临床特征.

遗 传性痉挛性截瘫 (HSPs)是一组具有临床及遗传异质性的疾病，其临床特点为下肢痉挛及无力 (以不同比例出现)。 若于童年后发病，症状通常会缓慢而平稳地进展；若于儿童早期发病，症状通常为非进展性并类似于痉挛型双瘫。

“单 纯型”HSP临床特点为：神经功能缺损仅限于下肢的痉挛性无力、高渗性膀胱功能障碍和下肢震动觉的轻微减退。“复杂型” HSP除上述单纯型HSP的损害外还同时伴有其他系统或神经系统的异常，如共济失调、癫痫、认知损害、痴呆、肌萎缩、锥体外系症状或周围神经病（排除引起 这些附加症状的其他病因）。

对单纯型HSP患者的神经检查证实：其肌张力呈现不同程度的增高（痉挛），尤其是 腘绳肌、股四头肌、腓肠肌、比目鱼肌和内收肌群；髂腰肌、腘绳肌和胫前肌无力；膝反射和踝反射亢进；经常（不总是）出现足趾振动觉的轻微减退；足底伸肌反应和痉挛步态。

诊断/检查.

诊断HSP需要:

• 典型的痉挛步态和神经检查发现下肢痉挛及无力；
• 经常 (尽管不总是)有一级亲属受累的家族史；和
• 排除其他疾病。

头颅和脊髓磁共振成象 (MRI)结果一般正常；单纯型HSP患者的脑脊液检查，肌电图，和神经传导检查通常正常。

基因检测越来越易获得，其对证实HSP的临床诊断格外重要。因为现如今的分子遗传学检测并未囊括所有已知会导致HSP的基因，所以即使没有确定导致HSP的致病性变异也不能排除HSP的诊断。

遗传咨询.

HSP基因型可由常染色体显性、常染色体隐性、X连锁或母系（线粒体）遗传。研究发现此基因型外显率高（估计90%）。遗传咨询依赖于准确的诊断和确定每个家族 遗传模式 。基因检测对于确定HSP的基因型很有帮助。如果一个家族被鉴定出有致病性变异，可对家族中怀孕风险增加的妇女做痉挛性截瘫某些类型的产前检查。

治疗.

目 前没有能防止或逆转HSP神经变性的治疗手段。治疗通常是为了减轻症状和通过物理和康复治疗增强力量和平衡能力；通过辅助器具加强功能性步态（例如：踝- 足矫正设备）；通过药物治疗和拉伸减轻痉挛（例如：口服和鞘内注射巴氯芬，肌内注射肉毒毒素）；通过药物缓解尿急症状。

HSP临床表现

HSP 主要表现为下肢无力和痉挛。若于儿童早期发病，症状通常为非进展性并类似于痉挛型双瘫。 若于童年后发病，症状通常会缓慢而平稳地进展。几年以后，少部分患者步态逐渐恶化的进入“功能性平台期” （即步态异常的进一步加重与年龄增长对疾病的贡献一致）.

分类. HSP临床上被分为单纯型（非综合征型）和复杂型(综合征型)，基因上根据遗传模式，染色体位点，和/或致病等位基因分类。HSP遗传位点根据他们被发现的时间顺序定名为SPG（代表“痉挛性截瘫”）1- 56[Fink 2013].

• "非复杂型" ("单纯型") HSP 临床特点为：神经功能损伤仅限于进行性的下肢痉挛性无力，高顺应性膀胱，下肢震动觉轻微减退。 [Harding 1983].
  单纯型HSP可在任何年龄发病，从儿童早期到成年晚期。症状可以是非进展性的（当疾病发生于儿童早期时）；或在之后的若干年缓慢进展（当症状于童年后出现时，早期发病的非进展性HSP症状可以类似痉挛型双瘫。）
  患者会经历行走困难（非进展性或者隐匿性恶化）并通常需要拐杖、步行器或者轮椅。可能会出现尿急和下肢感觉减退。
  单纯型HSP患者通常保留上肢正常的力量和灵活性并且语言、咀嚼和吞咽功能不受累。尽管可能会造成残疾，但是单纯型HSP并不缩短患者寿命。
• "复杂型" HSP 临床特点为：在单纯型HSP症状上同时还出现其他系统或者神经系统受累，包括共济失调、癫痫、智力损害、痴呆、肌萎缩、锥体外系症状或者周围神经病，这些伴随症状并不是由其它病因所致。

建立HSP的诊断

HSP诊断基础：

• 双侧下肢痉挛性无力通常伴随尿急，下肢症状可以是非进展性（儿童早期起病）或缓慢进展（童年后发病）
• 神经检查证实皮质脊髓束缺损影响双下肢（痉挛性无力，发射亢进，典型的伴双侧跖反射阳性，经常伴有下肢远端振动觉轻微受损和高顺应性膀胱。
• 家族史符合常染色体显性、常染色体隐性或X连锁、母系（线粒体）遗传。
• 排除其他疾病 (见鉴别诊断)
• 分子遗传检测；越来越容易获取并且对证实临床诊断的HSP具有潜在作用。

神经检查. 单纯型HSP患者有以下表现：

双下肢痉挛状态（主要为腘绳肌、股四头肌、内收肌群和腓肠-比目鱼肌）和无力（髂腰肌、腘绳肌、胫前肌为主）。痉挛状态和无力是可变的，一些患者有痉挛状态而无明显的无力，而其他患者有大约相同比例的痉挛和无力。

• 下肢腱反射亢进和跖反射阳性。
• 常有下肢远端振动觉的轻微损害。

神经病理.单纯型HSP最常被报道的病理学特征是轴索变性，以皮质脊髓束远端末尾处为重，其次，在脊髓纤维远端。可能出现前角细胞轻微丢失。如果存在脱髓鞘，其将与轴索变性的程度一致。[Schwarz & Liu 1956, Behan & Maia 1974].

