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1.
Exercise-induced cramp, myoglobinuria, and tubular aggregates in phosphoglycerate mutase deficiency 总被引:2,自引:0,他引:2
We report two patients in whom phosphoglycerate mutase (PGAM) deficiency was associated with the triad of exercise-induced cramps, recurrent myoglobinuria, and tubular aggregates in the muscle biopsy. Serum creatine kinase (CK) levels were elevated between attacks of myoglobinuria. Forearm ischemic exercise tests produced subnormal increases of venous lactate. Muscle biopsies showed subsarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM activities were markedly decreased (3% of the normal mean) and molecular genetic studies showed that both patients were homozygous for a described missense mutation (W78X). A review of 15 cases with tubular aggregates in the muscle biopsies from our laboratory and 15 cases with PGAM deficiency described in the literature showed that this clinicopathological triad is highly suggestive of PGAM deficiency. 相似文献
2.
McArdle disease (gycogenosis type V): analysis of clinical, biological and genetic features of five French patients 总被引:1,自引:0,他引:1
Delmont E Sacconi S Berge-Lefranc JL Aquaron R Butori C Desnuelle C 《Revue neurologique》2008,164(11):912-916
INTRODUCTION: McArdle disease (glycogenosis type V) is an autosomal recessive metabolic myopathy. Defect in glycogen breakdown is due to mutations of the gene for myophosphorylase (PYGM). Among patients of the department, we searched for correlations between disease phenotype, biochemistry analysis of muscle samples and PYGM genotype. METHODS: We included five patients whose muscle biopsy showed deposits of glycogen and negative histochemical staining for myophosphorylase. RESULTS: All patients exhibited exercise intolerance and high serum CK levels (mean 4400). Two of them had an acute renal insufficiency caused by rhabdomyolysis. One patient developed moderate late-onset muscle weakness of the proximal part of upper limbs. Muscle glycogen concentration was high (three times the normal). Myophosphorylase activity was undetectable in four muscle samples out of five. Two patients were homozygous and two other heterozygous for the R50X mutation of PYGM. The other one had a novel missense mutation S814N. Patients homozygous for R50X mutation had higher CK levels (8080 versus 1457, p=0.046), but disease severity and muscle glycogen concentrations were equivalent. CONCLUSIONS: Our patients had typical clinical and laboratory features of McArdle disease. Diagnosis was suggested by exercise intolerance with high CK levels. The R50X mutation was the most common (60% of the mutated alleles). We found no relationship between clinical severity, PYGM genotype and biochemistry analysis of muscle samples. 相似文献
3.
Mitochondrial myopathies (MM) are characterized by alterations in oxidative phosphorylation. The resultant increase in glycolytic flux produces a variable lactic acidosis. Intracellular acidification can induce both metabolic and, in the case of skeletal muscle, contractile dysfunction. Skeletal muscle lactate transporters have recently been identified which include both monocarboxylate transporter 1 (MCT1) and 4 (MCT4). Lactate import into oxidative skeletal muscle appears to be catalyzed by MCT1, whereas its extrusion from glycolytic fibers may be mediated by MCT4. We describe the expression of these isoforms in a patient with MM as compared to controls (n = 5). MCT4 content was 86% (>3 SD) higher in the patient with MM, whereas MCT1 content was less markedly elevated (47%), as compared to controls. These findings support previous work suggesting that the major role of MCT4 is to defend intracellular pH by extruding lactate and H(+) to the interstitium. The role of MCT1 in MM is less clear. 相似文献
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Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study 总被引:10,自引:0,他引:10
Transcellular transport of energy substrates across the vascular endothelial cells of the brain is accomplished by integral membrane carrier proteins, such as the glucose transporter GLUT1 and the monocarboxylic acid transporter MCT1. The abundance of these proteins may vary depending on age and nutritional status. In this study we compared the expression of MCT1 in cerebral cortex of suckling and adult rats to determine whether the former, which use considerably more monocarboxylates such as lactate and ketone bodies as fuel than do older rats, correspondingly express more MCT1 than adults. Using electron microscopic immunogold methods, we found that 17-day old suckling rat pups had 25 times more MCT1 labeling in the membranes of capillary endothelial cells than adults. This transporter was nearly equally distributed in luminal and abluminal membranes with less than 10% of the immunogold particles in the endothelial cytoplasmic compartment. The suckling rats also had 15 times more immunogold particles associated with pericyte membranes and 19 times heavier labeling of membranes associated with astrocytic end feet adjacent to microvessels. Neuropil and choroid plexus were lightly labeled. Some MCT1-positive astrocyte and neuron cell bodies were observed, suggesting active synthesis of MCT1 by these cells. The potential for regulation of expression of MCTs by dietary or other factors may have important consequences for the progression and treatment of cerebrovascular disorders and other diseases. 相似文献
6.
