摘要

定义

遗传性共济失调的发病率

常染色体显性小脑共济失调（ADCAs）的发病率约为1-5：100,000人[van de Warrenburg et al 2002, Ruano et al 2014]。

在常染色体显性共济失调中，SCA3是世界上最常见的，其次是SCA1,2,6和7（见图 1）。

图1.

SCA不同亚型的世界分布 [Schöls et al 1997, Moseley et al 1998, Saleem et al 2000, Storey et al 2000, Tang et al 2000, Maruyama et al 2002, Silveira et al 2002, van de Warrenburg et al 2002, Dryer et al 2003, Brusco et al 2004, (更多.).

• 早发性
• 慢病程

• 有时为阵发性共济失调
• 疾病进展非常缓慢

• 视网膜视力丧失

• 进展缓慢
• 有时为快速DTRs，振动觉减弱
• 少数情况下会出现认知障碍

• 偶尔癫痫发作

• 温和
• 有走动能力

• 缓慢进展的共济失调
• 30余岁时出现动作颤抖
• 反射亢进
• 不易察觉的帕金森病的可能
• 认知/精神疾病，包括老年痴呆症

• 轻度智力障碍
• 身材矮小

• 早期轴肌痉挛

• 纯共济失调
• 非常缓慢的进展

• 头部震颤

• 精神衰退
• 偶尔舞蹈症、肌张力障碍、肌阵挛癫痫

• 早期的感觉/运动神经病患者的共济失调
• 眼球震颤
• 构音障碍
• 腱反射减弱

• 进展缓慢
• 认知障碍较为少见
• 肌阵挛
• 反射亢进

• 早期构音障碍
• 痉挛性发声障碍
• 反射亢进
• 运动迟缓

• 轻度到严重的早发性认知功能障碍

• 构音障碍
• 异常眼动
• 振动觉和位置感觉的减弱

• 感觉神经病变

• 构音障碍
• 不规则的视觉追求

• 早发性震颤
• 运动障碍
• 认知减退

• 眼球震颤
• 眼肌瘫痪
• 上睑下垂
• 腱反射亢进

• 学习欠缺

• 反射亢进

• 感觉正常

• 皮肤改变在成年消失

• 反射亢进
• Babinski 反射

• 肌束颤动
• 舌肌萎缩
• 反射亢进

• 垂直眼动异常

• 成人发病
• 轴突神经病

• 成人发病
• 反射活跃
• 痉挛

• 舞蹈症
• 癫痫
• 痴呆
• 肌阵挛

• 轻度锥体束征
• 眼球追踪运动

• 耳聋
• 感觉丧失
• 嗜睡

• 低髓鞘化
• 基底神经节萎缩
• 强直
• 肌紧张不足
• 舞蹈症

• 认知迟缓
• 异常眼动
• 听力丧失

• 小儿癫痫
• 智力缺陷
• 小头畸形

• 小脑萎缩

ADCA个别亚型的流行可能因区域而异，通常由于奠基者效应。如，

• DRPLA在北美是罕见的，但在日本是常见的，其频率在日本不同地区之间也有所差异 [Matsumura et al 2003]。
• SCA2 在韩国流行。
• SCA3在葡萄牙更常见。它最初在来自亚速尔群岛的葡萄牙家庭，并被称为 Machado-Joseph病（MJD）。 它在日本和德国比在英国也更常见 [Leggo et al 1997, Schöls et al 1997, Watanabe et al 1998, Kim et al 2001, Silveira et al 2002]。

核苷酸重复障碍。 在发生CAG三核苷酸重复的常染色体显性共济失调患者中可进行预判（表 1）。预判是指在家族的后续世代中，疾病发病较早、严重性增加。 在三核苷酸重复疾病中，预判由于基因传递到后代而发生的CAG重复数目的扩增而导致。 ATN1 (DRPLA)和ATXN7 (SCA7) 具有特别不稳定的CAG重复序列[La Spada 1997, Nance 1997]。 在SCA7中，预判可能极端到早发性严重疾病的儿童在受影响的父母或祖父母患有症状之前就死于疾病并发症。 （参见遗传咨询。）

