线粒体基因突变所致的遗传性线粒体病

青年女性患者,慢性起病,临床表现为多系统损害。肾脏损害表现为少至中等量尿蛋白,尿隐血基本阴性,血清肌酐正常,高尿酸血症,血压正常,无贫血。肾外表现身材矮小、糖尿病、高频听力下降及预激综合征,母亲身高150 cm。肾活检病理表现为局灶节段性肾小球硬化(FSGS),肾小球多处足细胞、壁层上皮细胞、肾小管上皮细胞胞质内线粒体形态异常。基因检测分析到线粒体MT-TL1基因m.3243A>G突变,母系遗传。最终诊断为线粒体基因突变所致的遗传性线粒体病。     

IgA肾病合并线粒体病

16岁女性,典型肾病综合征起病,且足量激素治疗有效.肾活检病理组织学见肾小球节段轻度系膜增生性病变,免疫荧光IgG、IgA及Clq系膜区沉积,电镜下系膜区增宽,并见系膜区电子致密物沉积,肾小球足细胞足突广泛融合,病理诊断为IgA肾病(微小病变型).2年后患者肾病综合征复发,并出现多系统损害,血白细胞基因检测示8969G＞A基因突变,符合线粒体病.尽管重切电镜标本观察到肾小管上皮细胞胞浆中异常线粒体蓄积,但不能证实肾脏疾病与线粒体相关,最终诊断为IgA肾病合并线粒体病.     

线粒体DNA突变合并肾脏损害

目的:探讨3例线粒体病合并慢性肾脏病(CKD)患者的临床特点及预后. 方法:2011年5月至2012年9月在南京军区南京总医院全军肾脏病研究所住院的CKD患者中共3例经线粒体DNA(mtDNA)基因检测确诊线粒体病,分析其肾外受累及肾脏损害的临床表现和肾活检病理特点,并观察其预后. 结果:(1)3例患者中2例青少年(14岁),另1例30岁,全部患者均消瘦(体质量指数13 ～ 17 kg/m2).例1生长发育迟缓,例3为早产儿.例1、例2有糖尿病家族史,例2有尿毒症家族史.(2)3例患者病程3～7月,临床均表现为水肿、蛋白尿和胱抑素C增高,肾小管损伤明显,均无高血压和镜下血尿.例1和例3组织学示局灶节段性肾小球硬化(FSGS),例2肾小球轻度系膜增生伴小动脉节段透明变性.(3)3例患者中糖尿病(2例)、高乳酸血症(2例)、听力消失或下降(3例)、癫痫发作(1例)、脑梗塞(1例)、智力障碍(2例)、视野缺失(1例),心律失常(1例).(4)3例患者均经基因测序并证实mtDNA 3243 A＞G突变位点,例2母亲和弟弟也检出与患者相同突变位点.(5)经治疗3例均停免疫抑制剂,补充辅酶Q10和左卡尼汀等治疗,蛋白尿部分缓解,血清肌酐稳定. 结论:本文首次在国内报道3例伴肾脏损害的线粒体病患者,提示这类患者并非罕见,临床除肾脏受累外均伴明显的心脏和中枢神经系统损害.临床医师应加强对此类疾病的认识.     

线粒体基因突变糖尿病一家系分析

目的 探讨糖尿病(DM)家系中的线粒体基因突变位点.方法 采用PCR、DNA直接测序技术,对9例临床疑似线粒体基因突变DM家系进行线粒体基因突变高发区域tRNALeu(UUR)基因检测.结果 该家系发现与DM发病有关的突变位点均位于nt3243A→G,且家系中大部分患者伴有消瘦、耳聋、β细胞功能低下、发病年龄低的特点.结论 线粒体tRNALeu(UUR)基因3243位点A→G突变可导致DM和耳聋.     

