成人发病的肌原纤维肌病的临床和病理学特征(附2例报告)

目的 探讨成人发病的肌原纤维肌病的临床和病理学特征.方法 回顾性分析2例成年发病的肌原纤维肌病患者的临床资料.结果 2例患者表现为近端或远近端肌肉无力,进行性加重.光镜下可见肌纤维内和肌膜下颗粒样或团块样物质沉积,免疫组化为结蛋白.电镜发现1例肌膜下及肌原纤维间存在大小不一的包涵体,另1例肌原纤维排列紊乱,Z线不规则样增粗.常见突变基因检测未见异常.结论 成人发病的肌原纤维肌病临床无特异性表现,其病理学特征为肌纤维内可见异常物质沉积,电镜发现肌原纤维间包涵体结构或Z线异常.     

常染色体隐性遗传肌原纤维肌病的临床和病理学特点(附1例报告)

目的 探讨常染色体隐性遗传的肌原纤维肌病(MFMs)的临床和病理学特点.方法 回顾性分析1例病理确诊的常染色体隐性遗传MFMs患者的临床资料.结果 本例7岁起病,表现为四肢无力,缓慢进行性加重,由近端向远端发展,伴有心脏损害.其父母为近亲婚配,其兄自幼年出现相似的肌无力,38岁时猝死.肌肉病理检查示肌纤维空泡性改变,以非镶边空泡为主,部分肌纤维内出现结蛋白沉积;未发现结蛋白基因、αB晶体蛋白基因及肌收缩蛋白基因突变.结论 常染色体隐性遗传MFMs可幼年期发病,四肢无力由近端向远端发展,累及心肌;病理学特点为肌纤维空泡性改变和结蛋白沉积.     

成人型杆状体肌病二例临床病理和超微结构研究

目的 探讨成人型杆状体肌病的临床病理和超微结构特点。方法 对2例成人型杆状体肌病患者的肌肉组织病理和超微结构进行观察。结果 2例患者均以颈肌无力起病，以后四肢和躯干肌不同程度受累，无骨骼发育畸形。肌肉组织病理改变的特点为选择性I型纤维萎缩，改良Gomori三色法染色可见萎缩纤维内含大量深紫色颗粒状物。例1发现大量中央核纤维。电镜观察可见肌原纤维排列紊乱，大量杆状体形成。在例1的肌核内发现核内包涵体，结构特点与胞质内的杆状体相似。结论 成人型杆状体肌病临床缺乏特征性。肌肉病理中央核可与杆状体同时出现，与婴儿型和儿童型杆状体肌病相比，成人型患者肌纤维萎缩明显。肌核内可出现包涵体，其结构与胞质内杆状体一致。     

以胞质体-球形体为主要病理改变的肌原纤维肌病一家系

目的 报道1个以胞质体和球形体为主要病理改变的肌原纤维肌病家系,分析其临床、病理和基因特点.方法 家系中连续5代10例均在35～40岁出现进行性下肢无力,其中6例出现心肺损害症状,4例出现腹泻.对先证者肌肉活体组织检查标本行组织学、酶组织化学、免疫组织化学(抗tau蛋白、结蛋白、泛素、dysferlin以及dystrophin-C'、N'和R抗体)染色及电镜检查.对肌缩蛋白(MYOT)、α-B晶体蛋白链(CRYAB)、结蛋白、z带选择性接合PDZ蛋白(LDB3)、核纤层蛋白A/C(LMNA)、含硒蛋白N1(SEPN1)基因的外显子以及丝蛋白C(FLNC)基因的第48号外显子进行分析.结果 病理检查显示肌纤维内存在大量胞质体和球形体,伴随结蛋白、tau蛋白、泛素、dysferlin和dystrophin-C'、R蛋白阳性表达.电镜显示包涵体内含致密颗粒样物,其周围为放射样分布的细丝.没有发现上述7种基因外显子序列异常.结论 肌原纤维肌病具有多系统损害特点;肌纤维内存在的胞质体和球形体含有多种微管和膜相关蛋白;该病可能存在未知基因突变.     

