【初稿】 肌原纤维肌病

Myofibrillar Myopathy

英文原文链接

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翻译者：丁灿

Initial Posting: 2017-09-01 11:51:55; Last Update: 2018-03-17 11:30:56.

摘要

临床特征.

肌原纤维肌病（MFM) 的特点是缓慢进行性无力，既涉及近端肌肉也涉及远端肌肉。远端肌无力在约80％的患者中存在，在约25％的患者中比近端肌无力更为显著。少数患者有感觉异常症状，肌肉僵硬，疼痛或痉挛。大约20％的 个体有周围神经病变。 15％-30％有显性心肌病。

诊断/实验室检测.

肌原纤维肌病的诊断基于临床表现，肌电图（EMG），神经传导检查，以及最重要的肌活检。迄今为止，仅在约50％的病例中确定了肌原纤维肌病的遗传致病病因，已经在下列中鉴定了致病性遗传变异：编码结蛋白的DES；编码α-晶体蛋白B链的CRYAB；编码myotilin的MYOT；编码LIM 结合蛋白3的LDB3（ZASP）；编码filamin-C的FLNC和编码BAG家族分子伴侣调节剂3的BAG3。最近，又在两个新中被鉴定：编码四个半LIM蛋白1的FHL1和编码DnaJ同系物亚科B成员6的DNAJB6。

管理.

对症治疗对存在心律失常和/或心脏传导缺陷的患者应考虑起搏器和植入式心律转复除颤器（ICD）；对有进展性或危及生命心肌病的患者应考试心脏移植；对有高碳酸血症和其他早期呼吸衰竭症状的患者进行呼吸支持（连续或双水平气道正压通气），最初只在晚上，后期在白天也可以进行; 对有重度肌无力症状的患者行运动范围内的物理疗法和辅助装置。

其他： 肌肉加强训练的作用尚未得到确定。

遗传咨询.

肌原纤维肌病最常见的遗传方式是 。不符合这一遗传方式的有：X-连锁 遗传的FHL1和的CRYAB。CRYAB的移码突变导致终止密码子提前出现，最终蛋白无法被正常翻译。另外，在某些家庭中遗传方式无法得到确认。只有在确定之后，才可能进行和产前检查。

 

GeneReview 范围

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肌原纤维肌病：包括以下疾病
  • Alpha-B crystallinopathy
  • BAG3-相关性肌原纤维肌病
  • Desminopathy
  • DNAJB6-相关性肌原纤维肌病
  • FHL1-相关性肌原纤维肌病
  • Filaminopathy
  • Myotilinopathy
  • Zaspopathy

同义词和旧术语请参见命名法.

 

诊断

临床诊断

术语“肌原纤维性肌病”代指具有肌肉组织学上共同形态学特征、遗传学上异质性的一组疾病（译者注：请参见“命名”部分）。
肌原纤维肌病的诊断依据如下：

  • 慢性进行性肌无力病史 部分患者伴有皮肤感觉异常，肌肉萎缩，僵硬或疼痛，痉挛，呼吸困难和吞咽困难。大多数患者体检显示近端和远端肌无力。大约三分之一患者近端肌无力比远端肌无力显著；在另三分之一中远端肌无力更显著。面部肌肉无力较为罕见，但可能发生。肌腱反射正常或减少。
  • 肌电图 (EMG) 在多数患者中可发现异常电刺激（纤颤电位，正尖波，复杂的放电和肌强直放电）。运动单位电位显示肌病特征或肌病和神经原两种特征。在大约20％的个体中可以检测到异常的神经传导。
  • 肌活检 可以发现以下特征(见图 1):
    • 三染色冷冻切片中特征性改变：在不定比例的肌纤维中可见无定型，透明或颗粒状结构；
      • 边界明显的，氧化酶活性降低的异常肌纤维区域；
      • 许多强嗜刚果红的透明结构，在罗丹明荧光显微镜下最容易观察；和
      • 在不同数量的肌纤维中的小空泡
    • 免疫组化学染色显示蛋白质异常表达： myotilin (90% 的异常肌纤维中可以观察到), desmin (75%), α-晶体蛋白B  (75%), 肌营养不良蛋白 (70%), 和β-淀粉样前体蛋白 (70%)
    • 电子显微镜可见起始于Z盘的肌原纤维变性，肌节解体，降解纤维物质积累的多种形态的透明包涵体，膜性细胞器脱位以及它们在自噬泡中的降解 [Selcen et al 2004]。
    • 其他组织
    • 血清肌酸激酶浓度 可在正常范围或上升至不超过正常上限的七倍。
    Figure 1.