Roberto Fernandez-Hojas Maryann L Huie Carmen Navarro Carmen Dominguez Manuel Roig Diana Lopez-Coronas Susana Teijeira Kwame Anyane-Yeboa Rochelle Hirschhorn 《Neuromuscular disorders : NMD》2002,12(2):159-166
Glycogen storage disease type II is an autosomal recessive muscle disorder due to deficiency of lysosomal acid alpha-glucosidase and the resulting intralysosomal accumulation of glycogen. We found six novel mutations in three Spanish classic infantile onset glycogen storage disease type II patients with involvement of both cardiac and skeletal muscle; three missense mutations (G219R, E262K, M408V), a nonsense mutation (Y191X), a donor splice site mutation (IVS18 +2gt>ga) and an in frame deletion of an asparagine residue (nt1408-1410). The missense mutations were not found in 100 normal chromosomes and therefore are not normal polymorphic variants. The splice site mutation was subsequently detected in an additional 'Spanish' infantile onset glycogen storage disease type II patient from El Salvador. Further studies will be required to determine if the IVS18 +2gt>ga splice site mutation might in fact be a relatively common Spanish mutation. Mutations among Spanish glycogen storage disease type II patients appear to be genetically heterogeneous and differ from common mutations in neighboring countries. 相似文献
7.
Kitaguchi T Matsubara S Sato M Miyamoto K Hirai S Schwartz K Bonne G 《Neuromuscular disorders : NMD》2001,11(6-7):542-546
A case of autosomal dominant limb-girdle muscular dystrophy with atrioventricular conduction block (LGMD1B) has been documented. In this family, 13 members, nine males and four females, had cardiac arrhythmia requiring pacemakers. The proband, a 67-year-old male, had longstanding proximal muscle weakness later associated with cardiac arrhythmia but showed neither rigid spine nor joint contracture. His muscle enzymes were within normal range and muscle biopsy showed myopathic changes. Gene analysis of the proband revealed Tyr481His mutation in the exon 8 of lamin A/C (LMNA) gene which is adjacent to the codon mutated in reported cases of familial partial lipodystrophy. This is the first report of muscular dystrophy shown to have a mutation of LMNA in a Japanese family as well as the first case of missense mutation in the exon 8 with LGMD1B phenotype. 相似文献
8.
Nevo Y Soffer D Kutai M Zelnik N Saada A Jossiphov J Messer G Shaag A Shahar E Harel S Elpeleg O 《Journal of child neurology》2002,17(7):499-504
Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity. 相似文献
9.
Lactate is transported across cell membranes by diffusional, saturable cotransport with protons, mediated by monocarboxylate transporters (MCTs). This transport is bidirectional and in the absence of a transcellular H(+) gradient, it can increase the intracellular concentration of lactate up to but not beyond the extracellular level (or vice versa). If extra- and intracellular pH differ, however, the equilibrium level is determined by the gradients of both lactate anions and protons. Rates of lactate uptake are determined most often by measuring uptake of labeled lactate, e.g., [U-14C]lactate. In the case of lactate and other compounds that are metabolized, errors are introduced easily because continuing inwardly directed diffusional net transport of label can be achieved by intracellular metabolism, reducing the intracellular level of the nonmetabolized lactate and thus maintaining a concentration gradient between extra- and intracellular concentrations of the nonmetabolized compound (metabolism-driven uptake). For measurement of facilitated diffusion kinetics, it is essential that the period during which the uptake is measured is short enough that little or no metabolism-driven uptake contributes to the measured uptake (or that first-order regression analysis is carried out to obtain initial uptake rates from nonlinear traces). To achieve initial uptake rates, incubation periods well below 1 min are generally required. Lactate uptake is fast in astrocytes, which express powerful, low-affinity MCTs, i.e., MCT1 and MCT4. Due to the low affinity of these transporters, they respond to increased lactate gradients with enhanced transporter activity. The predominant MCT in neurons is the high-affinity MCT2, which can only increase its activity to a limited extent in the face of an increased lactate gradient. This is reflected by a high-affinity lactate uptake, although most investigators also have demonstrated a component of lactate uptake with lower affinity. In both neurons and astrocytes, however, facilitated diffusion is fast enough that under most conditions lactate fluxes will be determined mainly by the rate of metabolism-driven uptake, and MCT-mediated transport only will be rate-limiting after establishment of large transmembrane gradients. 相似文献
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Lauritzen F de Lanerolle NC Lee TS Spencer DD Kim JH Bergersen LH Eid T 《Neurobiology of disease》2011,41(2):577-584
