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This report describes a child having the syndrome of overlapping phenotypic features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Mitochondrial DNA analysis revealed a point mutation at position A3243G, whereas activity of thymidine phosphorylase and its corresponding gene analysis were normal. The most striking feature of this case was paralysis of one segment of the terminal ileum observed on laparotomy. The electron microscopic findings of the resected ileum and colon by limited right hemicolectomy disclosed accumulation of numerous enlarged mitochondria with ill-defined cristae which were similar to mitochondria reported in three previous MELAS cases and one MNGIE case with intestinal dysmotility. We emphasize that the MELAS and MNGIE phenotypes overlapped in this case and that the mechanism of acute ileus in MELAS was associated with functional paralysis of the intestine. 相似文献
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Kornblum C Broicher R Walther E Seibel P Reichmann H Klockgether T Herberhold C Schröder R 《Neurology》2001,56(10):1409-1412
To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction. 相似文献
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We compared the distribution of deleted mitochondrial DNA (Delta-mtDNA) in skeletal muscle of a patient with autosomal recessive (AR) and another with autosomal dominant (AD) progressive external ophthalmoplegia (PEO) by in situ hybridization (ISH). The patients studied had similar numbers of fibers deficient in cytochrome c oxidase (COX) activity (13.6% and 12.8%) and fibers with mitochondrial proliferation (5.5% and 5.3%). ISH suggested that each COX-deficient fiber contained a single species of Delta-mtDNA. Most deletions ablated the region between the genes encoding adenosine triphosphate (ATP) synthase subunit 8 and cytochrome b. Fibers that appeared to be depleted of mtDNA were also present. We conclude that muscle from patients with autosomally inherited PEO contains not only Delta-mtDNA but also focal depletion of mtDNA and that the distribution of these mtDNA defects appears to be similar. These changes most likely represent the common consequence of whatever genetic factors are responsible for the generation of Delta-mtDNA. 相似文献
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Mitochondrial changes are frequently observed in muscle fibers of patients with inclusion body myositis (IBM) and polymyositis
(PM), suggesting that mitochondrial function may be especially impaired in these forms of inflammatory myopathies. Intranuclear
and cytoplasmic tubulofilamentous inclusions are characteristic, although not totally specific for IBM. In the present cases,
the inclusions were strikingly pleomorphic when chloroquine had been given for long periods. The nuclear inclusions were always
tubular, whereas the cytoplasmic filaments had either a tubular, a helical, or a cross-striated structure with different diameters
and arrangements in association with myelin-like figures, and vacuoles. Abnormal mitochondria containing paracrystalline,
globoid, and other inclusions, noted in IBM, were occasionally also seen in PM or vasculitis. By contrast, in the latter,
no intranuclear or cytoplasmic tubulofilamentous inclusions were apparent in muscle fibers. This study reports for the first
time the presence of membrane-bound crystalloid inclusions in a muscle fiber with numerous abnormal mitochondria; similar
structures have thus far only been observed in macrophages. The identity and function of these inclusions remains unknown.
Using PCR analysis we detected different mtDNA deletions not only in IBM, but also in PM and vasculitis, indicating at least
some degree of association between the structural mitochondrial abnormalities and the mtDNA mutations. There was no topographical
correlation between the presence of tubular or helical filaments and the mitochondrial abnormalities. As already noted by
others, the mitochondrial changes in IBM were more frequent than expected in this age group. It is suggested that the presence
of the mtDNA deletions in IBM and PM are not primary, but rather the result of the underlying, presumably immunological disorder
causing nuclear and secondary or simultaneous mitochondrial changes.
