Dysferlin肌病11例临床与病理特征分析

目的探讨Dysferlin肌病的临床表现,辅助检查特点。方法回顾性分析收集的11例Dysferlin肌病患者(男8例,女3例)的临床特点,肌酸激酶、肌电图、病理活检及治疗,门诊随访2年判断肌力提高或降低至少1级为明显改变标准。结果 11例dysferlin肌病患者平均发病年龄(29.2±9.1)岁,男性居多,至确诊平均病程7年,主要表现为肌无力、肌萎缩。肢带型营养不良2B型(limb girdle muscle dystrophy 2B,LGMD2B)首发部位多为四肢近端,主要为下肢近端;Miyoshi肌病(miyoshi myopathy,MM)首发部位多为双下肢远端。所有患者肌酸激酶均升高平均5126 IU/L,肌电图显示肌源性损害,肌肉活检免疫组化染色肌纤维膜Dysferlin缺乏。目前无根治药物,Dysferlin肌病进展缓慢,随访2年病情无明显变化。结论 Dysferlin肌病诊断需要结合临床特点及相应辅助检查,可以早期诊断,避免漏诊、误诊。     

Dysferlin蛋白缺陷的Miyoshi肌病的临床与病理学特点

目的探讨dysferlin蛋白缺陷的Miyoshi肌病(MM)的临床与病理学特点。方法对3例MM患者的临床及病理资料进行分析。结果3例患者均为青少年起病,临床主要表现均为下肢远端无力伴肌肉明显萎缩,其中1例发病初期伴有小腿肌肉疼痛肿胀,1例下肢近端肌肉无力;3例患者血清肌酸磷酸激酶均明显升高,分别为7543IU/L、5657IU/L、8721IU/L;2例乳酸脱氢酶升高,分别为465IU/L、636IU/L。3例肌肉病理均为肌源性损害,肌细胞膜dysferlin蛋白明显缺失,dystrophin表达正常;其中1例肌肉病理有炎细胞浸润。结论MM患者均为青少年起病,临床以下肢无力及肌萎缩为特点,病理可见肌细胞膜dysferlin蛋白缺失。     

肢带型肌营养不良2B型的临床和病理特点

目的研究肢带型肌营养不良2B型的临床及病理特点。方法回顾性分析5例肢带型肌营养不良2B型患者的临床资料和骨骼肌病理检查结果。结果5例(3例四肢,2例双下肢)表现肌肉萎缩、肌无力,缓慢起病,进行性加重。病理检查5例骨骼肌均有不同程度肌纤维变性、坏死、再生,不同程度炎性细胞浸润;免疫组化染色:5例患者抗dysferlin单克隆抗体均无表达,抗Dystrophy、Sarcoglycan、dystroglycan单克隆抗体均表达正常,抗CD8+T细胞单克隆抗体均无表达,抗组织相容性复合体(MHC)-1单克隆抗体表达均上调。结论肢带型肌营养不良2B型的临床特点是缓慢起病,进行性加重的四肢(或双下肢)肌萎缩、肌无力;其病理学特点与多发性肌炎的改变相似。     

α-Sarcoglycanopathy的临床和病理学特征(附2例报告)

目的探讨α-Sarcoglycanopathy的临床和病理学特征。方法回顾性分析2例α-Sarcoglycanopathy患者的临床资料。结果本组2例患者均表现为近端肌肉无力,进行性加重。肌肉活检均可见肌间结缔组织及脂肪组织增生,肌纤维萎缩,偶见肌纤维变性、坏死和吞噬现象,未见炎细胞浸润;免疫组化染色示抗α-Sarcoglycan蛋白完全缺失,抗β、γ、δ-sacogiycan蛋白和抗dystrophin蛋白部分缺失。结论α-Sarcoglycanopathy临床表现较其他类型肌营养不良无特异性,病理学特征为免疫组化染色示抗α-Sarcoglycan蛋白完全缺失。     

Dysferlinopathy的免疫病理与基因突变分析

目的通过PCR-测序技术确定Dysferlinopathy患者的致病突变并探讨其分子免疫病理特点。方法收集临床拟诊肢带型肌营养不良及Miyoshi肌病患者,所有患者肌肉活检后进行组织学、酶组织化学、免疫组织化学(IHC)染色,对从外周血中提取的基因组DNA进行PCR-测序。结果 4例患者肌肉组织IHC染色证实肌纤维膜dysferlin蛋白缺失。基因检测发现1例患者含有DYSF(dysferlin基因)纯合突变、另3例患者含有复合杂合突变,其中c.2693del G、c.5511C>A、c.5516A>T、c.863A>T、c.1617C>A为首次报道的新发突变。3例患者IHC染色显示:肌纤维细胞膜区域存在不同程度的MHC-1免疫沉积,坏死肌纤维部位有C5b-9补体沉积。所有病例均有肌纤维内脂滴轻度增加。结论发现5种DYSF基因新发突变;免疫病理特点的研究有助于本病与炎性肌肉病的鉴别;脂滴增加现象支持继发于膜修复损伤的脂肪转运障碍参与病理发病机制。     

