杜氏肌营养不良与贝氏肌营养不良常规MRI的对比研究

目的 探讨常规MRI鉴别诊断杜氏肌营养不良（DMD）和贝氏肌营养不良（BMD）的价值。方法 回顾性分析经临床确诊为抗肌萎缩蛋白病697例患者的臀部及大腿肌肉影像学资料,比较DMD与BMD影像学征象的异同。结果 DMD与BMD患者肌肉脂肪浸润的分布规律一致,DMD总体脂肪浸润程度高于BMD（P=0.034）,且以臀大肌、股直肌、缝匠肌为著;肌肉总体水肿程度差异无统计学意义（P=0.065）,但DMD大腿后群肌肉及缝匠肌的水肿明显高于BMD。DMD与BMD患者肌肉萎缩及肥大的选择性受累规律一致,BMD股外侧肌、股中间肌、股内侧肌、半膜肌及股二头肌长头萎缩频率明显高于DMD（P<0.05）;DMD与BMD患者肌肉的肥大改变差异无统计学意义（P>0.05）。结论 常规MRI可鉴别诊断DMD与BMD。     

DMD/BMD患者的dystrophin基因表达研究

目的探讨杜氏进行性肌营养不良(DMD)/贝氏进行性肌营养不良(BMD)患者的dystrophin基因突变与蛋白质表达之间的关系。方法用多重连接探针扩增(MLPA)法检测14例DMD/BMD患者dystrophin基因突变,肌肉活检观察组织的形态结构特点,免疫组织化学染色检测患者腓肠肌组织中dystrophin蛋白的表达情况。结果 14例DMD/BMD患者中有3例检出dystrophin基因缺失,其余未检出基因突变。肌肉活检结果显示,14例患者均可见肌纤维大小不一,圆形化,肌纤维明显变性、坏死,不同程度再生;部分肌纤维间可见少量炎性细胞浸润,结缔组织增生。免疫组织化学染色显示,3例未表达dystrophin基因突变患者的肌纤维膜dystrophin蛋白不同程度表达减弱,其余11例患者可见肌纤维膜dystrophin蛋白质表达完全缺失。结论 MLPA联合肌肉活检及免疫组化染色可以鉴别诊断DMD/BMD,为患者的诊治和预后提供了依据。     

假肥大型肌营养不良患儿的肌肉病理及dystrophin免疫组化SP法检测的临床意义

目的探讨肌肉病理及抗肌萎缩蛋白（dystrophin）免疫组化SP法检测在假肥大型肌营养不良诊断中的临床价值。方法通过组织学观察和免疫组化SP法检测方法,对50例假肥大型肌营养不良患儿[40例Duchenne型营养不良（DMD组）,10例Becker型营养不良（BMD组）]肌纤维膜dystrophin的表达、肌肉病理改变及临床表现进行观察,并与30例其他疾病（多发性肌炎3例、皮肌炎6例、糖元累积病1例、脂质累积病15例、周围神经病2例、脊肌萎缩症3例）对照组患儿进行对比分析。结果肌肉病理显示：DMD组中有30例肌肉病理改变较重,10例较轻;BMD组的肌肉病理改变较轻,这些均与年龄有关。免疫组化显示：DMD组肌肌纤维膜均有严重的dystro-phin缺失,BMD组肌纤维膜有50%~70%的dystrophin缺失;对照组无dystrophin缺失。结论肌肉病理及dys-trophin SP免疫组化检测对假肥大型肌营养不良具有较大的临床意义。     

杜氏肌营养不良患儿行肌肉活检术的护理

肌肉活检术是确诊神经肌肉疾病的重要手段之一,主要适应症是患者出现肌肉无力、肌肉强直、肌肉疼痛或握痛等表现,肌电图显示肌源性损害,肌酸磷酸激酶升高[1].杜氏肌营养不良( Duchenne muscular dystrophy,DMD)是最常见的进行性肌营养不良,本病从肢体活动无力逐渐发展到生活不能自理直至死亡,预后极差,致残率和致死率极高[2].DMD的确诊有赖于在患儿的活检肌肉中发现Dystrophin蛋白的完全缺失[3].2004年10月～2010年8月,我科通过肌肉活检术诊断杜氏肌营养不良患儿93例,现将护理经验总结如下.     