Received: 12 May 1997 / Revised, accepted: 17 February 1998 相似文献
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Blakely EL Butterworth A Hadden RD Bodi I He L McFarland R Taylor RW 《Neuromuscular disorders : NMD》2012,22(7):587-591
Disorders of mitochondrial DNA (mtDNA) maintenance are clinically and genetically heterogeneous, embracing recessive mtDNA depletion syndromes affecting children and adult-onset multiple mtDNA deletion disorders. Here we show that mutation of MPV17 - a gene implicated in severe, infantile hepatocerebral mtDNA depletion disorders characterised by a loss of mtDNA copies - can also cause clonally-expanded mtDNA deletion and focal cytochrome c oxidase (COX) deficiency in skeletal muscle associated with an adult presentation of neuropathy and leukoencephalopathy. The mpv17 protein is therefore intimately involved in both the mtDNA replication and repair processes and associated with both quantitative and qualitative mtDNA abnormalities. 相似文献
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We describe a 17-year-old male with neurologic and cardiovascular disorders characterized by complete atrioventricular block and a mitochondrial cytopathy with clinical, structural, biochemical, and molecular features shared by chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. The patient's manifestations included progressive external ophthalmoplegia, bilateral ptosis, muscle weakness, delayed development, and progressive hearing loss with multiple mitochondrial DNA deletions, including an abundant 11-kb novel deletion and reduced specific activities of respiratory complexes I, III, and IV present in skeletal muscle. Ultrastructural analysis of biopsied muscle revealed a heterogenous mixture of normal and abnormal mitochondria with unusual cristae. This unique mitochondrial DNA deletion, which eliminates the origin of mitochondrial DNA replication for the light strand, may be responsible for generating an intermediate clinical phenotype. 相似文献
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Leber遗传性视神经病的线粒体基因突变及临床特征 总被引:2,自引:1,他引:1
目的 了解Leber遗传性视神经病 (LHON)线粒体基因突变及其临床特征。方法 采用PCR法扩增96例视神经病变患者mtDNA中ND1、ND4、ND6上的 3个片段后 ,用 377测序仪对mtDNA上 11778、346 0、14 4 84位点进行序列分析确定有无碱基突变。结果 96例患者中 4 0例 (41 7% )线粒体基因突变 ,其中男性 34例 (85 % ) ,女性 6例 (15 % ) ;34例 (85 % )为 11778位点突变 ,2例 (5 % ) 346 0位点突变 ,4例 (10 % ) 14 4 84位点突变 ;346 0及 14 4 84突变均为散发病例 ;有家族史者突变表达占 87 0 % (2 0 /2 3) ,无家族史者突变占 2 7 4 % (2 0 /73) ;头颅MR显示 11778突变者中 3例有脑白质区病灶 ,1例LHON合并垂体瘤 ;12例突变阳性者检查脑脊液 ,11例有炎性脱髓鞘改变。结论 LHON以 11778突变常见 ;起病及病程多样化、散发病例比例较高、眼底微血管病改变不易发现、脑脊液改变与炎性脱髓鞘雷同导致LHON在临床上易漏诊误诊 ,应尽早行突变检测明确诊断。 相似文献
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Ferreira M Evangelista T Almeida LS Martins J Macario MC Martins E Moleirinho A Azevedo L Vilarinho L Santorelli FM 《Neuromuscular disorders : NMD》2011,21(7):483-488
Diseases affecting mtDNA stability, termed nuclear-mitochondrial intergenomic communication disorders, are caused by a primary nuclear gene defect resulting in multiple mtDNA deletions.The aim of this study was to estimate the frequency of known etiologies and the spectrum of mutations in a cohort of 21 patients harboring multiple mtDNA deletions in skeletal muscle.We showed that 10 cases (48%) display mutations in POLG, including eight previously reported variants and two novel mutations (namely, p.Trp585X and p.Arg1081Gln). The novel mutations affect evolutionary conserved residues and were absent in a large set of control chromosomes. These findings expand the array of mutations associated with multiple rearranged mtDNA attributed to mutations in POLG. The relatively high diagnostic yield (about one in two cases) supports the notion that it is recommended to test POLG routinely in diagnostic laboratories whenever multiple mtDNA deletions are present, regardless of the age of onset of patients and their clinical phenotype. 相似文献
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Gamez J Ferreiro C Accarino ML Guarner L Tadesse S Martí RA Andreu AL Raguer N Cervera C Hirano M 《Neurology》2002,59(3):455-457
Clinical, biochemical, and genetic features of a Spanish family with mitochondrial neurogastrointestinal encephalomyopathy are reported. The proband presented with severe gastrointestinal dysmotility and the affected sister had extraocular muscle weakness. In both affected individuals, biochemical defects of thymidine phosphorylase and a pathogenic G-to-A transition mutation at nucleotide 435 in the thymidine phosphorylase gene were identified. The first thymidine phosphorylase mutation identified in Spain showed phenotypic variability at onset. 相似文献
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Chalmers RM 《Neurology》2002,58(4):670; author reply 670
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Luis G. Alcalá-González Anna Accarino Ramon Martí Daniel Sánchez-Tejerina Arnau Llauradó Fernando Azpiroz Carolina Malagelada 《Neurogastroenterology and motility》2023,35(10):e14643
Background
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms.Methods
Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022.Key Results
In this period, five patients diagnosed of MNGIE (age range 16–46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms.Conclusions and Inferences
MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated. 相似文献16.