广州管圆线虫线粒体基因组比较分析

目的 目的 比较我国大陆地区广州管圆线虫线粒体基因组的多态性。 方法 方法 在种群遗传学研究基础上, 选取7条雌虫进行线粒体基因组的测定。根据广州管圆线虫线粒体基因组已知序列 （GQ398121） 设计12对引物, 进行PCR扩增, 并对目的片段进行测序和拼接。利用多种生物学软件对测定的线粒体基因组进行基因定位、 结构图绘制、 核苷酸及变异位点分析、 进化关系分析。结果 结果 获得5个不同遗传类型的线粒体基因组。这些基因组的大小相似、 结构相同, 即 13 491～13 502对碱基, 含12个蛋白编码基因, 2个核糖体基因, 22个tRNA基因, 2个较大的非编码区。上述基因紧密地排列在同一条DNA链上, 并具有相同的转录方向。通过对这些基因组的比对发现, 变异位点745个, 占整个基因组的5.5%。其中, 缺失/插入突变59个, 碱基颠换105个, 碱基转换581个。这些突变位点均匀地分布在整个线粒体基因组中。结论 结论本研究提供了丰富的广州管圆线虫线粒体基因的突变位点, 为构建种内鉴别诊断技术提供了基础。     

mtDNA Cyt-b、 ATPase6在浸润性乳腺癌中的突变及意义

目的 检测线粒体DNA (mtDNA) Cyt-b、ATPase6在浸润性乳腺癌组织和癌旁组织的突变情况,寻找特异性位点.方法 采用PCR结合基因测序方法,对延边朝鲜族地区浸润性乳腺癌患者(30例)的癌组织及癌旁组织进行mtDNA Cyt-b、ATPase6基因测序,对照人线粒体DNA剑桥修定序列,分析其突变情况.结果 在研究对象的乳腺癌mtDNA中共发现Cyt-b基因区有6个高突变发生率位点,即A15326G、C14766T、G15301A、G15043A、T14783C、C15402T,其中A15326G、C14766T突变率最高;而ATPase6基因区共发现3个高突变发生率位点,即C8673T、A8729G、T8955C,其中C8673T、A8729G突变率最高.结论 mtDNA Cyt-b、mtDNA ATPase6高突变发生位点可为浸润性乳腺癌的诊断及乳腺癌细胞线粒体功能评价提供有价值的参考.     

急性髓系白血病患者线粒体DNA的D-loop区存在突变

目的研究线粒体DNA的D-loop区突变与白血病发生、发展的关系。方法应用盐析法对8例初治的成人急性髓系白血病患者及其生母和正常无关对照者的外周血基因组DNA提取、线粒体基因D-loop区PCR扩增、序列测定,对比分析白血病患者的线粒体基因D-loop区序列与其生母和健康无关对照者的线粒体基因D-loop区序列与标准剑桥线粒体基因D-loop区序列的差异。结果8例白血病患者中6例存在突变(突变率75%),共查出突变位点11个,突变类型均为D-loop区的T-C、A-C、G-A碱基替代突变。结论线粒体DNA的D-loop区在白血病患者中的突变率较高,D-loop区的突变在白血病发生发展过程中可能起作用。     

线粒体基因T3271C点突变致线粒体脑肌病伴乳酸血症和卒中样发作综合征一例

目的探讨线粒体脑肌病伴高乳酸血症和卒中样发作综合征(MELAS)的临床、影像、病理及基因突变特点。方法回顾性分析1例MELAS患者的临床资料,并复习文献报道的mtDNA T3271C突变所致线粒体病的病例。结果患者临床表现为反复癫痫发作、发作性头痛、高乳酸血症、智能减退等,头颅MRI示双侧额、颞、顶、枕叶多发异常信号,MRS示左侧额顶叶病变可见高耸倒置的Lac峰。肌肉活检病理见数个典型和不典型破碎红纤维。外周血基因检测提示mtDNA T3271C杂合突变,突变率28%。结论 mtDNA T3271C是MELAS较常见的致病性突变,MELAS临床表现多样,磁共振波普成像(MRS)改变明显有助诊断,但确诊仍需肌肉活检或基因检测。     