家族系Becker型肌营养不良26年回访

肌营养不良病是一种原发于肌肉的遗传性变性疾病，主要特点为进行性加重的肌肉萎缩和无力。Becker型肌营养不良是假肥大型肌营养不良的另一种类型，多在5—25岁缓慢起病，四肢近端肌肉受累明显，男性为主，40岁左右因各种并发症而死亡。本文对一个家族3代进行26年后回访。     

Duchenne型肌营养不良症的治疗

Duchenne型肌营养不良症(Duchenne muscular dystrophy,DMD)是一种X连锁致死性遗传性肌病,由Dystrophin基因突变导致抗肌萎缩蛋白缺失所致.DMD尚缺乏有效的治疗方法,但随着对该病发病机制和病理变化过程的认识不断深入,其治疗选择越来越多.这些治疗方法旨在恢复Dystrophin...     

进行性肌营养不良性心肌病合并左心室心肌致密化不全一例

Dystrophin蛋白缺乏性肌营养不良症常见,为性环链隐性遗传,而伴有心肌损害的肌营养不良症,常见于假性肥大型及强直性肌营养不良.该文报道1例此病患者的诊治经过.该患者在外院被诊为肌营养不良症,根据患者病史、临床表现、UCG、心脏MRI及肌肉活组织病理学检查等资料,符合进行性肌营养不良性心肌病、左心室心肌致密化不全诊断.临床医生应提高对该病的认识,做好遗传咨询、产前检查、携带者的家谱分析和检查对预防本病的发生至关重要.     

假肥大型肌营养不良治疗进展

假肥大型肌营养不良是一组严重性进行性遗传性肌病,有假肥大型肌营养不良(duchenne muscular dystrophy,DMD)和良性Duchenne肌营养不良(BMD)两种类型.由于DMD/BMD是X连锁隐性遗传性疾病,男性多发,且DMD最常见,全世界每3500～5000个新生儿中就会有一名患者,女性携带者大多...     

肌营养不良患者的综合呼吸管理

正肌营养不良(Muscular Dystrophy,MD)是一组遗传性疾病,有30多种亚型,临床主要表现是受意识支配活动的骨骼肌进行性萎缩和无力,其中Duchenne氏肌营养不良(Duchenne Muscular Dystrophy,DMD)最为常见,是X性连锁隐性遗传性肌病,男性新生儿的患病率约2.9/10000,研究认为与Xp21染色体上抗肌萎缩蛋白     

CK异常增高肌营养不良症1例分析

肌营养不良症是以进行性的肌肉萎缩无力为主要临床表现的疾病,发病原因包括遗传因素引起的肌肉变性疾病,以及个体自身基因突变;按遗传形式和主要临床表现,可将肌营养不良症分为以下数种类型:(1)假肥大型肌营养不良症,属于     

Muscle Function Recovery in Golden Retriever Muscular Dystrophy After AAV1-U7 Exon Skipping

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.     

Systematic use of dystrophin testing in muscle biopsies: results in 201 cases

We studied dystrophin with both immunohistochemistry and immunoblotting in 201 muscle biopsies stored in liquid nitrogen during the period 1985–92. The systematic use of dystrophin testing combined with DNA analysis and with 3–10 years' follow-up of the patients yielded a significant modification of the diagnoses made previously and identified dystrophinopathies with unusual expression and course. Seventeen out of 152 (11.18%) diagnoses in males and 8 out of 49 (16.32%) in females were modified by dystrophin testing. Most diagnostic errors (9 out of 27 diagnoses) were in the group Becker muscular dystrophy–limb girdle muscular dystrophy, confirming the clinical overlap of the two diseases. Unusual expressions of dystrophinopathy included muscular dystrophy with early elbow contractures (two patients), recurrent myoglobinuria (one patient), dilating cardiomyopathy (two patients), myoglobinuria and associated dilating cardiomyopathy (one patient), very late-onset benign myopathy (two patients and one manifesting carrier) and congenital myopathy (one manifesting carrier). In the group 'idiopathic hyperCKaemia', we did not find any dystrophinopathy in 34 males, whereas five out of nine females were found to be carriers. Immunohistochemical analysis of dystrophin using the monoclonal antibody against the C-terminus detected 99% of protein defects and was found to be the most cost-effective way of revealing dystrophinopathies. The combined use of immunohistochemical analysis with the antibody against the C-terminus and immunoblotting with the antibody against the core of the protein appears to be a highly reliable diagnostic approach (100% detection rate).     