虽然我们比较关注预判和三核苷酸重复扩增的现象，值得一提的是三核苷酸重复的数目也可以保持稳定或甚至在传递到后代时收缩。

阵发性共济失调

阵发性共济失调的特征是一段时间之内（几分钟到几小时）出现不稳定步态，通常伴随眼球震颤或构音障碍 [Jen et al 2007]。 在某些亚型中可能发生心肌病，眩晕或听力损失。 在疾病进程的后期可能出现永久性共济失调甚至小脑萎缩。

常染色体隐性遗传性共济失调

常染色体隐性遗传性共济失调参见 表 3:

• 表的第一部分列出了相对常见（即在> 5个家族中被发现，如FRDA、AOA1、AOA2和ATM等）或可治疗的（例如CTX、Refsum综合征和AVED）或常见于特定种族群体（例如法国人 - 加拿大人的ARSACS）的常染色体隐性共济失调。
• 表的第二部分列出了相对不常见的常染色体隐性共济失调（即在1-5个家庭中被发现） [Musselman et al 2014]。

它们的整体情况综述可见Embiruçu et al [2009]。

注意，与由许多相关基因之一的双等位基因致病性变体引起的共济失调和/或小脑发育不良相关的常染色体隐性障碍，不包括在本讨论和表 3中。例如：

• Joubert 综合征
• 先天性糖基化障碍
• 小脑发育不全 [Namavar et al 2011, Ahmed et al 2015]
• 过氧化物酶体合成障碍 , Zellweger谱系障碍
• Perrault 综合征

X-连锁的遗传性共济失调

除了脆性X震颤共济失调综合征（FXTAS），X-连锁的遗传性共济失调相当罕见 [Zanni & Bertini 2011].

痉挛性共济失调

五种病症被认定为痉挛性共济失调（SPAX）。 SPAX1以常染色体显性方式遗传，其他四个以常染色体隐性方式遗传。

线粒体障碍导致的共济失调

注意，许多核基因调节线粒体功能可以在常染色体隐性共济失调中突变（参见线粒体疾病概述和表 3, POLG）。

评估策略

一旦家族中的先证者（即家庭中首先被发现的病例）被怀疑患有遗传性共济失调，以下方法可用于确定导致疾病的遗传因素，以辅助遗传咨询和预后判断。对给定个体的遗传性共济失调的遗传因素的判断，通常涉及病史、体格检查、神经学检查、神经成像、三代家族史和分子遗传学检查。

临床表现

步态共济失调是这些疾病的常见临床表现。其他常见的症状包括：眼球震颤、构音障碍和辨距障碍。 脑成像常常显示小脑萎缩或发育不良。 发病年龄变化很大，但常染色体隐性遗传性共济失调常在儿童时期发病。患者也可能出现智力残疾、周围神经病变和视网膜异常等症状。

家族史

医者应获得患者的三代家族史，并应注意具有神经系统体征和症状的其他亲属。医者可以直接检查这些个体或审查他们的医疗记录，包括分子遗传学检测、神经影像学研究和尸体解剖检查的结果，来完成对亲属的相关发现的记录。

检测

除罕见情况外（如维生素E缺乏AVED），非基于DNA的临床测试通常是非特异性的。

遗传形式

超过一个受影响的家庭成员

• 常染色体显性遗传 (表 1 和 表 2)。家族史中多代的男性和女性个体受到影响，提示常染色体显性遗传。
  测试可优先于以下疾病，其中包括最常见类型的常染色体显性共济失调：SCA1, SCA2, SCA3, SCA6, 和 SCA7。 这五种疾病是由三核苷酸重复扩增引起的；许多临床实验室将它们包括在小批量检测中[Ruano et al 2014]。
• 常染色体隐性遗传(表 3)。 家族史中，只有近亲受影响（即家庭中的一代人）和/或当父母是近亲时，提示常染色体隐性遗传。
  从发生频率看， Friedreich 共济失调, 共济失调毛细血管扩张, AOA1, 和 AOA2 应当首先被考虑。 从可治疗性看，维生素 E 缺乏, Refsum 病, and 脑腱性黄色瘤应当被考虑，即使他们的发病率很低。
• X-连锁 遗传 (表 4)。受影响的个体是男性，并且通过女性彼此相关的家族史提示X连锁遗传。