Casali C Bonifati V Santorelli FM Casari G Fortini D Patrignani A Fabbrini G Carrozzo R D'Amati G Locuratolo N Vanacore N Damiano M Pierallini A Pierelli F Amabile GA Meco G 《Neurology》2001,56(6):802-805
The authors describe a family of Sephardic Jews with progressive external ophthalmoparesis, skeletal muscle weakness, and parkinsonism. Autosomal recessive inheritance was suggested by many consanguineous marriages, although a dominant disorder could not be excluded. No linkage to known progressive external ophthalmoparesis locus was found. The presence of cytochrome c oxidase-negative ragged-red fibers, biochemically reduced respiratory chain complexes, and multiple mitochondrial DNA deletions in muscle biopsies from four patients suggested a new mitochondrial disorder of intergenomic communication. 相似文献
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Jansson M Darin N Kyllerman M Martinsson T Wahlström J Oldfors A 《Acta neuropathologica》2000,100(1):23-28
We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized
by congenital joint contractures and slowly progressive, proximal muscle weakness and ophthalmoplegia. There is deterioration
of muscle function between 30 and 50 years of age. While young patients show minor pathological changes in muscle, the middle-aged
and old patients show rimmed vacuoles and inclusions of filaments measuring 15–18 nm in diameter. Except for the absence of
significant inflammation the histopathology is similar to that found in sporadic inclusion body myositis (s-IBM). In s-IBM
mitochondrial alterations including cytochrome c oxidase (COX) -deficient muscle fibers are common. These are due to multiple mitochondrial DNA (mtDNA) deletions. In this
study we investigated the occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young affected individuals
showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-deficient
muscle fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions. By in situ hybridization clonal expansions
of mtDNA with deletions were demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion breakpoints showed
nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletions are
present in this family with h-IBM. The same factors may be involved in the development of mtDNA deletions in s-IBM and this
family with h-IBM.
Received: 13 July 1999 / Revised: 6 October 1999 · Accepted: 12 October 1999 相似文献
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线粒体DNA A3243G点突变在成年患者中的临床特点 总被引:2,自引:1,他引:2
目的 探讨mtDNA A3243G点突变在成年患者的临床表现特点.方法 对发病年龄在18岁以上的36例患者的临床资料进行分析(5个家系28例,散发8例),其中23例行mtDNAA3243G点突变检查(5个家系15例,散发8例),14例行头颅影像学检查,10例进行了骨骼肌病理检查.结果 5个家系的28例患者中出现糖尿病17例(60.7%)、耳聋16例(57.1%)、卒中样发作9例(32.1%),三者可以并存或单独出现,少见表现包括心肌病和肾脏损害.23例mtDNA A3243G点突变患者中线粒体脑肌病伴随乳酸血症和卒中样发作(MELAS)14例(61.0%),其主要表现为认知功能障碍、言语障碍和头痛;其余9例包括无症状的基因突变携带者3例(13.0%)、线粒体糖尿病和(或)神经性耳聋2例(8.7%)、自主神经功能异常2例(8.7%)、糖尿病伴不孕症1例(4.3%)和心肌病1例(4.3%).14例MELAS患者的头颅影像学检查显示以枕叶和颞叶受累为主,额叶最少;10例肌肉病理检查发现9例存在不整红边纤维.mtDNA A3243G点突变比例均值在MELAS患者为28.75%±13.69%,非MELAS患者为25.08%±11.54%,两者差异没有统计学意义.结论 mtDNAA3243G点突变在成年患者主要累及中枢神经、胰岛以及听神经.认知功能障碍、言语障碍和头痛是成年MELAS的主要临床表现.家族中多例患者出现糖尿病和耳聋,提示该突变并非MELAS突变,应当关注mtDNA A3243G点突变家系中非MELAS患者的存在. 相似文献
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Alexander Nicholas Yevgenya Kraytsberg Xinhong Guo Konstantin Khrapko 《Experimental neurology》2009,218(2):316-319
mtDNA deletions are pathogenic mutations that remove substantial portions of the mitochondrial genome. mtDNA deletions accumulate with age and have been implicated in various degenerative diseases. There are multiple mtDNA per cell and mtDNA mutations become toxic only if they accumulate to substantial intracellular levels, i.e. exceed so-called “phenotypic threshold”. This is usually achieved via clonal expansion of a single initial mutated molecule. Intracellular mitochondrial genomes are analogous to a population of individuals in that mitochondria are born by division and die by degradation. Clonal expansion within cells is thus analogous to genetic drift within populations and is driven by a combination of random processes and selection. mtDNA mutations occurring early in development are expected to end up spread across tissues, while mutations of late origin are expected to be localized, i.e. limited a single post-mitotic cell or progeny of a single stem cell. We have explored the extent and timing of clonality of mtDNA deletion in human muscle using single-molecule PCR. We analyzed deletions from two nearby locations within the same tissue sample. Altogether we analyzed over 130 mutant molecules, but almost every deletion type detected was represented by several identical mutant molecules, so that altogether there were only 21 different kinds of deletions, implying that essentially all deletions were clonal. At the same time the sets of deletions in the two locations were completely different. This observation implies that all of the clonal expansions spanned very small areas and therefore that the corresponding mutations were likely events of older age. More studies are necessary to further validate these findings in muscle and to explore the other tissues. 相似文献