Monocarboxylate transporter 1 (MCT1) facilitates the transport of important metabolic fuels (lactate, pyruvate and ketone bodies) and possibly also acidic drugs such as valproic acid across the blood-brain barrier. Because an impaired brain energy metabolism and resistance to antiepileptic drugs are common features of temporal lobe epilepsy (TLE), we sought to study the expression of MCT1 in the brain of patients with this disease. Immunohistochemistry and immunogold electron microscopy were used to assess the distribution of MCT1 in brain specimens from patients with TLE and concomitant hippocampal sclerosis (referred to as mesial TLE or MTLE (n=15)), patients with TLE and no hippocampal sclerosis (non-MTLE, n=13) and neurologically normal autopsy subjects (n=8). MCT1 was present on an extensive network of microvessels throughout the hippocampal formation in autopsy controls and to a lesser degree in non-MTLE. Patients with MTLE were markedly deficient in MCT1 on microvessels in several areas of the hippocampal formation, especially CA1, which exhibited a 37% to 48% loss of MCT1 on the plasma membrane of endothelial cells when compared with non-MTLE. These findings suggest that the uptake of blood-derived monocarboxylate fuels and possibly also acidic drugs, such as valproic acid, is perturbed in the epileptogenic hippocampus, particularly in MTLE. We hypothesize that the loss of MCT1 on brain microvessels is mechanistically involved in the pathophysiology of drug-resistant TLE, and propose that re-expression of MCT1 may represent a novel therapeutic approach for this disease. 相似文献
12.
David Z. Gerhart Bradley E. Enerson Olga Y. Zhdankina Richard L. Leino Lester R. Drewes 《Glia》1998,22(3):272-281
The nucleotide sequence of the rat monocarboxylate transporter MCT2 was determined from brain-derived cDNA. A polyclonal antibody was raised in chickens against the carboxyl terminal end of the deduced amino acid sequence and affinity purified. The MCT2 antibody identified a 46-kDa band on immunoblots and labeled kidney, skeletal muscle, and stomach consistent with the reported cellular expression for this transporter. Light microscopic immunocytochemistry indicated that the MCT2 transporter was abundant in glial limiting membranes, ependymocytes, and neuropil, particularly in the lacunosum molecular layer of hippocampus and the molecular layer of cerebellum. Labeled astrocytes were commonly observed in white matter. The distribution of this transporter differed in several respects from that previously reported for MCT1. MCT2 was abundantly distributed in astrocyte foot processes and was usually not detected in other cells of the cerebrovasculature, including vascular smooth muscle cells, pericytes, and endothelium. In addition, the granular layer of cerebellum, which showed little MCT1 labeling, exhibited MCT2 labeling of cellular processes in the neuropil surrounding the granule and Purkinje cells. The results lend support to the concept that astrocytes play a significant role in cerebral energy metabolism by transporting lactate and other monocarboxylates. GLIA 22:272–281, 1998. © 1998 Wiley-Liss, Inc. 相似文献
13.
Based on recent work demonstrating age-dependent ketogenic neuroprotection after traumatic brain injury (TBI), it was hypothesized that the neuroprotection among early post-weaned animals was related to induced cerebral transport of ketones after injury. Regional changes in monocarboxylate transporter 2 (MCT2) were acutely examined with immunohistochemistry after sham surgery or controlled cortical impact injury among postnatal day 35 and adult rats. Both ages showed elevated MCT2 expression in the ipsilateral cerebral vasculature after TBI. Using Western blotting, MCT2 expression was 80-88% greater in microvessels isolated from postnatal day 35 rats at all time points relative to adults. The increased MCT2 expression was temporally correlated with an age-related increase in cerebral uptake of ketones, when ketones were made available after injury. 相似文献
14.
We aimed to correlate pathologic findings with MTM1 mutation type in a series of molecularly defined XLMTM cases. Clinical data from 15 XLMTM patients and their corresponding 16 muscle biopsies were studied. All patients were infants (range: 6-217 days old) when initially biopsied. The proportion of myofibers with central nuclei did not correlate with clinical outcome, however, morphometric studies showed that survivors had larger myofiber diameters in infancy than those who died (10.4+/-3.9microm versus 8.9+/-3microm; p<0.001). As a corollary, patients with MTM1 missense mutations had larger myofiber diameters (11.1+/-4microm), than those with truncation/deletion mutations (8.6+/-2.7microm) (controls 11.7+/-2.5microm) (p<0.0001). These data indicate that differences in myofiber size correlate with MTM1 mutation type and patient outcome. Failure to attain and/or maintain myofiber size, along with fiber type perturbations and the misplacement of myofiber nuclei and other organelles, are important components of XLMTM muscle pathology. 相似文献
15.