单独案例

• 如果只知道一个家庭的一个成员受到影响，则可考虑疾病是获得性的（非遗传原因）、原发性致病性突变导致的常染色体显性共济失调。致病性突变降低的外显率与常染色体显性共济失调、单发的常染色体隐性或X-连锁 疾病，或者替代亲子鉴定相关。
• 如果没有鉴定到共济失调的获得性的原因，则受影响的个体预计有的13％的概率为 SCA1, SCA2, SCA3, SCA6, SCA8, SCA17, Friedreich ataxia, AOA1, 或 AOA2 [Abele et al 2002, Ruano et al 2014]。

可供鉴别的临床特点

用以区分多种遗传性共济失调的临床特点有：

• 由于所有形式的常染色体显性遗传性共济失调之间的广泛的临床重叠，在具有共济失调的任何给定个体中和在与常染色体显性遗传一致的家族史中难以在没有分子遗传学检测的情况下建立诊断。 注意，视网膜疾病提示SCA7，葡萄牙血统建议SCA3，癫痫发作和美洲印第安人血统建议SCA10，而舞蹈病建议SCA17或DRPLA。[Ashizawa et al 2013]。见表 1
• 临床症状如智力残疾，癫痫发作，眼睛异常或周围神经病变可能有助于区分一些常染色体隐性遗传性共济失调。见表 3。
• 与正常功能不同的一段时间的共济失调（几分钟至几小时），强烈地提示阵发性共济失调。见表 2。
• 突出的痉挛状态表明患者患有其中一种痉挛性共济失调。见表 5。

在没有区别临床特征的情况下，可以考虑多基因批量检测。批量检测可以围绕遗传性共济失调（如最常见的常染色体显性遗传性脑脊髓共济失调）的特定的相对小的子集定向，或者可以围绕范围广泛的疾病进行检测（如所有已知的遗传性共济失调）。

Other其它

族群性。单基因检测可以根据个人的种族背景加以考虑。

发病率。病症的流行可以用于进行一系列单基因测试（即，按照最常见至最不常见的遗传性共济失调的顺序进行测试），或多基因批量检测的顺序选择（即，选择仅包括五或六种最常见的遗传性共济失调）。

最常见的成人发病的常染色体显性共济失调是SCA1，SCA2，SCA3，SCA6和SCA7；最常见的常染色体隐性共济失调（通常是儿童时期发作）是Friedreich共济失调，AOA1，AOA2和共济失调毛细血管扩张症。

遗传咨询

遗传咨询是向个人和家庭提供关于遗传疾病的性质、遗传特征和影响的信息，以帮助他们做出明智的医疗和个人决定的过程。 以下部分涉及遗传风险评估、家族史和遗传测试的使用，以阐明家庭成员的遗传状况。本节不是为了解决患者个人可能面临的所有个人、文化或伦理问题，也不能替代遗传学专业人士的咨询。—ED.

