Nonaka肌病伴面部肌肉受累

目的 报道1个伴随面部肌肉受累及的Nonaka型远端性肌肉病家系的临床和病理特点，讨论其发病机制。方法 先证者在中年早期起病。主要临床表现为胫前肌为主的四肢远端肌无力和肌萎缩，伴随有面肌和胸锁乳突肌力弱以及眼睑下垂，股四头肌不受累。肌酶轻度升高。肌电图提示肌源性损害。对患者进行胫前肌活检，进行组织学，酶组织化学和超微结构检查。家族中其妹妹也具有相同的临床表现。出现下肢远端为主的肌无力和肌萎缩。结果 肌肉病理改变特点是出现肌纤维肥大和萎缩。伴随核内移和肌纤维分裂现象。在部分肌纤维内可见镶边空泡和胞浆体。电镜下可见肌纤维内和核内的管丝包涵体以及髓样小体，其中出现在膜下的管丝包涵体具有细胞核的轮廓，可以看到细胞核变性后形成致密破碎结构。结论 结合患者的家庭史，临床表现和病理学改变特点。此患者可以考虑为Nonaka肌病，我们证实此病可以伴随面部肌肉的受累及。其发病机制可能与肌核的变性有关。     

有镶边空泡远端肌病合并周围神经病变一例

有镶边空泡远端肌病（distal myopathy with rimmed vacuoles，DMRV）是一种常染色体隐性遗传的远端肌病，由日本学者Nonaka等。于1981年首先报道，2002年Kayashima等证明日本DMRV患者中位于9p12-13的GNE基因存在突变。经典DMRV在15—40岁起病，首发症状为步态异常，肌无力和肌萎缩主要累及下肢远端肌群，以胫前肌最严重，股四头肌不受累，随着病情逐渐发展，     

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。二者血清肌酸激酶水平正常,MRI表现为不同程度肌肉脂肪化,组织病理学可见肌营养不良样改变,部分肌纤维内镶边空泡形成,核内移增多或个别肌纤维再生。基因检测提示先证者及其父均携带DNAJB6基因c.161A>C(p.Glu54Ala)杂合突变,为中国大陆首次报道,分别为肢带型肌营养不良症D1型(LGMD?D1型)和远端型肌病型,该家系明确为常染色体显性遗传性DNAJB6基因突变所致肌病家系。结合文献提示DNAJB6基因突变所致肌病临床表现存在异质性,同一家系可表现为不同的临床亚型。结论DNAJB6基因突变可导致肢带型肌营养不良症和远端型肌病两种表型,肌肉病理均呈现镶边空泡和肌营养不良样改变。该家系进一步扩展了DNAJB6基因突变的表型谱。     

散发性眼咽远端型肌病的临床、肌肉影像与电生理特点

目的探讨眼咽远端型肌病(oculopharyngodistal myopathy,OPDM)的临床、电生理及肌肉核磁影像特点及病理、分子遗传学特点。方法报告1例临床诊断OPDM的临床特点、肌电图、肌肉核磁及病理分析结果、分子遗传学资料,对受累肌肉分布情况及肌电图改变,结合文献进行比较分析。结果患者25岁发病,肌肉受累顺序先后为:眼肌、咽喉肌、肢体远端、双下肢近端,肌酸激酶轻度升高。心脏超声:左室增大,二尖瓣轻度反流,左室舒张功能下降。肌电图显示:脱髓鞘性周围神经病,肌源性损害,为混合性损害。肌肉病理显示:肌源性损害伴镶边空泡肌纤维、可疑线粒体代谢异常。肌肉核磁:小腿脂肪化明显重于大腿,小腿以后群肌受累为主。二代测序未发现已知的远端性肌病、肌营养不良、肌原纤维肌病、空泡性肌病基因突变。结论该患者为散发病例,OPDM作为一类独立表型的肌病,以肌肉受累为主,可以出现脱髓鞘性周围神经损害、心脏受累等多系统表现。     