慢性乙型肝炎合并Gilbert综合征患者33例临床及其基因突变分析

目的 探讨慢性乙型肝炎合并Gilbert综合征患者的临床特点及其基因突变位点分析.方法 对33例慢性乙型肝炎合并Gilbert综合征患者的肝脏生物化学指标、病理组织学特点及基因检测位点分析,对基因检测结果根据不同突变位点进行分析,数据分析应用x2检验和t检验. 结果 33例患者Gilbert综合征特异性编码的UGT1A1基因检测显示突变位点集中表现在启动子上游PBREM-3263 (-3279)突变(23例)和启动子TATA盒TA插入突变(21例),以及编码区外显子EXON1上的GGA-AGA Gly71Arg突变(18例),3个常见位点突变之间差异无统计学意义(x2=1.640,P＞ 0.05).结论 慢性乙型肝炎合并Gilbert综合征患者诊断依靠传统方法仍比较困难,而基因检测为该疾病的诊断提供了更有利的帮助.     

伴糖尿病的遗传综合征(续)代谢亢进性线粒体综合征(Ernster-Luftz综合征)

正文表现 肌病 中枢神经病变 心肌病变 眼病变 酸中毒 高血糖 又称线粒体肌病综合征(mitochondrial encaphalomyopathies syndrome)系线粒体(mt)基因突变所致的一种线粒体功能障碍性线粒体病(mitochondrialdisorders).1959年Ernster等首先报道,1962年Luftz等进一步命名为线粒体肌病.     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Fibromyalgia and widespread pain were common in Gulf War veterans with unexplained illness referred to a rheumatology clinic. Increased tenderness was demonstrated in the postmenstrual phase of the cycle compared with the intermenstrual phase in normally cycling women but not in users of oral contraceptives. Patients with fibromyalgia had high levels of symptoms that have been used to define silicone implant-associated syndrome. Tender points were found to be a common transient finding associated with acute infectious mononucleosis, but fibromyalgia was an unusual long-term outcome. The common association of fibromyalgia with other rheumatic and systemic illnesses was further explored. A preliminary study revealed a possible linkage of fibromyalgia to the HLA region. Patients with fibromyalgia were found to have an impaired ability to activate the hypothalamic pituitary portion of the hypothalamic pituitary adrenal axis as well as the sympathoadrenal system, leading to reduced corticotropin and epinephrine response to hypoglycemia. Much interest has been expressed in the literature on the possible role of autonomic dysfunction in the development or exacerbation of fatigue and other symptoms in chronic fatigue syndrome. Mycoplasma genus and mycoplasma fermentans were detected by polymerase chain reaction in patients with chronic fatigue syndrome. It was reported that myofascial temporomandibular disorder does not run in families. No major therapeutic trials in fibromyalgia, chronic fatigue syndrome, or myofascial pain syndrome were reported over the past year. The effectiveness of cognitive behavioral therapy and behavior therapy for chronic pain in adults was emphasized. A favorable outcome of fibromyalgia and chronic fatigue syndrome in children and adolescents was reported.     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

The prevalence of chronic widespread pain in the general population in Israel was comparable with reports from the USA, UK, and Canada. Comorbidity with fibromyalgia (FM) resulted in somatic hyperalgesia in patients with irritable bowel syndrome. One sixth of the subjects with chronic widespread pain in the general population were also found to have a mental disorder. Mechanisms involved in referred pain, temporal summation, muscle hyperalgesia, and muscle pain at rest were attenuated by the N-methyl-D-aspartate (NMDA) antagonist, ketamine, in FM patients. Delayed corticotropin release, after interleukin-6 administration, in FM was shown to be consistent with a defect in hypothalamic corticotropin-releasing hormone neural function. The basal autonomic state of FM patients was characterized by increased sympathetic and decreased parasympathetic systems tones. The severity of functional impairment as assessed by the Medical Outcome Survey Short Form (SF-36) discriminated between patients with widespread pain alone and FM patients. Chronic fatigue syndrome (CFS) occurred in about 0.42% of a random community-based sample of 28,673 adults in Chicago, Illinois. A significant clinical overlap between CFS and FM was reported. Cytokine dysregulation was not found to be a singular or dominant factor in the pathogenesis of CFS. A favorable outcome of CFS in children was reported; two thirds recovered and resumed normal activities. No major therapeutic trials in FM and CFS were reported over the past year.     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