肢带型肌营养不良2A型临床和病理特点

目的探讨肢带型肌营养不良2A型(LGMD2A)的临床及病理特点。方法回顾性分析7例基因确诊的LGMD2A型患者的临床资料和骨骼肌病理检查结果。结果 1例尚未出现临床症状。1例症状很轻,仅有易疲劳伴运动时小腿痛,肌力检查正常。另外5例均以下肢近端肌无力缓慢起病,进行性加重,之后上肢近端肌不同程度受累,均伴有翼状肩胛及跟腱挛缩,仅1例见腓肠肌肥大及脊柱畸形,下肢近端肌群肌力检查提示伸髋及髋内收受累最重,其次为屈髋及屈膝,髋外展及伸膝受累最轻。该5例患者的骨骼肌病理均呈肌营养不良样病理改变,表现为肌纤维大小不等、结缔组织增生及不同程度坏死、再生,NADH染色2例见大量分叶纤维。结论 LGMD2A的临床变异较大,其典型临床特点为慢性进行性近端肌无力伴翼状肩胛、关节挛缩,股后肌群及内侧肌群较股前肌群受累明显。其肌肉病理缺乏特异性。     

25例肢带型肌营养不良症临床分析

目的　探讨肢带型肌营养不良症 (LGMD)临床和实验室检查的特点。方法　对根据临床症状体征、血清肌酸激酶、肌电图、肌肉病理及dystrophin免疫组化确诊的 2 5例LGMD患者进行分析。结果　我国LGMD多为散发 ,发病相对较晚 ,多数首先累及骨盆带肌 ,进展缓慢 ,对肢体功能影响较轻 ,免疫组化染色显示dystrophin正常。结论　根据LGMD临床特点 ,结合肌电图、肌肉病理 ,特别是dystrophin免疫组化染色可以作出诊断 ,而肌聚糖病等LGMD亚型的诊断只能依靠检测基因或基因产物来确定     

类固醇肌病的临床和病理特点分析（附10例报道）

目的：探讨类固醇肌病的临床和病理特点。方法：收集2007至2011年收治的10例有使用糖皮质激素史,并经肌肉活检病理证实的类固醇肌病患者的临床资料,分析并总结其临床和病理特点。结果：10例类固醇肌病患者中女性6例、男性4例,年龄14~79（51.1±18.5）岁。使用激素后至起病时间为7 d至14个月。所有病例均表现为四肢近端无力,股四头肌均呈不同程度萎缩,7例以双下肢近端受累为主,3例同时有上臂肌群萎缩;血清肌酸激酶（CK）和CK-mb均正常,9例乳酸脱氢酶（LDH）值高于正常上限;肌电图示轻度肌源性损害;肌肉活检均可见肌纤维大小不一;酶学染色提示：Ⅱ型纤维选择性萎缩。结论：类固醇肌病好发于中老年人群,多在使用糖皮质激素数周至数月后发生,肌无力和肌萎缩以下肢近端为主,血清CK基本正常,LDH轻度增高,肌肉病理示选择性Ⅱ型纤维萎缩为其病理特点。     

DNAJB6基因突变致显性遗传性肌病一家系并文献复习

目的 总结常染色体显性遗传性DNAJB6基因突变所致肌病的临床表型和基因突变特点.方法 回顾分析一家系2例DNAJB6基因突变所致肌病患者的临床表现、实验室、肌肉影像学、神经电生理学、肌肉病理学和基因检测结果,并进行文献复习.结果 先证者主要表现为四肢远近端肌无力,下肢重于上肢、近端重于远端,其父呈姿势异常,上楼需扶持...     

肢带型线粒体肌病一个家系的临床和病理特点研究

目的研究肢带型线粒体肌病一个家系中患者的临床和骨骼肌病理特点。方法对一组以进行性肌肉无力为主要特点的家系中的3名患者进行临床资料收集及肌肉活检病理分析,对家系成员行线粒体基因检测。结果该家系患者发病年龄为30~47岁,主要表现为躯干肌及四肢近端肌无力和运动耐力下降,晚期出现呼吸肌受累。血肌酸激酶水平轻度升高,血乳酸升高,电生理检查结果示肌源性损害。骨骼肌病理检查显示3名患者均存在典型的破碎红纤维(RRF),且患者病程越长(分别为2年、4年和14年),肌无力严重程度越重,RRF数量越多(分别为5%、10%和30%)。细胞色素c氧化酶(COX)染色中RRF以深染为主,也可见阴性的RRF。琥珀酸脱氢酶(SDH)染色均未发现琥珀酸脱氢酶高反应性血管(SSVs)。基因检测发现该家系存在mt DNA A3243G突变。结论肢带型线粒体肌病患者选择性累及躯干和四肢近端肌群,骨骼肌中的RRF数量与患者病情进展程度呈正相关。     

Distal anterior compartment myopathy with early ankle contractures

Dysferlinopathies exhibit marked heterogeneity in the initial distribution of muscle involvement at the onset of the disease. We describe a Japanese patient with dysferlinopathy who exhibited distal anterior compartment myopathy (DACM) with early contractures of the ankle, whose pedigree included patients with two other types of dysferlinopathy. The existence of three phenotypes of dysferlinopathy in one pedigree is reported, indicating the involvement of molecules other than dysferlin in the pathogenesis.     