伴有破碎红纤维的包涵体肌炎的临床及病理学特点(附1例报告)

目的 探讨伴有破碎红纤维的包涵体肌炎的临床及病理学特点.方法 回顾性分析1例伴有破碎红纤维的包涵体肌炎患者的临床资料.结果 本例为中年男性,四肢近端进行性肌萎缩,血清肌酶轻度增高,肌电图示肌源性损害.肌活检示部分萎缩的肌纤维出现镶边空泡,空泡内含有嗜碱性颗粒,部分坏死肌纤维有吞噬细胞及炎症细胞浸润,改良Gomori染色见破碎红纤维,细胞色素酶染色见蓝纤维;泛素染色示肌纤维中有泛素阳性物质沉积.mtDNA突变分析未见线粒体DNA突变.结论 伴有破碎红纤维的包涵体肌炎以近端肌肉受损为著,病理表现除包涵体和炎症性改变外,还存在代谢紊乱和异常折叠的蛋白沉积的特征.     

伴有明显胃肠道症状的脂质沉积性肌病1例报告

目的:探讨脂质沉积性肌病(LSM)的临床和病理。方法:通过一例确诊为LSM的病例的临床症状、实验室检查、肌电图及病理检查,系统回顾LSM的发病机理、临床表现、病理及治疗。结果:该患四肢无力伴胃肠道症状,血清肌酶高、病理检查Ⅰ型纤维明显萎缩并有大量脂滴沉积,在肌纤维膜下和肌原纤维之间均可以见到脂肪滴成串或堆排列。结论:LSM是脂代谢异常性肌病。可表现有胃肠道症状,确诊还需病理检查。     

16例线粒体肌病和线粒体脑肌病电镜观察分析

目的探讨线粒体肌病与脑肌病患者肌肉的超微结构特征,分析该病的病因和可能的发病机制。方法对16例线粒体肌病与脑肌病患者的肌活检组织进行光镜和电镜超微病理观察。结果电镜观察16例,在肌原纤维间和肌膜下可见弥漫的线粒体数目增多,13例表现为形态异常,可见巨大线粒体,嵴结构不清,排列紊乱,呈同心圆样,均可见线粒体内类结晶状包涵体,有的同时伴有糖原颗粒的异常增多、脂滴沉积及溶酶体异常,有的线粒体只能靠双层膜结构及残存的嵴被识别。3例仅线粒体数量增多,未见其他异常。结论电镜观察肌膜下和肌原纤维间线粒体异常增多且形态异常,特别是线粒体内类结晶状包涵体,对本病的诊断有重要价值。     

脂质沉积性肌病的临床及病理学特点

目的探讨脂质沉积性肌病(LSM)的临床及病理学特点。方法对14例LSM患者的临床及骨骼肌病理资料进行分析。结果14例LSM患者的主要临床表现为以近端肌无力起病,渐累及全身,其中13例四肢受累,1例双下肢受累,2例颈肌受累,伴肌痛2例、肌萎缩3例;血清肌酸激酶正常5例,不同程度增高9例;14例肌电图均呈肌源性损害;14例骨骼肌病理检查(HE、MGT染色)可见大量肌纤维胞浆内散在空泡,油红"O"染色空泡红染;透射电镜分析可见沿肌纤维长轴散在串珠样膜性空泡结构。结论LSM临床表现为非特异性肌无力;肌纤维内脂质沉积是LSM主要病理表现;骨骼肌病理检查是确诊LSM的可靠方法。     

脂质沉积性肌病临床、神经电生理及肌肉病理研究

目的 研究脂质沉积性肌病(LSM)的临床、神经电生理及肌肉病理学特征.方法 回顾性分析8例LSM患者的临床、肌肉病理和神经电生理资料.结果 此组患者为亚急性或慢性起病,主要表现为近端肌无力,活动后易疲劳,血清肌酶升高;HE染色见肌纤维内出现大量裂隙样改变及微小空泡,油红O染色反应增强,表现为肌纤维内空泡或裂隙充满脂肪滴,ATP染色显示两型肌纤维均受累,以I型肌纤维为主;电镜证实肌纤维内有大量脂肪滴沉积.部分病例肌电图表现为肌源性损害.8例LSM患者经卡尼汀和糖皮质激素治疗均有效.结论 LSM是一种以肌无力和运动不耐受为主要表现的脂质代谢性肌病,病理改变以肌纤维内脂质沉积为主,采用卡尼汀和糖皮质激素等治疗效果较好.     

