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)

The diagnosis of mitochondrial respiratory chain deficiency is usually made by analysis of mitochondrial respiratory chain activity in muscle biopsy. We describe 4 patients in whom the diagnosis was based on mitochondrial respiratory chain deficiency in liver alone. In 3 patients, liver complex IV activity was deficient, and the 4th patient had liver complex I deficiency (relative to citrate synthase and complex II activity). The enzyme activities in skeletal muscle biopsies from these patients were normal or equivocal. The age at presentation and the neurological symptoms differed from one patient to another. All 3 patients with complex IV deficiency had non-specific white matter changes on brain MRI. None of the patients had clinical or biochemical evidence of liver disease. These findings illustrate the wide variety of presentations associated with liver mitochondrial respiratory chain deficiency. They also demonstrate the importance of mitochondrial respiratory chain enzyme analysis in liver, in addition to muscle, even in cases where the primary clinical deficit is neurological and there is no liver disease.
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PMID:The importance of liver biopsy in the investigation of possible mitochondrial respiratory chain disease. 1613 50

Cellular labeling with ferumoxides (Feridex IV) superparamagnetic iron oxide nanoparticles can be used to monitor cells in vivo by MRI. The objective of this study was to use histology and MRI to evaluate an in vivo, as opposed to in vitro, technique for labeling of mononuclear leukocytes as a means of tracking inflammatory processes in the brain. Long-Evans rats were intravenously injected with 20 mg/kg ferumoxides, ferumoxtran-10, or ferumoxytol with or without protamine sulfate. Leukocytes and splenocytes were evaluated by cell sorting and iron histochemistry or were implanted into the brain for MRI. Injection of ferumoxides/protamine sulfate complex IV resulted in iron labeling of leukocytes (ranging from 7.4 +/- 0.5% to 12.5 +/- 0.9% with average 9.2 +/- 0.8%) compared with ferumoxides (ranging from 3.9 +/- 0.4% to 6.3 +/- 0.5% with average 5.0 +/- 0.5%) or protamine sulfate alone (ranging from 0% to 0.9 +/- 0.7% with average 0.3 +/- 0.3%). Cell sorting analysis indicated that iron-labeled cells were enriched for cell types positive for the myelomonocytic marker (CD11b/c) and the B lymphocyte marker (CD45RA) and depleted in the T cell marker (CD3). Neither ferumoxtran-10 nor ferumoxytol with protamine sulfate labeled leukocytes. In vivo ferumoxides/protamine sulfate-loaded leukocytes and splenocytes were detected by MRI after intracerebral injection. Ferumoxides/protamine complex labeled CD45RA-positive and CD11b/c-positive leukocytes in vivo without immediate toxicity. The dose of feumoxides in this report is much higher than the approved human dose, so additional animal studies are required before this approach could be translated to the clinic. These results might provide useful information for monitoring leukocyte trafficking into the brain.
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PMID:In vivo leukocyte labeling with intravenous ferumoxides/protamine sulfate complex and in vitro characterization for cellular magnetic resonance imaging. 1789 31

Although linked with cardiac dysfunction, the association of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and pulmonary artery hypertension (PAH) has not been previously described. PAH and right ventricular heart failure were identified by echocardiography in a 3-year-old boy with a history of hypotonia, microcephaly and developmental delay. He initially presented with a 10-day history of dyspnoea, dependent oedema and reduced oral intake. Lactic acidosis was noted on serial arterial blood sampling and cerebrospinal fluid. Muscle biopsy demonstrated cytochrome-c oxidase-positive 'ragged-red' fibres consistent with MELAS; subsequent analyses revealed the m.3243A>G point mutation most commonly associated with MELAS. The mutation was heteroplasmic, representing 92% of the total mtDNA from a lung sample. Nitric oxide and epoprostenol were administered without significant clinical or echocardiographic improvement of his PAH. A 'mitochondrial cocktail' including biotin, riboflavin, carnitine and coenzyme Q10 also was provided. Five months after presentation, he developed seizures; MRI imaging of his brain demonstrated multiple focal lesions. His clinical status worsened with increasing cardiopulmonary failure. He died two months later. Although therapy for both MELAS and PAH remains limited, recent investigations suggest a beneficial role for l-arginine in both conditions, implying a possible common pathophysiology. Mitochondrial diseases such as MELAS should be considered in cases of idiopathic PAH, particularly when associated with multisystem involvement including short stature, hearing loss, renal dysfunction, retinopathy, diabetes mellitus, migraines, seizures, ophthalmoplegia, fatigability and weakness.
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PMID:Pulmonary artery hypertension in a child with MELAS due to a point mutation of the mitochondrial tRNA((Leu)) gene (m.3243A>G). 1818 Oct 29