遗传方式

如果先证者具有与共济失调相关的综合征（如Friedreich 共济失调或FXTAS），则患者可对该病症进行咨询。

家庭成员风险——常染色体显性遗传

先证者的父母

• 大多数诊断为常染色体显性遗传性共济失调的个体具有受影响的父母，尽管有时候家族史为阴性。
• 家族史可能是阴性的，原因如下：患者父母的早期死亡，未能识别家族成员中的常染色体显性共济失调，父母晚期发作，无症状亲本中致病性等位基因的外显率降低，或原发突变。

先证者的近亲

• 近亲的风险取决于先证者父母的遗传状况。
• 如果一个先证者的父母具有突变等位基因，则近亲遗传了该突变等位基因的风险为50％。

先证者的后代。具有常染色体显性遗传共济失调的个体具有50％的概率将突变的等位基因传递给每个后代。

其他家庭成员。 其他家庭成员的风险取决于先证者父母的情况。 如果父母受到影响，他或她的家庭成员可能面临风险。

家庭成员风险——常染色体隐性遗传

先证者的父母

• 父母是专性杂合子，因此携带致病性变体的单拷贝。
• 杂合子是无症状的。

先证者的近亲

• 理论上，先证者的每个近亲有25％的机会受到影响，50％的机会成为无症状携带者，25％的机会不受影响且不是载体。

先证者的后代。 所有后代都是携带突变等位基因的杂合子。

其他家庭成员。 每一个先证者父母的近亲有50%的概率是携带者。

携带者检测

对于高危亲属的携带者检测需要事先鉴定家族中的致病性变体。

家庭成员风险——X-连锁遗传

先证者的父母

• 受影响的男性的父亲不会患有该疾病，也不会是致病性变体的携带者
• 有受影响的儿子和另一个受影响的男性亲属的妇女是专性杂合子。

先证者的近亲

• 近亲的风险取决于母亲的携带者状况。
• 如果先证者的母亲具有致病性变体，则在每次妊娠中传播它的机会是50％。继承致病变种的男性近亲将受到影响；继承致病变种的女性近亲将是携带者，通常不会受到影响。
• 如果先证者是单独的病例（即家族中的单个事件），并且如果在母亲的白细胞DNA中不能检测到致病性变体，因为母体是生殖系嵌合体的可能性，近亲的风险低但大于一般群体的风险。

先证者的后代。受影响男性的所有女儿都是携带者；他的儿子都不会受到影响。

其他家庭成员。先证者的母方的姑母可能有成为携带者的风险，而她的后代（取决于他们的性别）可能有成为携带者或受影响的风险。

携带者检测

对具有X-连锁疾病风险的女性的携带者检测需要事先鉴定家族中的致病性变体。

遗传咨询的相关问题

高危症状成年亲属的检测是可能的，特别是在分子遗传学检测已经确定了家庭中的特定疾病和致病性变种。 这种检测应在正式遗传咨询中进行。

总体来讲，分子遗传学检测结果在预测无症状个体的发病年龄、严重程度、症状类型或进展速率方面没有作用。

对年龄小于18岁的无症状个体的分子遗传学检测被认为是不合适的（当该无症状个体处于成人发病的风险中，且该疾病没有治疗方式时）。主要原因是其否定了儿童的自主性，却没有强制的益处。 此外，这种信息可能对家庭动态、未来歧视和污名化产生风险，此类信息引起的焦虑可能产生的不健康的影响。

另见National Society of Genetic Counselors关于未成年人对成人发病情况的遗传检测的立场声明，以及American Academy of Pediatrics and American College of Medical Genetics and Genomics 的政策声明：儿童遗传测试和筛查中的伦理和政策问题。

DNA银行用以储存DNA（通常从白细胞中提取），以备将来使用。 因为测试方法和我们对基因、等位基因变体和疾病的理解可能会在将来得到完善，所以应考虑对受影响个体的DNA进行存储。

产前测试和胚胎植入前遗传诊断

一旦在受影响的家庭成员中鉴定出了致病性变体，就可以对有更高风险的孕者进行遗传性共济失调和植入前遗传诊断。 然而一般来说，发病年龄、疾病严重程度、特定症状和疾病进展的速度是可变的，并且不能通过家族史或分子遗传学检测来准确预测。 参见病因，ADCA，核苷酸重复序列障碍。