散发性包涵体肌炎临床病理分析

目的探讨散发性包涵体肌炎(sIBM)患者的临床及病理特点。方法收集2例于2008年至2010年就诊并明确诊断为s1BM的患者临床、病理资料。两例患者均有股四头肌无力和萎缩,1例出现肢体远端无力和上肢无力。2例患者均进行了肌肉活体组织检查标本的组织学、酶组织化学染色和免疫组织化学染色。结果 2例患者肌酶均轻度升高。肌电图检查示1例呈肌源性损害,1例呈神经源性损害。2例患者的骨骼肌主要病理改变都是肌内衣炎细胞浸润、肌纤维萎缩,肌纤维内嗜碱性镶边空泡。免疫组织化学染色提示CD8+淋巴细胞浸润为主,1例患者镶边空泡肌纤维内Ubiquitin染色阳性。结论本文2例sIBM以股四头肌损害明显,病情缓慢进展,依靠肌肉活检确定诊断。     

有镶边空泡远端肌病一家系GNE基因突变分析

目的探讨有镶边空泡远端肌病(DMRV)基因突变型。方法回顾性分析了中国DMRV一家系姐妹患者的临床、病理资料及其家系调查结果,对其GNE基因进行序列分析。结果一家系2代7人中有2例(均为第二代)发病,均为女性,青年晚期起病,首发症状为步态异常,四肢远端受累明显,股四头肌受累相对较轻;病情缓慢进展,发病后10年左右不能行走。主要病理改变为镶边空泡形成,肌浆或肌核内可见细丝状包涵体。2例患者突变位点相同,均为T1574C和C1943T复合杂合子突变,患者父亲携带单一C1943T点突变,其母亲和胞兄、胞姐均携带T1574C单一杂合子突变。结论中国DMRV一家系与日本人比较,其临床和病理改变一致。中国人DMRV患者也存在GNE基因复合杂合子突变,1574T→C为我们首次发现的致病性突变。     

远端型肌病1例报告

<正>远端型肌病是一组主要靠肌肉活检来确诊的疾病。病理主要表现以镶边空泡为特征。现报道1例我院收治的经病理证实的远端型肌病。1临床资料患者男,47岁,因"双下肢无力7 y,双上肢无力1 y"就诊。既往史、家族史无特殊。主要阳性体征:四肢肌张力正常,双上肢远端肌肉萎缩,以第一骨间肌为主,大小鱼际肌轻度萎缩,双下肢胫前肌轻到中度萎缩。双上肢远端肌力Ⅳ级,近端Ⅴ级,双下肢远端Ⅳ,近端Ⅳ-级。深浅感觉系统正     

GNE基因新发突变致GNE肌病一例临床表型及生物信息学分析

目的报告1例GNE肌病患者,总结其临床表型和基因型特征,扩展GNE基因突变谱。方法与结果男性患者,33岁,双下肢远端对称性无力,以小腿前群肌显著,缓慢进展;父母为近亲婚配;血清肌酸激酶升高(1139U/L);肌电图呈肌源性损害;双下肢CT显示轻度肌萎缩;肌肉组织活检可见肌纤维大小不等,肌细胞核内移,约2%的肌纤维存在镶边空泡;基因检测显示,患者存在GNE基因外显子9 c.1624CT(p.Pro542Ser)纯合突变,其母、其子和其女均携带GNE基因外显子9 c.1624CT(p.Pro542Ser)杂合突变,该突变尚未报道,经生物信息学分析判断为有害,根据美国医学遗传学和基因组学会指南判断为Ⅱ类可能的致病性突变。患者最终明确诊断为GNE肌病,该家系明确诊断为GNE肌病家系。结论本研究系统报道1例GNE肌病患者的基因型和临床表型信息,扩展GNE基因突变谱,加深临床医师对疾病的认识。     