脂质沉积性肌病的临床、神经电生理和骨骼肌病理分析

目的 探讨脂质沉积性肌病(LSM)的临床表现、神经电生理及肌肉病理特点.方法 回顾分析16例LSM的临床表现、肌电图和神经传导、肌肉活检病理改变.结果 LSM主要临床特点为亚急性或慢性起病,以近端肌无力为主,症状呈波动性,肌无力重而肌萎缩轻.血清肌酶有不同程度的升高,肌电图多为肌源性损害,激素、核黄素治疗有效.临床上容易误诊为多发性肌炎、肌营养不良症、心肌炎、胃肠道疾病等.肌肉病理学特点为肌纤维内可见大量均匀的小筛孔样空泡,部分空泡融合成大泡或形成裂隙状.ORO染色证实筛孔样空泡被大量红染的脂肪颗粒充填,受累肌纤维以Ⅰ型纤维为主.4例患者行电镜检查可见肌原纤维间有大量脂滴沉积,其中1例伴有异常线粒体增多.结论 LSM是一种以易疲劳和肌无力为主要临床表现的脂质代谢障碍性肌病,肌无力较重而肌萎缩轻.神经电生理改变相对较轻,部分患者肌电图为肌源性损害.激素、核黄素治疗可获得良好疗效,肌肉活检病理学检查是诊断LSM的重要手段.     

Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations.     

New phenotype and pathology features in MYH7-related distal myopathy

Laing distal myopathy is an autosomal dominant disease due to mutations in the gene encoding for the human slow-β myosin heavy chain, MYH7. Most reports describe it as a mild, early onset myopathy with involvement usually restricted to foot extensors, hand finger extensors and neck flexors, and unspecific findings on muscle biopsy. We identified the first two Italian families with Laing distal myopathy, harboring two novel mutations in the MYH7 gene and performed clinical, neurophysiological, pathological, muscle MRI and cardiological investigations on affected members from the two families. Subjects from one family presented a moderate-severe phenotype, with proximal together with distal involvement and even loss of ambulation at advanced age. One patient displayed atypical muscle biopsy findings including cytoplasmic bodies and myofibrillar myopathy-like features. Affected members from the second family shared a very mild phenotype, with weakness largely limited to long toe and foot extensors and/or late onset. No patient showed any sign of heart involvement. Our study significantly broadens the clinical and pathological spectrum of Laing distal myopathy. We suggest that MYH7 screening should be considered in undiagnosed late-onset distal myopathy or cytoplasmic body myopathy patients.     

Myopathy with tubulin-reactive inclusions in two cats

Many types of inclusions have been described in human myopathies including but not limited to nemaline rod bodies, cylindrical spirals, tubular aggregates, cytoplasmic bodies, reducing bodies, and fingerprint bodies, and hyaline inclusions in myofibrillar myopathy and inclusion body myositis. There are very few reports describing inclusions in spontaneously occurring myopathies in cats, and these reports are limited to nemaline rod myopathy. A myopathy with tubulin-reactive crystalline inclusions has recently been reported in a human patient with a clinical presentation of myalgia and fatigue. Similarly, a myopathy with chronic, slowly progressive muscle weakness has been identified here in two unrelated cats. Inclusions were the only pathological change in skeletal muscle biopsies and, ultrastructurally, groups of crystalline structures were evident that had a subsarcolemmal or central location, rhomboid or rectangular shapes, lacked orientation, and were not membrane bound. The crystalline structures reacted positively with an antibody against tubulin. This feline myopathy may be the equivalent of the human myopathy with tubulin-positive crystalline inclusions.     

Widening the spectrum of filamin-C myopathy: Predominantly proximal myopathy due to the p.A193T mutation in the actin-binding domain of FLNC

We report three patients with a predominantly proximal myopathy due to p.A193T mutation in the actin-binding domain of FLNC, which has so far only been associated with a distal myopathy. They presented with a late onset myopathy characterized by predominant limb-girdle and proximal weakness. We describe the clinical, electrophysiological, pathological, muscle imaging and genetic features. One of our patients did not have typical histological features for a myofibrillar myopathy in muscle biopsy. This observation is important for the recognition of the full clinical spectrum of filamin-C-related myopathies. Muscle imaging has an important role in distinguishing the different filamin-C myopathy types.     