    图1.

    在肌原纤维肌病中观察到的典型肌肉组织学特征

    分子遗传检测

     迄今为止，MFM的遗传基础仅在50%的中被阐明。已报导的有

    临床检测

    表1.

    肌原纤维肌病的分子遗传检测

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    1由该的导致 MFM
    的比例 2    		检测方法检测到的 3
    DES7%4核苷酸变异 5
    /分析未知，尚未报导 7
    CRYAB3% 4核苷酸变异
    / 分析6未知，尚未报导 7
    MYOT9%4核苷酸变异
    / 分析6未知，尚未报导7
    LDB311%4核苷酸变异
    特定测序 6 的核苷酸变异8
    / 分析6未知，尚未报导7
    FLNC3% 4核苷酸变异
    / 分析6未知，尚未报导 7
    BAG35% 4核苷酸变异
    / 分析6未知，尚未报导 7
    FHL13% 4核苷酸变异
    DNAJB62%4核苷酸变异
    1.见 表A. 基因与数据库 中染色体位点和蛋白的相关信息。
    2.比例基于梅奥诊断的MFM队列数据。
    3.见分子遗传 中该基因的等位基因变异的相关信息。
    4.序列分析检测到的那些良性变异，可能良性变异，，可能致病或致病变异。致病变异可以包括小的基因内缺失/插入和，无义,和；不检测典型的外显或全缺失/重复。在解释 结果时需要考虑的问题，点击此处。
    5.预计99%的致病性变异位于编码区。
    6.

    无法检出的 DNA之编码区，侧翼区的缺失与重复可以由以下方法检测出：定量PCR， 长片段PCR，多重链接探针依赖扩增（MLPA），和/片段的 (CMA) 。


    7.在DES, MYOT, LDB3, CRYAB, FLNC, 或 BAG3 基因缺失或重复导致MFM未见报道。
    8.不同实验室检测的外显子不完全相同。

    检测策略

    在中确诊/建立诊断

    针对有患病风险的无症状成年家庭成员进行的预测性检测需要先确定家族中的。产前诊断和

      (PGD) 需要事先确定家族中的。

     

    临床特征

    临床描述

    在梅奥诊所的80例MFM患者中，发病年龄从2岁到77岁不等。诊断年龄在11到82岁。与BAG3有关的肌原纤维肌病（Bag3病）特征性起病年龄是十岁内或十几岁时，这个病通常是致命性的。 Desminopathies 也可能在十岁内发病，通常伴有心肌病。除上述病外，大部分的MFM在40岁以后发病。

    MFM的主要表现症状是慢性进行性肌无力；少数个体有感觉症状，肌肉僵硬，疼痛或痉挛。无力感可能涉及近端和远端肌肉；远端肌肉无力比近端无力更常见25％。周围神经病变的客观临床体征或EMG表现在大约20％的个体可以观察到，但肌活检研究提示周围神经受累的频率更高。显性心肌病可表现为首发症状，也可能在15％-30％个体的肌原纤维肌病的进展过程中出现。呼吸肌无力可导致限制性通气障碍。外显率问题：在DES家系中观察到携带致病性变异的家庭成员具有不同的临床表现：一些仅表现出心肌病，一些表现出肌病和心肌病的迹象，一些具有降低的，既没有肌病也没有心肌病。