成人发病疾病的产前诊断的请求比较罕见。在医疗专业人员和家庭内部可能存在产前测试的差异，特别是考虑终止妊娠而进行的测试。 虽然大多数中心会将产前检查的决定认为是父母的选择，但是对这些问题的讨论是适当的。

患者管理

对症状的治疗

共济失调的患者管理通常旨在通过既定的康复医学和职业和物理治疗方法为协调问题提供帮助。

拐杖，步行者和轮椅对于步态共济失调是有用的。

特殊装置可用于帮助手写，按扣和使用餐具。

语言治疗可能有利于有发音障碍的人。 计算机设备可用于帮助有严重言语障碍的人。

对主要症状的预防

除了AVED、Refsum综合征、CTX和CoQ10 缺乏外，没有针对遗传性共济失调的特异性治疗。

参考文献

发表的准则/共识声明

1. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-2-17. [PubMed]
2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 2-2-17.

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Suggested Reading

• Rottnek M, Riggio S, Byne W, Sano M, Margolis RL, Walker RH. Schizophrenia in a patient with spinocerebellar ataxia 2: coincidence of two disorders or a neurodegenerative disease presenting with psychosis? Am J Psychiatry. 2008;165:964–7. [PubMed]

Chapter Notes

Revision History

• 3 November 2016 (tb) Revision: addition of FGF12, ATP1A3, POLR3A, POLR3B, SLC25A46, TSFM, VWA3B, WDR73, ATP2B3, and citations
• 3 March 2016 (tb) Revision: addition of CACNA1G, C9orf72, SCN2A, ATG5, PMPCA, TXN2, UBA5, and citations
• 11 June 2015 (tb/aa) Revision: addition of SNX4 (SCAR20), RNF216 (Gordon Holmes syndrome), and citations
• 2 April 2015 (tb) Revision: mutation of PNKP added as a cause of AR ataxia; ITPR1 added as the gene associated with SCA16
• 5 March 2015 (tb) Revision: addition of SPG7 – Table 5
• 26 November 2014 (tb) Revision: addition of PNPLA6,CLN5, and CWF19L1
• 30 October 2014 (tb) Revision: addition of Brown-Vialetto-Van Laere syndrome 2 (caused by mutation of SLC52A2) and Wolfram syndrome (caused by mutation of WFS1)
• 16 October 2014 (aa) Revision: addition of SCA40, caused by mutation of CCDC88C
• 2 October 2014 (tb) Revision: SCA21, Lichtenstein-Knorr Syndrome added
• 28 August 2014 (tb) Revision: addition of ELOVL5 and LAMA
• 14 August 2014 (me) Comprehensive update posted live
• 3 April 2014 (tb) Revision: to information on KIAA0226 [Assoum et al 2013]
• 20 March 2014 (tb) Revision: SCA34; SPTBN2 associated with autosomal recessive cerebellar ataxia; update in prevalence information
• 27 February 2014 (tb) Revision: addition of CLCN2, WWOX, and links to OMIM Phenotypic Series
• 13 February 2014 (tb) Revision: review of spastic ataxia
• 23 January 2014 (tb) Revision: edits to prevalence, clinical features of ADCA, AR single cases; added SCA37 to Tables 1&2; added SCA32 and SCA34 to Table 1.
• 7 November 2013 (tb) Revision: autosomal recessive SCA with eye movement abnormalities (most notably tonic upgaze) caused by mutations in GRID2
• 17 January 2013 (tb) Revision: mutation in KCND3 found to cause SCA19 and SCA22 (SCA19/22)
• 3 January 2013 (tb) Revision: clinical testing available for SCA35
• 1 November 2012 (tb) Revision: mutations in EEF2 identified as causative for SCA26
• 11 October 2012 (tb) Revision: mutations in VAMP1 identified as causative for SPAX1; mutations in GRM1 identified as causative for ARCA
• 13 September 2012 (tb) Revision: addition of Onat et al [2013]
• 31 May 2012 (tb) Revision: to include Pfeffer et al 2012 re: ataxia associated with missense mutations in MTATP6; SCA18 assigned by OMIM to ataxia phenotype described by Brkanac et al 2002 and 2009.