散发性包涵体肌炎临床与肌肉病理特点

目的 探讨散发性包涵体肌炎(sIBM)的临床和肌肉病理特点。方法 回顾性分析5例sIBM患者的临床和肌肉病理资料。结果 本组5例患者中，男3例，女2例；发病年龄36～68岁，平均49.8岁；出现症状至确诊时间为2～12年，平均6.2年。5例患者均以双下肢无力隐匿起病，症状缓慢进展，逐渐发展为四肢无力。脑神经正常，四肢肌张力减低，腱反射减低或消失，上肢近端肌力Ⅲ～Ⅴ级，远端肌力Ⅲ～Ⅳ级；下肢近端肌力Ⅱ～Ⅴ级，远端肌力Ⅲ～Ⅳ级。5例患者均有不同程度的肌肉萎缩。EMG检查示4例呈肌源性损害，1例呈肌源性和神经源性共存的混合性损害。肌肉病理表现为肌纤维大小不等，可见萎缩和肥大肌纤维，散在有变性坏死肌纤维，伴炎性细胞浸润。5例患者均可见镶边空泡，4例可见炎性细胞侵入非坏死肌纤维现象。淋巴细胞亚群免疫组化染色可见CD8和CD68阳性淋巴细胞浸润。结论 sIBM好发于中老年人，除上肢远端指屈肌和下肢股四头肌无力以外，部分患者早期可有下肢远端肌无力。肌肉病理发现肌纤维中有镶边空泡和炎性细胞浸入非坏死肌纤维是确诊sIBM的重要依据。     

强直性肌营养不良Ⅰ型临床、病理、骨骼肌磁共振特点

目的总结11例强直性肌营养不良Ⅰ型(DM1)患者的临床、病理和双下肢肌肉受累的特点。方法回顾性分析2012年01月至2020年10月就诊于南京鼓楼医院神经内科的11例DM1患者的临床、骨骼肌活检病理及5例双下肢骨骼肌磁共振的特点。结果11例患者均有不同程度的肌强直、伴有肌无力/肌萎缩症状,肌无力/肌萎缩远端重于近端。骨骼肌病理特点:10/11例患者可见Ⅰ型肌纤维轻度萎缩,部分患者可见核内移、核聚集、肌浆块现象。双下肢肌肉磁共振:5例患者双下肢远端脂肪浸润重于近端,双侧肌肉受累程度不对称,大腿肌肉脂肪浸润以股中间肌最严重,小腿肌肉以腓肠肌、比目鱼肌、腓骨长肌最严重。结论骨骼肌磁共振对诊断强直性肌营养不良Ⅰ型有重要的提示意义。     

远端型肌病71例的临床及肌肉病理分析

目的　探讨远端型肌病的临床表现及肌肉病理特点。方法　对71例远端型肌病患者进行回顾性分析。结果　71例患者中,Nonaka型26例,呈散发或常染色体隐性遗传,多以胫前肌无力为首发症状,肌肉坏死较轻,镶边空泡(rimmedvacuole,RV)多见,可见管状细丝包涵体;Miyoshi型38例,呈散发或常染色体隐性遗传,多以腓肠肌力弱为首发症状,肌肉变性坏死严重,RV少见;TMD型2例,均为散发病例,病变主要局限于胫前肌,病情进展较慢,有肌肉变性坏死,可见RV;Welander型4例,呈散发或常染色体显性遗传,以手指、腕部无力为首发症状,可波及下肢远端,轻度肌肉变性坏死,偶可见RV;OPDM型1例,呈常染色体显性遗传,表现为下肢远端肌无力伴眼外肌、面部肌肉、咽肌无力,肌肉坏死不显著,可见RV。结论　在中国Miyoshi型、Nonaka型、TMD型、Welander型及OPDM型远端型肌病均可见到,各型临床表现及病理改变与国外报道基本一致。     

GNE Myopathy: Etiology,Diagnosis, and Therapeutic Challenges

GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic “rimmed” vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.     

Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy

Distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (hIBM) share similar clinical features, including onset in young adulthood with preferential involvement of the anterior compartment of the lower legs and sparing of the quadriceps femoris muscles. The most significant muscle pathology is the presence of rimmed vacuoles, which appear to play a major role in muscle atrophy and weakness. After the discovery of the gene locus in both DMRV and hIBM on chromosome 9 and mutations in the gene encoding the enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), it became clear that they are allelic disorders. From gene analysis, it is evident that these diseases are not restricted to people of Japanese and Jewish ancestry, but that they are widely distributed throughout all ethnic groups. Although defective glycosylation to a muscle fiber has been suggested, the mechanism by which myofibrillar degeneration is followed by rimmed vacuole formation remains to be clarified.     

MRI findings in studies of distal myopathy with rimmed vacuoles

A case of distal myopathy with rimmed vacuoles was studied with MRI, which showed a characteristic distribution of the affected muscles. A 41-year-old man who presented a slowly progressive weakness in his lower legs starting 11 years previously was admitted to our hospital of further investigation. Neurological examinations showed muscular wasting and weakness in the neck flexors, the flexors of the forearm, the flexors and adductors of the thigh and the extensors of the lower legs. Needle electromyography showed a myopathic pattern. Muscle biopsy revealed a variation in fiber size, an increase in internal nuclei, fatty infiltration and scattered rimmed vacuoles in a histochemical study. Electron microscopy revealed that rimmed vacuoles contained numerous lamellar bodies and glycogen particles. T1 and T2 weighted MRI showed high signals in the m. adductor of thigh m. biceps femoris, m. semimembranosus, m. semitendinosus, m. tibialis anterior, m. tibialis posterior, m. extensor digitorum longus, m. extensor digitorum brevis, m. peroneus, and m. gastrocnemius. There were three merits for the application of MRI to distal myopathy, (1) easy detection of the affected muscles as fatty change is expressed with a high signal intensity by MRI, (2) no affection by the presence of bones in MRI, and (3) the possibility to have a transverse section and a sagittal and coronal section in MRI. In this case MRI was very useful to detect the affected muscles and to observe the progress.     

全身性癫癎伴高热惊厥附加症致病基因的连锁定位研究

目的　定位全身性癫癎伴高热惊厥附加症的致病基因。方法　采用全基因组扫描的连锁分析方法对全身性癫癎伴高热惊厥附加症4个家系进行研究。结果　在染色体5q34多点连锁分析显示最大LOD值为3. 815。染色体单体型分析将连锁范围缩小至D5S820至D5S1476之间4. 0厘摩(cM)的区域。结论　全身性癫癎伴高热惊厥附加症致病基因定位在染色体5q34。     

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.     

Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy

BACKGROUND: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal-recessive disorder with preferential involvement of the tibialis anterior muscle that starts in young adulthood and spares quadriceps muscles. The disease locus has been mapped to chromosome 9p1-q1, the same region as the hereditary inclusion body myopathy (HIBM) locus. HIBM was originally described as rimmed vacuole myopathy sparing the quadriceps; therefore, the two diseases have been suspected to be allelic. Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). OBJECTIVE: To determine whether DMRV and HIBM are allelic. METHODS: The GNE gene was sequenced in 34 patients with DMRV. The epimerase activity in lymphocytes from eight DMRV patients was also measured. RESULTS: The authors identified 27 unrelated DMRV patients with homozygous or compound-heterozygous mutations in the GNE gene. DMRV patients had markedly decreased epimerase activity. CONCLUSIONS: DMRV is allelic to HIBM. Various mutations are associated with DMRV in Japan. The loss-of-function mutations in the GNE gene appear to cause DMRV/HIBM.     

Inclusion body myositis associated with chronic thyroiditis, Sj?gren's syndrome and autoimmune cholangitis]

A 67-year-old woman was admitted to our hospital, because of wasting of the thigh muscles. Muscular atrophy was confined to the thigh muscles, suggesting that she had quadriceps myopathy. Muscle biopsy from quadriceps muscle revealed characteristic findings, such as invasion of the endomysium and muscle fibers by inflammatory cells, the presence of rimmed vacuoles and ragged red fibers; thereby, she was diagnosed as having inclusion body myositis (IBM). Based on elevated titers of autoantibody as well as biopsy findings from salivary gland and liver, she was also diagnosed as having chronic thyroiditis, Sj?gren's syndrome and autoimmune cholangitis. Currently, the pathogenic mechanism underlying IBM is not clarified, however, various factors have been suggested to contribute to it, such as viral infection or mitochondrial insufficiency. Although the pathogenic backgrounds underlying IBM are likely heterogeneous, an autoimmune-mediated mechanism may be related to the pathogenesis of IBM in the present patient.