    基因型-表型相关性

    不存在能够可靠预测特定致病的形态学特征。目前唯一确定的 -相关性是：

    外显率

    现有数据不足以得出有关的结论。

    遗传早现

    尚没有记录的令人信服的证据。

    命名

    "… 肌原纤维肌病的光学显微特征在20世纪70年代和80年代被描述为“含有包涵体的肌病" [Nakashima et al 1970], "有肌原纤维聚集的非典型性肌病”[Kinoshita et al 1975], " 包涵体心肌病" [Clark et al 1978], "有肌细胞浆内密集颗粒纤维物质的心肌骨骼肌肌病" [Fardeau et al 1978], "常染色体显性球体肌病" [Goebel et al 1978], "有肌细胞浆小体和结蛋白丝的肌病" [Edström et al 1980], "胞浆体肌病" [Wolburg et al 1982], "Mallory体样包涵体先天性肌病" [Fidzianska et al 1983], 以及 "心肌病伴肌膜下蚓状沉积" [Calderon et al 1987]. 然而之后人们发现，不同的作者描述了同一个病理学表现，命名了不同的名字；多个被认为是某种单一疾病特异性的病理表现，被发现可以存在于同一个肌肉组织标本中，甚至同一个肌肉纤维内；每一个病理学改变都涉及到了Z盘的肌原纤维Edström et al [1980]注意到某些包涵体或者其周围的物质可以与desmin产生反应。由此得来了”desmin储存性肌病" [Horowitz & Schmalbruch 1994] 和后来的 "desmin相关性肌病" [Goebel 1997]. 1996和1997年，详细的免疫组化研究显示，异常肌纤维中聚集的不仅仅是desmin，还包括很多蛋白质，这样促成了肌原纤维肌病这个没有特指的术语的使用  [De Bleecker et al 1996, Nakano et al 1997]…"

    [Selcen et al 2004; 经Oxford大学出版社同意重印]

    肌原纤维肌病也称为desmin储存性肌病，desmin相关性肌病或蛋白质过剩性肌病。 肌原纤维肌病是遗传异质性的，致病蛋白或相关基因仅在少数病例中是已知的。因为除了结蛋白之外的其他多种蛋白也在肌肉中过表达，并且因为肌原蛋白与结蛋白不相关，所以在确定发生致病变异的基因之前，通称“肌原纤维肌病“是合适的。当疾病相关或蛋白质被确定时，可以使用具体的病名，例如 desminopathy, α-B crystallinopathy, myotilinopathy, zaspopathy (Markesbery-Griggs 迟发型远端肌病), filaminopathy, 或BAG3相关性肌原纤维肌病。

    译者注：肌原纤维肌病包括所有Z线或与其相关的蛋白质异常导致的肌病，包涵体或蛋白沉积是这一类肌病的病理学共同特征。

    .

    患病率

    目前还无法估计肌原纤维肌病的患病率。

    遗传（等位基因）相关疾病

    每种类型的MFM均可能发生心肌病。

    CRYAB致病性变异可以导致白内障而不导致肌原纤维肌病。

    MYOT致病性变异可能导致肢带型肌营养不良类似的，被命名为 LGMD1A [Hauser et al 2000] 以及一种远端型肌病 [Fischer et al 2006, Pénisson-Besnier et al 2006] (参加Limb-Girdle Muscular Dystrophy 概述)。FHL1致病性变异与几种表型相关：X-连锁 儿童期发病的降低型肌病；X-连锁早期发病的严重型肌病；FHL1-相关性X-连锁 Emery-Dreifuss 肌营养不良； X-连锁肌病合并体位肌肉萎缩； X-连锁显性 肩腓肌病。DBAJB6 致病性变异与LGMD1E相关。

     