A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy

We report a family with adult-onset myofibrillar myopathy with BAG3 mutation who presented peroneal weakness and axonal polyneuropathy, mimicking axonal Charcot-Marie-Tooth disease. The male proband noticed difficulty in tiptoeing at age 34. At age 42, the examination showed muscle weakness and atrophy in distal lower extremities with diminished patellar and Achilles tendon reflexes. Thermal and vibration sensations were also impaired in both feet. The serum CK level was 659 U/L. On muscle imaging, predominant semitendinosus muscle atrophy coexisted with atrophies in the quadriceps, gastrocnemius and lumbar paraspinal muscles. The muscle biopsy showed myofibrillar myopathy with fiber type grouping. His 68-year-old mother also had suffered from distal leg weakness and sensory impairment since her forties. A heterozygous mutation in BAG3 (P470S) was identified in both patients. Clinical features of myofibrillar myopathy with axonal polyneuropathy were consistent with BAG3-related myopathy. Our patients showed remarkably mild presentations without cardiomyopathy, unlike the majorities of previously reported cases.     

Filamin C-related myopathies: pathology and mechanisms

The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy.     

Novel recessive myotilin mutation causes severe myofibrillar myopathy

We identified the first homozygous and hence recessive mutation in the myotilin gene (MYOT) in a family affected by a severe myofibrillar myopathy (MFM). MFM is a rare, progressive and devastating disease of human skeletal muscle with distinct histopathological pattern of protein aggregates and myofibrillar degeneration. So far, only heterozygous missense mutations in MYOT have been associated with autosomal dominant myofibrillar myopathy, limb-girdle muscular dystrophy type 1A and distal myopathy. Myotilin itself is highly expressed in skeletal and cardiac muscle and is localized at the Z-disc and therefore interacts in sarcomere assembly. We performed whole-exome sequencing in a German family clinically diagnosed with MFM and identified a homozygous mutation in exon 2, c.16C?>?G (p.Arg6Gly). Using laser microdissection followed by quantitative mass spectrometry, we identified the myotilin protein as one component showing the highest increased abundance in the aggregates in the index patient. We suggest that the combined approach has a high potential as a new tool for the confirmation of unclassified variants which are found in whole-exome sequencing approaches.     

Myotilinopathy in a family with late onset myopathy

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.     

Nonaka肌病的骨骼肌存在内质网应激改变

目的 探讨我国Nonaka肌病患者骨骼肌病理改变特点.方法 收集2002年1月到201 1年3月我院就诊的Nonaka肌病患者共13例,其中男性7例,女性6例,男女比例1.17:1,平均年龄39.5岁,平均病程4.15年,平均发病年龄35.4岁.主要表现为双足抬起无力,股四头肌早期不受累,1例患者以上肢无力起病.对13例患者进行骨骼肌活体组织检查,标本作组织病理学、超微病理学及免疫组织化学检查.免疫组织化学染色的第一抗体分别为tau蛋白、β-淀粉样蛋白、泛素抗体,抗内质网分子伴侣相对分子质量为78 000的葡萄糖调节蛋白( GRP78)及calnexin抗体、抗凋亡蛋白细胞质天冬氨酸特异性半胱氨酸蛋白酶12(caspase-12)、Bax抗体,同时取3例慢性疲劳综合征患者的骨骼肌、2例肌原纤维肌病患者的骨骼肌分别作为健康对照和疾病对照.所有患者进行尿苷二磷酸-N-乙酰葡萄胺-2-表位酶基因序列检测.结果 12例取材为胫前肌的患者经光镜检查显示肌营养不良样改变伴随肌纤维内镶边空泡形成.部分肌纤维空泡含有tau蛋白、β-淀粉样蛋白抗体及泛素阳性物质,内质网分子伴侣蛋白GRP78及calnexin在这些肌纤维内明显增加,凋亡相关蛋白caspase12、Bax表达升高.结论 Nonaka肌病患者的骨骼肌存在异常蛋白沉积,由此诱发的内质网应激和凋亡反应可能参与了肌纤维的损伤过程.