There continues to be an emerging body of literature related to fibromyalgia and the related conditions chronic fatigue syndrome and myofascial pain. During the past year, the most notable contributions included a large multicenter study providing new diagnostic criteria for the classification of fibromyalgia and clinical studies describing the overlap of fibromyalgia, chronic fatigue syndrome, and myofascial pain. Pathophysiologic studies were often preliminary and uncontrolled but the focus of these studies on abnormal nociception, neurohormones, and muscle metabolism provides an exciting hypothesis to unify pain, fatigue, and sleep disturbances, the primary symptoms of fibromyalgia. Unfortunately, new therapeutic trials were neither innovative nor especially encouraging.     

Diagnosis of non-Zollinger-Ellison syndrome, non-carcinoid syndrome, enteropancreatic neuroendocrine tumours

The diagnosis of entero-neuropancreatic tumours different from Zollinger-Ellison syndrome and carcinoid syndrome require an high index of suspicion and even when they are associated to virulent syndromes such as VIPoma or insulinoma syndrome the mean delay in diagnosis is of 4 years. Symptomatic hypoglycaemia due to inappropriate insulin release from insulinoma and watery diarrhoea leading to dehydration caused by elevated circulant vaso-intestinal peptide levels are present in the 90% and 100% of the patients at presentation of the respective syndrome. Somatostatinoma syndrome has a far more subtle presentation and it tends to present much later during the disease course. The diagnosis is based on the presence of gallstones, diabetes, weight loss, diarrhoea and steatorrhoea. Growth hormone releasing factor neuroendocrine tumours (GRFoma) present with acromegaly and account for less than 2% of the acromegalic patients in which the growth hormone is from an ectopic source located in the pancreas. The Cushing's syndrome diagnosis due to rare ectopic neuroendocrine tumour adrenocorticotropic hormone secretion can be made only with selective angiography, whereas non-functional and pancreatic polypeptide producing neuroendocrine tumours (PPoma) present without any symptoms. Finally, multiple endocrine neoplasia type one occurs more commonly with somatostatinoma or GRFoma, conversely patients with multiple endocrine neoplasia type one can develop insulinoma (20%) or PPoma (60%).     

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome.

Fibromyalgia was almost completely absent from an urban affluent population compared with poor urban and rural communities. Seventeen percent of Gulf War veterans with soft tissue syndromes had fibromyalgia, a much higher rate than was seen in previous studies of rheumatic disease in the military population. A state of central hyperexcitability in the nociceptive system was reported in fibromyalgia. Altered functioning of the stress-response system has been further documented in fibromyalgia and chronic fatigue syndrome. Administration of growth hormone to patients with fibromyalgia who have low levels of insulin-like growth factor 1 resulted in improvement in their symptoms and tenderness. An association between chronic fatigue syndrome and initial infections was demonstrated. A correlation between particular immunologic abnormalities and measures of disease severity was documented in chronic fatigue syndrome. Concomitant fibromyalgia in other rheumatic diseases was a major contributor to poor quality of life. A favorable outcome of fibromyalgia in children was reported; the majority of patients improved over 2 to 3 years of follow-up. Treatment of patients with fibromyalgia continues to be of limited success.     

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

The eosinophilia-myalgia syndrome, which is associated with the ingestion of L-tryptophan that contained products, occurred as an epidemic in the United States in 1989. Eosinophilia-myalgia syndrome is similar in many ways to the toxic-oil syndrome, which occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, which has been noted since 1974 to occur sporadically. Recent studies have clarified the epidemiology, histopathology, and clinical features of eosinophilia-myalgia syndrome. These studies are reviewed, and comparisons to the related syndromes, toxic-oil syndrome and diffuse fasciitis with eosinophilia, are made.