Progression of muscular co-activation and gait variability in children with Duchenne muscular dystrophy: A 2-year follow-up study

BackgroundDuchenne muscular dystrophy is an X-linked muscle disease caused by dystrophin absence. Muscle weakness is a major determinant of the gait impairments in patients with Duchenne muscular dystrophy and it affects lower limbs more often than upper limbs. Monitoring progression of motor symptoms is key to plan treatments for prolonging ambulation.MethodsThe progression of gait impairment in a group of ten patients with Duchenne muscular dystrophy was observed longitudinally three times over a period of 2 years by computerized gait analysis system. Spatio-temporal parameters of gait, and variability indicators were extracted from kinematics, while lower limb muscles coactivation were measured at the baseline and at each follow-up evaluation. The 6-min walk test was used to evaluate functional capacity at each time session.FindingsWe found a significant increase in stride width and in both stride width and stride length variability at the 1-and 2-year follow-up evaluations. Furthermore, significant higher values in proximal muscle coactivation and significant lower values in both distal muscle coactivation and functional capacity were found at the 2-year follow-up evaluation. Significant negative correlations between muscle coactivation at proximal level and functional capacity and between muscle coactivation at distal level and gait variability were observed.InterpretationOur findings suggest that patients with Duchenne muscular dystrophy exhibit decline in functional capacity after 2 years from the baseline. Moreover, to cope with disease progression, patients try to maintain an effective gait by changing the balance dynamic strategies (i.e. increase in proximal muscle coactivation) during the course of disease.     

Deficiency of dystrophin-associated proteins in Duchenne muscular dystrophy patients lacking COOH-terminal domains of dystrophin.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a cytoskeletal protein tightly associated with a large oligomeric complex of sarcolemmal glycoproteins including dystroglycan, which provides a linkage to the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosis. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycoprotein complex. However, truncated dystrophin lacking these domains was reported to be localized to the sarcolemma in four DMD patients recently. Here we report that all of the dystrophin-associated proteins are drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains of dystrophin are required for the proper interaction of dystrophin with the dystrophin-associated proteins and also support our hypothesis that the loss of the dystrophin-associated proteins in the sarcolemma leads to severe muscular dystrophy even when truncated dystrophin is present in the subsarcolemmal cytoskeleton.     

Expression of myoferlin in skeletal muscles of patients with dysferlinopathy

Myoferlin is a novel protein of unknown function with high homology to dysferlin, the gene mutations of which cause limb girdle muscular dystrophy type 2B and Miyoshi myopathy. The myoferlin gene seems to be a candidate for the modifier, and because of the high homology to dysferlin myoferlin may work as a compensator for the absence of dysferlin in dysferlinopathy. This hypothesis is based on the observation that utrophin, which has 80% homology with dystrophin, is overexpressing in the dystrophin deficient myofibers. To test this hypothesis, we investigated the myoferlin expression by immunoblot and immunohistochemical analysis in muscles of five patients with dysferlinopathy. For this aim, we generated a myoferlin specific antibody that does not cross react with dysferlin, and performed the immunoblot, immunohistochemical and immunoelectron microscopic studies. Immunohistochemical analysis showed that the antibodies against myoferlin and dysferlin clearly stained the normal human myofiber surface membranes. The electron microscopy of single immunogold labeled samples for myoferlin showed the presence of the molecular signal along the normal muscle cell membrane. Immunoblot analysis showed that the intensity of 230-kDa myoferlin band of dysferlinopathy muscle extracts was similar to that of normal muscle extracts. The immunostaining of dysferlinopathy muscles with anti-myoferlin antibody revealed a weak immunoreactivity along the muscle cell surface. Thus, the compensatory overexpression of myoferlin was not detected in muscles with dysferlinopathy.     