MRI at 7 Tesla has been used to investigate the accumulation of manganese in the occipital cortex of common marmoset monkeys (Callithrix jacchus) after administering four fractionated injections of 30 mg/kg MnCl(2) . 4H(2)O in the tail vein. We found a statistically significant decrease in T(1) in the primary (V1) and secondary (V2) areas of the visual cortex caused by an accumulation of manganese. The larger T(1) shortening in V1 (DeltaT(1) = 640 ms) relative to V2 (DeltaT(1) = 490 ms) allowed us to robustly detect the V1/V2 border in vivo using heavily T(1)-weighted MRI. Furthermore, the dorso-medial (DM) and middle-temporal (MT) areas of the visual pathway could be identified by their T(1)-weighted enhancement. We showed by comparison to histological sections stained for cytochrome oxidase (CO) activity that the extent of V1 is accurately identified throughout the visual cortex by manganese-enhanced MRI (MEMRI). This provides a means of visualizing functional cortical regions in vivo and could be used in longitudinal studies of phenomena such as cortical plasticity, and for non-destructive localization of cortical regions to guide in the implementation of functional techniques.
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PMID:Manganese-enhanced MRI visualizes V1 in the non-human primate visual cortex. 1932 8

Cytochrome c oxidase (COX) is the terminal enzyme of the respiratory chain, with subunits originating both from the mitochondrial and nuclear genome. An eleven-year-old female presented initially with a seizure followed two months later with tonic-clonic seizures, weakness and aphasia. MRI of the cerebral hemispheres showed multiple infarcts. Previous history suggested gross and fine motor control deficits with learning difficulties. A muscle biopsy showed a specific decrease of COX staining in all fibres and pleomorphic mitochondria. Respiratory chain studies confirmed an isolated complex IV defect in muscle, whilst fibroblasts showed an initial COX activity below normal which rapidly came up to the normal range on culture. Sequencing of mtDNA revealed an heteroplasmic m.7023G>A mutation in the COX1 gene, with levels of 96% in muscle, 70% in blood and 50% in the initial skin fibroblast culture dropping to 10% in later passages. The mutation was present in a critical region of the COX1 gene, the V374M change being close to the two histidine residues His376 and His378 co-ordinating with the heme a and a (3), and His367 which co-ordinates a magnesium ion. This case highlights that a MELAS-like syndrome can occur with isolated COX deficiency.
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PMID:A novel mitochondrial DNA mutation in COX1 leads to strokes, seizures, and lactic acidosis. 1956 96

The topographic organization of the forepaw barrel subfield in layer IV of rat primary somatosensory cortex (S1) is a good model for studying neural function and plasticity. The goal of this study was to test the feasibility of functional MRI (fMRI) to map the forepaw digit representations in the S1 of the rat and its plasticity after digit amputation. Three dimensional echo-planar imaging with 300 micron isotropic resolution at 11.7 T was used to achieve high signal-to-noise ratios and laminar layer resolution. By alternating electrical stimulation of the 2nd (D2) and 4th (D4) digits, functional activation in layer IV of the barrel subfields could be distinguished using a differential analysis. Furthermore, 2 and a half months after the amputation of the 3rd digit in baby rats, the overlapping area between D2 and D4 representations was increased. This indicates that the forepaw barrel subfield previously associated with the ablated digit is now associated with the representation of nearby digits, which is consistent with studies using electrophysiology and cytochrome oxidase staining.
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PMID:Mapping plasticity in the forepaw digit barrel subfield of rat brains using functional MRI. 2080 51