    鉴别诊断

    主要的鉴别诊断是迟发型肌病，尤其是以远端受累为主的肌病：

    • I型强直型肌营养不良症(DM1)是会影响骨骼肌、平滑肌、眼球、心脏、内分泌系统和中枢神经系统的多系统疾病。临床表现按照从轻到重可以分为三种：轻度，典型和。轻度DM1的特征是白内障和轻度肌强直（肌肉持续收缩）；寿命是正常的。 典型DM1的特点是肌肉无力和消瘦，肌强直，白内障，并常有心脏传导异常。先天性DM1的特点是出生时出现肌张力低下和严重全身无力，常伴有呼吸功能不全和早期死亡; 智力残疾是比较常见的。 DM1是由DMPK基因中 CTG 的扩增引起的。 基因检测在近乎100%个体中可以检测到致病变异。 DM1的遗传方式是。 
    • 2型强直型肌营养不良症(DM2),也称为近端强直型肌病 (PROMM)。这个病的特征在于肌强直和肌肉功能障碍（无力，疼痛和僵硬），不太常见的症状包括了心脏传导阻滞，虹膜后囊下白内障，胰岛素不敏感型2型糖尿病，以及睾丸功能衰竭。虽然也有报道有患者十岁内出现肌强直症状，常见的起病年龄是三十多岁。最常见的发病症状为波动或偶发性肌肉疼痛，可能会导致颈部屈肌和手指屈肌衰弱和无力；随后，肌肉无力发展到涉及肘伸肌和髋伸屈肌。踝关节背屈肌群以及面部的肌无力较为少见。肌强直很少引起严重的症状。CNBP (ZNF9) 是目前唯一的已知与DM2相关的。在其1号中有一个复杂的重复序列单元, (TG)n(TCTG)n(CCTG)n。该重复序列单元的扩增导致DM2。扩增的CCTG单元数目范围可以从75个到大于11000个（平均约为5000个重复单元）。在患病个体中检测到CNBP CCTG扩增的频率超过了99%。DM2的遗传方式是。
    • 运动和感觉神经病变
    • 包涵体肌病2型(IBM2)的特征是成年起病，缓慢进展的远端肌肉无力。肌无力的最初表现为步态紊乱、由胫前肌无力导致的足下垂。终末阶段肌无力可进展至手和大腿，但通常四头肌不受影响。患病个体发病20年后通常依赖轮椅。肌肉组织病理学典型病变是边缘空泡和特征性丝状内含物。GNE基因是唯一已知的与IBM2相关的，其编码产物是激酶 UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase。 IBM2的遗传方式是 。
    • 包涵体肌炎是一种进展缓慢的空泡性肌病，多为。与自身炎性渗出物和嗜刚果红小包涵体有关。
    • Dysferlinopathy,由DYSF基因上的致病性突变导致的一组肌肉疾病，主要可以分为两大类：以远端肌无力为主的Miyoshi 肌病；和以近端肌无力为主的2B型肢带型肌营养不良（LGMD2B）。Miyoshi肌病的特点是年轻成年患者，肌无力和萎缩-最显著的是腿远端，特别是腓肠肌和比目鱼肌的无力；一段时间之后，肌无力可以进展到大腿和臀部肌肉。LGMD2B的特征是青春期或成年期的骨盆和肩胛带肌肉无力，进展缓慢。 Dysferlinopathy的遗传方式是常染色体隐性遗传。
    • 其它主要影响远端肌肉的肌营养不良症包括胫骨肌营养不良症 (Udd远端肌病), telethoninopathy, 由MYH7 致病性突变导致的 Laing 远端肌病， Welander's远端肌病， 面肩肱肌营养不良,​​​​​​​， anoctamin-5 相关性肌营养不良，以及其它散发性或显性遗传的肌营养不良症。
     

    疾病管理

    初次诊断后的评估

    当患者诊断确定之后，为确定患者的疾病程度和需求，建议进行以下评估：

    • 肌电图
    • 常规心电图识别心律失常和心脏传导阻滞；如果怀疑间歇性心律失常，则进行长程心电图监测；如果有心脏症状则行超声心动图。
    • 若存在呼吸系统症状则行呼吸功能检查。
    • 咨询临床遗传医师或遗传咨询师。