Restoration of dystrophin expression in mdx mice by intravascular injection of naked DNA containing full-length dystrophin cDNA

Duchenne muscular dystrophy (DMD) is a lethal, X-linked, recessive disease caused by a defect in the dystrophin gene. No effective therapy is available. Dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD. However, successful treatment for DMD requires restoration of dystrophin in the affected muscle fibers to at least 20% of the normal level. Current gene transfer methods such as intramuscular injection of viral vector or naked DNA can only transfect a small area of muscle, and therefore is of little clinical utility. We have developed a semisystemic method for gene transfer into skeletal muscle of mdx mice, an animal model for DMD. Naked DNA was injected through the tail artery or vein of mice, in which the aorta and the vena cava were clamped at the location just below the kidneys. The DNA solution was thus forced into the blood vessels of both legs. Luciferase gene expression was detected in all muscle groups in both legs. The effects of injection speed, injection volume, and ischemia time on gene expression were also optimized. LacZ staining was used to check the spread of gene expression in muscle. Although the percentage of transfected fibers was modest (approximately 10%), beta-galactosidase was found in all muscle groups of both legs. Finally, plasmid DNA encoding full-length dystrophin gene was injected into mdx mice and widespread restoration of dystrophin protein was observed in all muscles of both hind limbs. In conclusion, these results demonstrate that the semisystemic delivery of naked DNA is a potential approach towards the long-term goal of gene therapy for DMD.     

Abnormal expression of laminin suggests disturbance of sarcolemma-extracellular matrix interaction in Japanese patients with autosomal recessive muscular dystrophy deficient in adhalin.

Dystrophin is associated with several novel sarcolemmal proteins, including a laminin-binding extracellular glycoprotein of 156 kD (alpha-dystroglycan) and a transmembrane glycoprotein of 50 kD (adhalin). Deficiency of adhalin characterizes a severe autosomal recessive muscular dystrophy prevalent in Arabs. Here we report for the first time two mongoloid (Japanese) patients with autosomal recessive muscular dystrophy deficient in adhalin. Interestingly, adhalin was not completely absent and was faintly detectable in a patchy distribution along the sarcolemma in our patients. Although the M and B2 subunits of laminin were preserved, the B1 subunit was greatly reduced in the basal lamina surrounding muscle fibers. Our results raise a possibility that the deficiency of adhalin may be associated with the disturbance of sarcolemma-extracellular matrix interaction leading to sarcolemmal instability.     

mdx小鼠骨骼肌组织成肌、成脂、成骨基因的特异性表达

背景：干细胞移植是治疗肌营养不良症的有效方法之一,但移植的干细胞在病理骨骼肌中成肌表达较低。目的：通过比较mdx小鼠和C57小鼠的骨骼肌形态及成肌、成脂、成骨基因表达的差异,探讨mdx小鼠骨骼肌病理改变的可能机制。方法：取mdx小鼠与C57小鼠的骨骼肌组织行冰冻切片,苏木精-伊红染色和Vonkossa染色观察两种小鼠肌肉组织的形态特征;提取mdx小鼠和C57小鼠骨骼肌组织总RNA,real-timePCR检测成肌、成脂、成骨相关基因的表达。结果与结论：mdx小鼠骨骼肌有肌纤维坏死和再生,伴有轻度脂肪、纤维结缔组织增生,Vonkossa染色可见钙结节沉积,而C57小鼠的骨骼肌细胞形态清晰,核位于细胞周边。与C57小鼠比较,mdx小鼠肌肉组织成骨、成脂基因表达有不同程度的上调（P〈0.05）,而成肌基因表达下调（P〈0.05）。dystrophin基因缺失及成肌基因表达下调、成骨和成脂基因上调是造成mdx小鼠肌肉组织变性坏死的原因。     

The paradox of muscle hypertrophy in muscular dystrophy

Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy.