boy with a novel mutation in SURF1 associated with an unusually mild clinical course. At 39 months, there were no MRI lesions, and a follow-up MRI at 8 years of age showed only brainstem and cerebellar involvement without lesions in the basal ganglia or subthalamic nuclei. These data confirm that the spectrum of MRI findings in LS is variable and that SURF1 mutations should be considered in patients with encephalomyopathy and COX deficiency even when early MRI findings are negative.
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PMID:Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. 1521 16


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