We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal-appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed.
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PMID:A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis. 2179 50

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases. We report two novel GFM1 mutations in two unrelated patients with encephalopathy and liver failure respectively. The first patient had intrauterine growth retardation, seizures, encephalopathy and developmental delay. Brain MRI showed hypoplasia of the vermis and severe pontine atrophy of the brainstem that were similar to those reported in patients with mitochondrial translation deficiencies. The second patient had liver failure with hypoglycemia. Respiratory chain analysis showed a complex IV deficiency in muscle of both patients. A 10K SNP genotyping detected several regions of homozygosity in the two patients. In vitro translation deficiency prompted us to study genes involved in mitochondrial translation. Therefore, we sequenced the GFM1 gene, encoding the mitochondrial translation factor EFG1, included in a shared homozygous region and identified two different homozygous mutations (R671C and L398P). Modeling studies of EFG1 protein suggested that the R671C mutation disrupts an inter-subunit interface and could locally destabilize the mutant protein. The second mutation (L398P) disrupted the H-bond network in a rich-beta-sheet domain, and may have a dramatic effect on local structure. GFM1 mutations have been seldom reported and are associated with different clinical presentation. By modeling the structure of the protein and the position of the various mutations we suggest that the clinical phenotypes of the patients could be related to the localization of the mutations.
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PMID:Toward genotype phenotype correlations in GFM1 mutations. 2198 55

We report an illustrative case of a 74-year-old man who, in the absence of intercurrent illness, presented with rapid cognitive decline. MRI showed bilateral, symmetrical, high T2-weighted signal in the anterior basal ganglia and medial thalami, extending to the periaqueductal grey matter, basal ganglia and basal frontal lobes. A (18)F-fluorodeoxyglucose-positron emission tomography scan showed widespread reduction of metabolism in the cortex of the frontal, temporal and parietal lobes, posterior cingulate gyrus, precuneus and caudate nuclei, with sparing of the sensorimotor cortex, thalami and lentiform nuclei. A mild vitamin B12 deficiency was found and despite normal thiamine levels, intravenous (IV) thiamine and vitamin B therapy was commenced, with a short course of IV methylprednisolone and tetracycline. Repeat neuropsychological assessment four weeks following treatment revealed increased alertness and interactiveness but significant cognitive decline persisted. Unexpectedly, the patient suffered a transmural anterior myocardial infarction six weeks after presentation and died within 24hours. An a autopsy showed: global reduction in cytochrome oxidase (COX) activity in all skeletal muscles examined; bilateral, symmetrical, hypervascular, focally necrotizing lesions in the substantia nigra, periaqueductal grey matter, superior colliculi, medial thalami anteriorly and posteriorly, as well as in the putamena but the mammillary bodies were not affected. Biochemical analysis of fresh muscle confirmed selective deficiency of complex IV of the oxidative phosphorylation chain. A diagnosis of late-adult onset Leigh syndrome was made. Multiple genetic studies failed to identify the specific underlying mutation. The relevant literature is reviewed.
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PMID:Late-adult onset Leigh syndrome. 2720 85

We report two patients with Leigh syndrome that showed a combination of facial dysmorphism and MRI imaging indicating an SURF1 deficiency, which was confirmed by sequence analysis. Case 1 is a 3-year-old girl with failure to thrive and developmental delay. She presented with tachypnea at rest and displayed facial dysmorphism including frontal bossing, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, slightly upturned nostril, and hypertrichosis dominant on the forehead and extremities. Case 2 is an 8-year-old boy with respiratory failure. He had been diagnosed as selective complex IV deficiency. Case 2 displayed facial dysmorphism and hypertrichosis. Since both patients displayed characteristic facial dysmorphism and MRI findings, we sequenced the SURF1 gene and identified two heterozygous mutations; c.49+1 G>T and c.752_753del in Case 1, and homozygous c.743 C>A in Case 2. For patients with Leigh syndrome showing these facial dysmorphism and hypertrichosis, sequence analysis of the SURF1 gene may be useful.
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PMID:Two Japanese patients with Leigh syndrome caused by novel SURF1 mutations. 2241 Apr 71


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