    对症治疗

    心律失常和/或心脏传导阻滞的个体需要考虑植入式除颤器（ICD）。有进行性或危及生命心肌病的个人应考虑心脏移植。

    有高碳酸血症以及其他通气障碍症状的患者行呼吸支持，最初可仅在晚间使用，后期在白天也可以应用。呼吸支持的方式包括持续或双水平气道正压通气(CPAP或BIPAP)。

    对肌肉无力的患者进行康复治疗以及辅助装置协助。对脊柱侧凸患者行脊柱融合术是合适的。矫形器（Orthoses）适用于足下垂。

     

    预防并发症：二级预防

    有心律失常性心肌病的患者，应植入起搏器或植入性复律除颤器。

    检测随访

    以下措施是适当的：

    • 定期体检以检测疾病进展速度，频率为每年一次或根据病情发展确定
    • 每年心电图和/或超声心动图以早期发现心肌病。
    • 有劳力性或夜间性呼吸困难的患者定期肺功能检查。

    家系成员风险评估

    有关家庭成员的风险等遗传咨询问题请参见  。

    怀孕

    如果由明显的腹部肌肉无力症状，患病的怀孕妇女在分娩时需要协助。

    尚在研究阶段的治疗方案

    在ClinicalTrials.gov中检索可获取有关多种疾病和病症的临床试验信息。注意：本病可能没有对应的临床试验。

    其它

    强化训练的作用尚未确定。

     

    遗传咨询

    是为遗传疾病患者个体及其家庭提供疾病自然病程、遗传传递和影响的信息，帮助他们做出明确的医学和个人决策。下面的这些章节涉及通过遗传风险评估、家族史和遗传检测来明确家庭成员的遗传背景。这些内容并不意味着解决个体所面临的所有的个人、文化、伦理等问题，也不意味着可以替代遗传专业人士的咨询—编者按.

    遗传方式

    肌原纤维肌病(MFM)最常见的遗传方式是。下列情况是例外：

    家庭成员的风险评估–方式

    父母

    注意：大约25%被确诊 MFM的患者的父或母亲是。家族史可能为阴性，原因包括未能认识到某些个体患病，父或母亲在发病前已经去世，或者患病的父或母亲起病年龄较晚。
    的兄弟姐妹

    的后代.显性遗传的MFM患者的每个后代有50％的几率携带该. 。
    其他家庭成员 其他家庭成员的风险取决于父母的遗传背景。如果其父母同样或携带，的家庭成员则有患病风险。

    家庭成员的风险评估 – 方式

    父母

    的兄弟姐妹

     
    • 在受孕时，个体的同胞有25％的机会是病人，50％可能性是无症状 ，25％的机会为正常并且不是。
    • 一旦高风险同胞确定未患病，那么他/她为概率为2/3。
       
    • （）是无症状的。

    的后代.除非MFM患者与另一个个体 或与一个CRYAB生育孩子，一般情况下常隐MFM患者的后代肯定是一个（），带有CRYAB。
    其他家庭成员，父母的每一个同胞均有50%的风险为。

    ()检测

    一旦在家族中鉴定出CRYAB，就可以进行携带检测。

    家庭成员的风险评估 – X连锁遗传方式

     父母

    的兄弟姐妹

    • 同胞的患病风险取决于母亲是否是
    • 如果的母亲携带FHL1 ，每次怀孕把这个变异传给下一代的几率都是50%。遗传到此变异的男性将会是；而遗传到这个变异的女性则是，也可能会出现严重的临床症状。 
    • 如果是病例（家族中仅有的一个病人）并且在母亲的白细胞DNA中不能检测到，则同胞患病的风险较低；但由于母亲. 的可能性，患病风险仍然高于一般人群。 

    男性的后代.患病男性的儿子不会遗传到FHL1而女儿将遗传到。

    其他家庭成员. 母亲的姐妹有的风险，她们的后代有为或者风险，取决于后代的性别。

    注意：能够鉴定出de novo具体是在哪一位家庭成员身上出现的。这个信息可以帮助确定大家族中成员的遗传风险状态。

     

    杂合体()检测

    如果家族中的FHL1已经被鉴定，则可以对有风险的女性亲属进行。

    相关的问题

    有确证的de novo的家庭。临床症状符合 而父母双亲均不患病，或者检测到而父母不携带，那么非常可能由新发变异致病。不过，其他非医学性的可能性也需要留意，包括(例如辅助生殖)或者领养的孩子。
    家庭计划

     
    • 讨论遗传风险，确定变异的状态以及商讨产前检查的最佳时机是在怀孕之前。 
    • 应当向、或有风险的年轻夫妇提供 (包括对后代遗传风险，生育选择等）。

    DNA库指将DNA（一般从白细胞中提取）储存起来以备将来使用。因为检测方法、对、变异以及疾病的理解都将不断发展，可以考虑够把个体的DNA存放在DNA库。

    产前检查和植入前诊断

    如果在的家庭成员中已经得到确定，那么针对高风险妊娠的，则具有了可操作性。

     

    Resources

    GeneReviews staff has selected the following disease-specific and/orumbrella support organizations and/or registries for the benefit of individualswith this disorder and their families. GeneReviews is not responsible for theinformation provided by other organizations. For information on selectioncriteria, click here.

    • Muscular Dystrophy Association - USA (MDA)
      222 South Riverside Plaza
      Suite 1500
      Chicago IL 60606
      Phone: 800-572-1717
      Email: mda@mdausa.org
    • Muscular Dystrophy UK
      61A Great Suffolk Street
      London SE1 0BU
      United Kingdom
      Phone: 0800 652 6352 (toll-free); 020 7803 4800
      Email: info@musculardystrophyuk.org
    • Sudden Arrhythmia Death Syndromes (SADS) Foundation
      508 East South Temple
      Suite #202
      Salt Lake City UT 84102
      Phone: 800-786-7723 (toll-free); 801-531-0937
      Email: sads@sads.org

    分子基因学

    Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. -ED.

    Table B.

    OMIM Entries for Myofibrillar Myopathy (View All in OMIM)

    View in own window

    102565FILAMIN C; FLNC
    123590CRYSTALLIN, ALPHA-B; CRYAB
    125660DESMIN; DES
    300163FOUR-AND-A-HALF LIM DOMAINS 1; FHL1
    601419MYOPATHY, MYOFIBRILLAR, 1; MFM1
    603883BCL2-ASSOCIATED ATHANOGENE 3; BAG3
    604103MYOTILIN; MYOT
    605906LIM DOMAIN-BINDING 3; LDB3
    608810MYOPATHY, MYOFIBRILLAR, 2; MFM2
    609200MYOPATHY, MYOFIBRILLAR, 3; MFM3
    609452MYOPATHY, MYOFIBRILLAR, 4; MFM4
    609524MYOPATHY, MYOFIBRILLAR, 5; MFM5
    611332DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 6; DNAJB6

    Molecular Genetic Pathogenesis

    Because myofibrillar myopathy is caused by pathogenic variants in any of eight different genes and each disease-associated may have different types of pathogenic variants, the molecular pathogenesis may vary from case to case. However, in all myofibrillar myopathies, the initial pathologic change involves disintegration of the Z-disk, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.

    Animal models. Desmin knockout mice show normal development of cardiac and skeletal muscle but subsequently show myofiber necrosis and phagocytosis [Capetanaki et al 1997]. This model is not comparable with human cases of desminopathy in which pathogenic variants weaken sarcomere structure and are associated with abnormal accumulation of desmin and other proteins. Transgenic mice that produce an inactivated form of human desmin (p.Arg173_Glu179del) show desmin immunoreactive aggregates in myocardium [Muñoz-Mármol et al 1998]. Transgenic mice expressing an α-B crystallin mutated protein (p.Arg120Gly) develop a severe cardiomyopathy with abnormal accumulation of desmin and α-B crystallin in the heart; muscle pathology was not mentioned in this report [Wang et al 2001].

    DES

    Gene structure.DES consists of nine exons. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. More than forty pathogenic variants including , frameshifting nucleotide , small , and splice-site variants have been reported [Goldfarb et al 2004]. See Table 2.

    Table 2.

    Selected DES Pathogenic Variants

    View in own window

    DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
    c.517_537delp.Arg173_Glu179delNM_001927-.3
    NP_001918-.3

    Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

    Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen-.hgvs.org). See Quick Reference for an explanation of nomenclature.

    Normal . Desmin, comprising 470 amino acids, is a constituent of intermediate filaments in cardiac and skeletal muscle linking Z-disks with each other and to the subsarcolemmal cytoskeleton.

    Abnormal . Expression data suggest abnormal aggregation of mutated desmin molecules in heterologous systems. Pathogenic variants may interfere with desmin assembly and filament formation [Bär et al 2006].

    CRYAB

    Gene structure.CRYAB consists of three exons. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. A nonsense variant, a variant, and a small frameshifting have been reported [Vicart et al 1998, Selcen & Engel 2003]. Recently, inheritance was shown for the p.Ser115ProfsTer14 [Forrest et al 2011] and Ser21AlafsTer24 [Del Bigio et al 2011] frameshift variants. See Table 3.

    Table 3.

    Selected CRYAB Pathogenic Variants

    View in own window

    DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
    c.60delC 1p.Ser21AlafsTer24NM_001885-.1
    NP_001876-.1
    c.343delT 2p.Ser115ProfsTer14
    c.358A>Gp.Arg120Gly

    Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

    Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen-.hgvs.org). See Quick Reference for an explanation of nomenclature.


    1.
    2.

    Homozygosity in an individual for this in an form of MFM [Forrest et al 2011]

    Normal . Alpha crystallin B chain (α-B crystallin) is a small heat-shock chaperone protein required for maintaining the structural integrity of desmin. It is composed of 175 amino acid residues.

    Abnormal . Mutated alpha crystallin B chain molecules form smaller molecular-weight polymers than wild type in human muscle. In heterologous cells that constitutively express desmin, misfolded desmin molecules appear in aggregates.

    MYOT (TTID)

    Gene structure.MYOT consists of ten exons. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. Five variants have been reported; all are in 2 [Hauser et al 2000, Hauser et al 2002, Selcen & Engel 2004]. See Table 4.

    Table 4.

    Selected MYOT Pathogenic Variants

    View in own window

    DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
    c.170C>Tp.Thr57IleNM_006790-.2
    NP_006781-.1

    Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

    Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen-.hgvs.org). See Quick Reference for an explanation of nomenclature.

    Normal . Myotilin is a key Z-disk protein that interacts with α-actinin, filamin-C, and actin. It has 498 amino acid residues.

    Abnormal . Mutated myotilin is predicted to weaken the linkage of Z-disk filaments to thin filaments. Transgenic mice with the p.Thr57Ile and muscle disease similar to LGMD1A have been described [Garvey et al 2006].

    LDB3 (ZASP)

    Gene structure.LDB3 consists of 16 exons. It is alternatively spliced. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. Three variants have been reported [Selcen & Engel 2005]. See Table 5.

    Table 5.

    Selected LDB3 Pathogenic Variants

    View in own window

    DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
    c.440C>T 1p.Ala147ValNM_001080116-.1
    NP_001073585-.1

    Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

    Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen-.hgvs.org). See Quick Reference for an explanation of nomenclature.


    1.

    Presents as a distal myopathy (see Genotype-Phenotype Correlations)

    Normal . LIM -binding protein 3 (Zasp) is a key Z-disk protein that interacts with α-actinin and protein kinase C. It has 283 amino acid residues.

    Abnormal . Mutated LIM -binding protein 3 (Zasp) is predicted to weaken the linkage of Z-disk filaments to thin filaments.

    FLNC

    Gene structure. Two FLNC transcript variants encoding different have been found for this (see Table A, Gene). The longer isoform, NM_001458.4, consists of 48 exons.

    Pathogenic variants. One nonsense variant and deletions have been reported [Vorgerd et al 2005, Shatunov et al 2009, Luan et al 2010].

    Normal . Filamin-C is a Z-disk protein that interacts with actin and myotilin. The protein NP_001449.3 has 2725 amino acid residues.

    Abnormal . Mutated filamin-C has a disturbed secondary structure that prevents normal dimerization.

    BAG3

    Gene structure.BAG3 consists of four exons. No splice variants have been identified. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. The variant p.Pro209Leu has been reported [Selcen et al 2009]. See Table 6.

    Table 6.

    Selected BAG3 Pathogenic Variants

    View in own window

    DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
    c.626C>Tp.Pro209LeuNM_004281-.3
    NP_004272-.2

    Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

    Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen-.hgvs.org). See Quick Reference for an explanation of nomenclature.

    Normal . BAG family molecular chaperone regulator 3 (Bag3) is a co-chaperone for the Z-disk and has anti-apoptotic properties. It has 575 amino acid residues.

    Abnormal . Mutated Bag3 may alter the folding of Bag3 or may allosterically affect the binding properties of the canonical Bag3 domains.

    FHL1

    Gene structure.FHL1 has three alternatively spliced transcript variants that encode different protein with different tissue localizations and protein interactions. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. Selected reports of pathogenic variants include Quinzii et al [2008], Schessl et al [2008], Windpassinger et al [2008], Selcen et al [2011].

    Normal . FHL1 is a Z-disk related protein and some of its shuttle between cytoplasm and nucleus.

    Abnormal . Not known; likely effect.

    DNAJB6

    Gene structure.DNAJB6 has published two alternatively spliced transcript variants that encode different protein . The longer transcript variant, NM_058246.3, has ten exons. For a detailed summary of and protein information, see Table A, Gene.

    Pathogenic variants. Pathogenic variants have been reported [Harms et al 2012, Sarparanta et al 2012].

    Normal . The transcript NM_005494.2 encodes a protein isoform with 241 amino acid residues (NP_005485.1). DnaJ homolog subfamily B member 6 (DNAJB6) is a member of heat shock protein family with molecular chaperone function.

    Abnormal . In vitro studies demonstrated that the pathogenic variants increase the half-life of DNAJB6 and reduce its anti-aggregation effect [Sarparanta et al 2012].

     

    References

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    Suggested Reading

    • Olivé M. Extralysosomal protein degradation in myofibrillar myopathies. Brain Pathol. 2009;19:507鈥�15. [PubMed: 19563542]
    • Piñol-Ripoll G, Shatunov A, Cabello A, Larrodé P, de la Puerta I, Pelegrín J, Ramos FJ, Olivé M, Goldfarb LG. Neuromuscul Disord. 2009;19:418鈥�22. [PMC free article: PMC2695848] [PubMed: 19433360]
    • Schröder R, Schoser B. Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol. 2009;19:483鈥�92. [PubMed: 19563540]
    • Selcen D. Myofibrillar myopathies. Curr Opin Neurol. 2008;21:585鈥�9. [PMC free article: PMC4151125] [PubMed: 18769253]
    • Shalaby S, Mitsuhashi H, Matsuda C, Minami N, Noguchi S, Nonaka I, Nishino I, Hayashi YK. J Neuropathol Exp Neurol. 2009;68:701鈥�7. [PubMed: 19458539]

    Chapter Notes

    Revision History

    • 29 October 2012 (me) Comprehensive update posted live
    • 27 July 2010 (cd) Revision: for BAG3 mutations available clinically
    • 2 February 2010 (me) Comprehensive update posted live
    • 10 March 2008 (cd) Revision: and available clinically for zaspopathy (LDB3 mutations)
    • 1 March 2007 (me) Comprehensive update posted live
    • 9 January 2006 (ds) Revision: included disorders added (zaspopathy, filaminopathy)
    • 1 July 2005 (ds) Revision: DES testing clinically available
    • 28 January 2005 (me) Review posted live
    • 2 August 2004 (ds) Original submission