• 26 April 2012 (tb) Revision: autosomal recessive SCA caused by mutation in ANO10 added
• 16 February 2012 (tb) Revision: SCA35 added
• 26 January 2012 (tb) Revision: updated information on SCA with axonal neuropathy; SCAR9 added
• 15 September 2011 (tb) Revision: additional rare form of autosomal recessive ataxia
• 21 July 2011 (tb) Revision: addition of SCA36
• 17 February 2011 (me) Comprehensive update posted live
• 6 January 2009 (cd) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as probable cause of SCA20
• 25 September 2008 (tb) Revision: heterozygous mutations in AFG3L2 identified as the cause of SCA28
• 27 February 2008 (tb) Revision: deletion of part of ITPR1 identified as cause of SCA15
• 18 December 2007 (tb) Revision: mutations in TTBK2 associated with SCA11
• 27 June 2007 (me) Comprehensive update posted to live Web site
• 27 October 2006 (tb) Revision: SCA16 reassigned to 3p26.2-pter
• 31 August 2006 (tb) Revision: clinical testing available for infantile-onset spinocerebellar ataxia (IOSCA)
• 4 August 2006 (tb) Revision: clinical testing available for SCA5, SCA13, SCA27, and 16q22-linked SCA
• 27 April 2006 (tb) Revision: mutations in KCNC3 cause SCA13; additions to Causes- Autosomal Dominant Cerebellar Ataxias, References
• 1 February 2006 (tb) Revision: mutations in SPTBN2 cause SCA5
• 19 December 2005 (tb) Revision: Marinesco-Sjögren caused by mutations in SIL1
• 8 November 2005 (tb) Revision: SCA28
• 17 October 2005 (tb) Revision: SCA27
• 14 September 2005 (tb) Revision: author changes
• 12 July 2005 (tb) Revision: SCA4 gene and protein identified
• 4 April 2005 (tb) Revision: SCA26 added
• 8 February 2005 (me) Comprehensive update posted to live Web site
• 23 November 2004 (tb) Revision: author changes
• 14 October 2004 (tb/cd) Revision
• 30 June 2004 (tb) Revision: SCA20 added
• 11 June 2004 (tb) Revision: SCA12 gene identified
• 27 May 2004 (ca) Revision: addition of SCA world map (Figure 1)
• 23 January 2004 (tb) Revision: SCA19
• 30 December 2003 (tb) Revision: change in test availability
• 2 October 2003 (tb) Revision: X-linked sideroblastic anemia gene identified
• 17 July 2003 (tb) Revision: SCA22
• 20 May 2003 (tb) Revision
• 27 February 2003 (me) Comprehensive update posted to live Web site
• 9 January 2002 (tb) Revision: SCA18
• 8 November 2001 (tb) Revision: SCA15, SCA18
• 14 August 2001 (tb) Revision: SCA17
• 25 July 2001 (tb) Revision: SCA16
• 11 April 2001 (tb) Revision: SCA12
• 8 December 2000 (tb) Revision: SCA10
• 15 November 2000 (tb) Revision: AOA
• 8 November 2000 (tb) Revision: SCA10
• 25 September 2000 (tb) Revision: SCA8
• 25 August 2000 (tb) Revision: SCA14
• 7 August 2000 (tb) Revision: Hereditary Ataxias/Clinical Features & References
• 14 June 2000 (tb) Revision
• 22 May 2000 (tb) Revision
• 14 January 2000 (tb) Revision
• 25 October 1999 (tb) Revision
• 31 August 1999 (tb) Revision
• 11 March 1999 (tb) Revision: SCA8
• 5 March 1999 (tb) Revision: SCA10
• 28 October 1998 (me) Overview posted to live Web site
• 23 June 1998 (tb) Original submission