Monocarboxylates like lactate are provided by astrocytes and can be used as fuel by neurons and oligodendrocytes. In an autoimmune inflammatory environment, homeostatic functions of astrocytes are incompletely understood. In primary Lewis rat astrocytes, co-culture with MHC class II-restricted myelin basic protein (MBP)-specific T cells in the presence of MBP resulted in a marked upregulation of the astrocytic lactate transporter MCT1 that is to export lactate into the extracellular space. It was evident that the increase in MCT1 was triggered by T cells in an antigen-dependent manner. The glial isoform of the glucose transporter GLUT1 was not regulated under these conditions. T-cell blasts that had been pre-activated by antigen and splenic antigen-presenting cells (APCs) beforehand also led to an increase in the expression of astrocytic MCT1 after co-culture. Resting T cells did not induce a relevant upregulation of MCT1 in astrocytes. However, resting T cells stimulated the expression of MCT1 when anti-MHC class II antibodies, but not when anti-MHC class I antibodies, were added to the co-culture. Therefore, even in the presence of inactive T cells, complexation of MHC class II molecules on astrocytes might lead to the regulation of certain astrocytic transport proteins. Consistent with the in vitro experiments, an upregulation of MCT1 was observed in the spinal cord of autoimmune encephalitic rats while GLUT1 expression appeared to be unchanged. This T-cell-mediated regulation of MCT1 might contribute to a compensatory or protective mechanism in order to guarantee substrate pools for neurons and oligodendrocytes under inflammatory conditions. 相似文献
16.
Previous studies have identified several genetic loci associated with the development of familial inclusion body myopathy. However, there have been few genetic analyses of sporadic inclusion body myositis (sIBM). In order to explore the molecular basis of sIBM and to investigate genotype-phenotype correlations, we performed a clinicopathological analysis of 21 sIBM patients and screened for mutations in the Desmin, GNE, MYHC2A, VCP, and ZASP genes. All coding exons of the five genes were sequenced directly. Definite IBM was confirmed in 14 cases, probable IBM in three cases, and possible IBM in four cases. No cases showed missense mutations in the Desmin, GNE, or VCP genes. Three patients carried the missense mutation c.2542T>C (p.V805A) in the MYHC2A gene; immunohistochemical staining for MYHC isoforms in these three cases showed atrophy or loss of muscle fibers expressing MYHC IIa or IIx. One patient harbored the missense mutation c.1719G>A (p.V566M) in the ZASP gene; immunohistochemical studies of Z-band-associated proteins revealed Z-band abnormalities. Both of the novel heterogeneous mutations were located in highly evolutionarily conserved domains of their respective genes. Cumulatively, these findings have expanded our understanding of the molecular background of sIBM. However, we advocate further clinicopathology and investigation of additional candidate genes in a larger cohort. 相似文献
17.
目的对比分析重型颅脑损伤患者在神经外科重症监护室(NICU)做床旁移动CT(MCT)扫描和转运患者到放射科做常规CT(CCT)扫描时,所需要的医护人员数、累计工作量、相关并发症发生率等,总结移动CT临床应用技术特色和优势。
方法介绍重型颅脑损伤患者床旁移动CT扫描和常规CT扫描的方法,对比分析2010年8月至2015年12月北京军区总医院附属八一脑科医院1917例在NICU做移动CT床旁扫描和593例在放射科做常规CT扫描的相关并发症及技术操作失误、需要的医护人员数及累计工作量,并依据伤情将MCT组和CCT组分为特重型(GCS 3~5分)和重型(GCS 6~8分)两个亚组,分析移动CT在颅脑损伤的临床应用技术特色和优势。
结果在NICU应用移动CT为重型颅脑损伤患者行床旁移动CT扫描,操作简便安全,无需转运患者。移动CT组中GCS 3~5和GCS 6~8分亚组的并发症发生率分别为3.32%和0%,而相同GCS亚组的常规CT扫描组并发症发生率高达26.87%,18.82%(P<0.05)。移动CT床旁扫描仅需要3名医护人员参加,GCS 3~5分和GCS 6~8分亚组耗时分别为(15.02±1.53) min和(13.01±1.31) min,3人累计工作耗时分别为(45.05±1.54) min和(39.03±1.32) min,而转运患者到放射科做常规CT扫描需要5名医护人员参加,其与MCT相同GCS亚组的耗时分别为(40.04±4.32) min和(30.03±3.13) min,5人的累计工作耗时高达(200.23±4.45) min和(150.18±3.35) min (P<0.05)。
结论在NICU使用移动CT床旁扫描操作简便,安全可靠,可显著减少因院内转运患者到放射科做常规CT扫描引起的相关并发症,明显减少医护人员数量和累计工作时间。 相似文献
18.
Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber's hereditary optic neuropathy
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Lodi R Carelli V Cortelli P Iotti S Valentino ML Barboni P Pallotti F Montagna P Barbiroli B 《Journal of neurology, neurosurgery, and psychiatry》2002,72(6):805-807
Occipital lobe and calf muscle energy metabolism were studied in vivo by magnetic resonance spectroscopy (31P-MRS) in four members of a family harbouring the mitochondrial DNA G3460A mutation causing Leber's hereditary optic neuropathy (LHON). Three siblings carried 100% mutated mitochondrial DNA (homoplasmy), while their mother had coexistence of mutated and wild-type mitochondrial DNA (heteroplasmy). Indices of brain energy metabolism on 31P-MRS were abnormal in all subjects examined, but the muscle oxidative phosphorylation rate was normal. These findings indicate a tissue specific distribution of the biochemical expression of the G3460A LHON mutation and suggest that extramitochondrial factors, such as nuclear genes, may influence expression of this mutation in vivo. 相似文献
19.
Caspers M Pavlova A Driesen J Harbrecht U Klamroth R Kadar J Fischer R Kemkes-Matthes B Oldenburg J 《Thrombosis and haemostasis》2012,108(2):247-257
Deficiencies of natural anticoagulant proteins including antithrombin (AT), protein C (PC) and protein S (PS) are important causes of inherited thrombophilia. This study aimed to report on the practical experience gained in performing genetic analyses of a large cohort of patients with AT, PC and PS deficiencies and to relate this knowledge to clinical application. We genotyped a large cohort of 709 unrelated patients with AT (231), PC (234) and PS (244) deficiencies referred to us by physicians throughout Germany. Mutations were detected by direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The highest mutation detection rate (MDR) was found for the SERPINC1 gene (83.5%), followed by the PROC (69%) and PROS1 (43%) genes. Even at AT activities close to the normal range (75%), the MDR was 70%. Contrastingly, for PC and PS deficiencies, the MDR dropped significantly and mildly lowered to subnormal values. At PS activities >55% for PS no mutations were detected. Mutation profiles of all three genes were similar with the highest prevalence for missense mutations (63-78%), followed by nonsense (7-11%), splice-site mutations (7-13%), small deletions (1-8%), small insertions/duplications (1-4%) and large deletions (3-6%). In conclusion, genetic testing is a useful diagnostic tool for diagnosing thrombophilia. Based on our data, genetic analysis for patients with AT deficiency is indicated for all subnormal activities. In contrast, genotyping is not advisable for PC activities >70% and for PS activities >55%. 相似文献
20.
R. Lodi D. J. Taylor S. J. Tabrizi S. Kumar M. Sweeney N. W. Wood P. Styles G. K. Radda A. H. V. Schapira 《Annals of neurology》1997,42(4):573-579
We used 31P magnetic resonance spectroscopy (31P-MRS) to asses in vivo skeletal muscle mitochondrial function in 10 Leber's hereditary optic neuropathy patients/carriers with a mitochondrial DNA (mtDNA) mutation at one of three nucleotide positions, 11,778, 14,484, and 3,460. We studied one affected patient for each mutation and two unaffected carriers with the 11,778 or 3,460 mutation and three carriers with 14,484. All subjects were homoplasmic except the two 3,460 carriers, who showed 80% and 15% of mutated mtDNA. 31P-MRS at rest disclosed some abnormalities in all subjects. In particular, the phosphorylation potential was below the normal range in all cases. During recovery from exercise, the maximum rate of mitochondrial ATP production (Vmax) was reduced to 27% of normal in the 11,778 mutation and to 53% in the 14,484 mutation patient/carrier groups. Mitochondrial Vmax was within the normal range in all subjects with the 3,460 mutation but correlated inversely with the percentage of mutated mtDNA. This in vivo study shows that the 11,778 mutation causes a mitochondrial impairment more severe than the 14,484 and that the 3,460 mutation results in only a mild depression of muscle mitochondrial function. 相似文献