Dysferlinopathy associated with rigid spine syndrome

Dysferlinopathy and rigid spine syndrome occurring in a 50‐year‐old man is reported. The patient noticed stiffness of knee and ankle joints, which gradually extended to neck, wrist and elbow joints leading to difficulty in anterior flexion. Muscular weakness and wasting of the lower extremities had developed since age 40, accompanied by a limitation of anterior bending of the spine. Elevated serum CK was noticed. Muscle CT revealed atrophy with moderate fatty replacement of muscles in the neck, shoulder and pelvic girdle, and marked replacement in the para‐vertebral muscles, posterior compartment of hamstrings and calf muscles. Electromyography showed a typical myogenic pattern, and muscle biopsy disclosed dystrophic changes, compatible with limb‐girdle muscular dystrophy 2B. Loss of dysferlin expression was verified by immunohistochemistry, which was confirmed by a mini‐multiplex Western blotting system. Gene analyses of the dysferlin gene disclosed compound heterozygotes for frameshift (G3016 + 1A) and a missense mutation (G3370T). This study might propose some clues to resolve the combination of musular dystrophies and rigid spine syndrome.     

Progressive dysphagia in limb-girdle muscular dystrophy type 2B

Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype.     

Pattern of skeletal muscle involvement in primary dysferlinopathies: a whole‐body 3.0‐T magnetic resonance imaging study

Objectives and methods – Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0‐T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). Results – Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole‐body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. Conclusions – Whole‐body 3.0‐T MRI is a non‐invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole‐body high‐field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.     

Muscle pathology in dysferlin deficiency

Dysferlin deficiency is being increasingly recognized in limb-girdle dystrophy and distal myopathy but its role in the development of muscle pathology is still poorly understood. For this purpose, 26 muscle biopsies from 25 dysferlinopathy patients were analysed by routine histochemistry and by immunohistochemistry with eight different antibodies, and scored for inflammatory response and type of cell infiltrate, fibre degeneration and regeneration, fibre type composition and severity of histopathological changes. In cases with an advanced-stage dystrophic pattern we observed type 1 fibre predominance exceeding 80%, suggesting a selective loss of type 2 fibres or a conversion process. The extent of muscle fibre regeneration and degeneration in dysferlinopathy was intermediate between sarcoglycanopathy and Duchenne dystrophy or myositis, suggesting a rather aggressive course of the disease. An increased inflammatory response was observed in the majority of our patients (16/26), who also showed an active dystrophic pattern. Type and localization of cellular infiltrates suggest that inflammatory reaction is secondary to necrosis. Major histocompatibility complex (MHC) class I molecules were overexpressed in dysferlinopathy, mainly in association with fibre phagocytosis and regeneration; their occasional expression in non-necrotic fibres might represent a marker of ongoing necrosis. Muscle inflammation might be triggered by the structurally altered membrane consequent to dysferlin defect.     

Phenotypic variability associated with Arg26Gln mutation in caveolin3

Caveolin3 (CAV3) is a protein associated with dystrophin, dystrophin-associated glycoproteins, and dysferlin. Mutations in the CAV3 gene result in certain autosomal-dominant inherited diseases, namely, rippling muscle disease (RMD), limb-girdle muscular dystrophy type 1C (LGMD1C), distal myopathy, and hyperCKemia. In this report we show that a previously reported family with RMD has a mutation in the CAV3 gene. Affected individuals had either a characteristic RMD phenotype, a combination of RMD and LGMD1C phenotypes, or a LGMD1C phenotype, but one mutation carrier was asymptomatic at age 86 years. This phenotypic variability associated with mutations in CAV3 has been reported previously but only in a few families. It is important to remember the significant phenotypic variability associated with CAV3 mutations when counseling families with these mutations. These observations also suggest the presence of factors independent of the CAV3 gene locus that modify phenotype.     

Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effect in the Italian population

Dysferlin, the protein product of the dysferlin gene (DYSF), has been shown to have a role in calcium-induced membrane fusion and repair.

Dysferlin is absent or drastically reduced in patients with the following autosomal recessive disorders: limb-girdle muscular dystrophy type 2B (LGMD-2B), Miyoshi myopathy (MM) and distal anterior compartment myopathy.

To date, less than 45 mutations have been described in DYSF and a wide inter- and intra-familial variation in clinical phenotype has been associated with the same mutation. This observation underlines the relevance of any new report describing genotype/phenotype correlations in dysferlinopathic patient and families.

Here we present the results of clinical, biochemical and genetic analysis performed on one MM and three LGMD Italian families. By screening the entire coding region of DYSF, we identified three novel mutations (two missense substitutions and one frame shift microdeletion). The possible existence of a founder effect for the Arg959Trp mutation in the Italian population is discussed.