HSP鉴别诊断

鉴别诊断包括：

• 结构异常 包括颅内或脊髓(例如：脊髓拴系综合征和脊髓压迫症)
• 其他运动神经元病 如慢性进展性肌萎缩侧索硬化(ALS)或原发性侧索硬化(PLS)
• 脑白质营养不良 如平稳进展的多发性硬化，维生素B12缺乏，克拉伯病Krabbe ，异染性脑白质营养不良，和肾上腺脊髓神经病变。
• 脊髓小脑共济失调(SCAs) (例如Machado-Joseph 病[SCA 3], Friedreich共济失调,  Charlevoix-Saguenay痉挛性共济失调或其他痉挛性共济失调)。见遗传性共济失调。
• 感染 (例如：人类免疫缺陷病毒[HIV AIDs]，热带痉挛性截瘫 (也被叫做人类T细胞白血病病毒Ⅰ型 [HTLV1] -相关性脊髓病)，和神经梅毒。
• 代谢异常 (回顾于 Sedel et al [2007])包括同型半胱氨酸再甲基化缺陷(这是由于亚甲基四氢氨酸还原酶(MTHFR)缺乏)和 氰钴胺素C疾病, 尿素循环障碍, 生物酶缺乏症,苯丙酮尿症,甘氨酸脑病, 脑叶酸缺乏症, 高肌肽病, 脑腱黄瘤病, Sjögren-Larsson综合征, 成人葡萄糖多聚体病,和核苷磷酸化酶缺乏症
• 早发性痴呆 包括额颞叶痴呆-ALS(肌萎缩侧索硬化概述)和由于PSEN1 (编码早老素-1)、 PSEN2 (编码早老素-2),或APP(编码淀粉样前体蛋白)突变导致的家族性阿尔兹海默病(见早发性家族性阿尔兹海默病)
• 多巴反应性肌张力障碍 所有患病个体均有必要考虑多巴反应性肌张力障碍--尤其是儿童--伴随进行性步态异常。见鸟苷酸环化水解酶-1缺乏性多巴反应性肌张力障碍, 酪氨酸羟化酶缺乏。

 HSP患病率

HSP患病率估计从1.3:100,000 (在爱尔兰) [McMonagle et al 2002], 到9.6: 100,000 (在西班牙) [Sedel et al 2007].

HSP基因型. 迄今为止，多达56个HSP位点和41个HSP-相关基因已经被鉴定出。

评估策略

建立受累患者痉挛性截瘫原因的评估包括：

• 临床评估. 完整的病史, 神经病史, 和体格检查
• 家族史.包含3代家族史并注意其他可能患有HSP的亲属。家族成员中相关信息的收集可以通过对这些个体的直接检查或回顾他们的医学检查结果包括神经影像，神经病理，神经系统体格检查和分子遗传学检测。
• 分子遗传学检测, 对于许多HSP患者临床可行
  • 其中一个基因检测策略是基于下列一些因素(但不仅限于这些因素)进行连续单基因 分子遗传学检测：
    • 遗传模式
    • 临床发现 (如：起病年龄, 附加临床特征, MRI结果)
    • 患病率(如：SPG4 (编码spastin), 单一引起显性遗传HSP的最常见原因，它导致的HSP约占受累的个体的30 to 40%)
    • 患者种族
  • 另一个基因检测策略是用包含表1 ，表2，表3，和表4基因的表型靶向检测。注意:检测的基因和表型靶向检测方法在不同的实验室和随着时间推移变化。

遗传方式

HSP可以常染色体显性,常染色体隐性或X-连锁方式遗传,这取决于一个家族中的基因亚型。

家庭成员患病风险 — 常染色体显性HSP

先证者父母 

• 大多被诊断常染色体显性HSP的患者父母受累, 尽管偶尔会有因新生 致病性变异导致的HSP的先证者
• 导致常染色体显性HSP的新生变异频率未知。

先证者同胞

• 先证者同胞患病风险取决于先证者父母的基因状态。
• 如果先证者的父母一方有一个突变的等位基因, 则同胞遗传这个突变等位基因概率为50%。
• 同一家庭不同成员、拥有相同致病性变异的不同家庭、或不同HSP基因型之间，起病年龄和病变程度高度不相同。

先证者子女。常染色体显性HSP患者的每个子女都有50%的风险会遗传致病性变异.

家庭成员患病风险 — 常染色体隐性HSP

先证者父母 

• 受累个体的父母是肯定杂合子,因此携带一个突变等位基因.
• 杂合子(携带者)无症状.

先证者同胞 

• 怀孕中,每个同胞有25%的几率受累, 50%的几率成为无症状携带者,25%的几率不受累且不是携带者。
• 受累个体的未受累同胞有2/3的几率是杂合子.
• 杂合子无症状.

先证者子女 . 常染色体隐性HSP个体的子女是肯定杂合子(携带者)，其带有一个突变的致HSP的等位基因。

家庭成员的患病风险— X-连锁HSP

先证者父母 

• 有一个 受累的儿子和另一个受累的男性亲戚的女人肯定是杂合子。
• 如果 家系分析显示一个受累的 男性是一个单发的病例 (一个没有痉挛性截瘫家族史的男性患者), 需要考虑以下几种关于其母亲携带者状态的可能性:
  • 他有新发的 致病性变异且他的母亲不是携带者.
  • 他的妈妈有新发的 致病性变异, 可以是 "胚系突变" (即：在她怀孕时发生突变并因此出现于她身体的每个细胞中), 或是"胚系嵌合" (即：突变仅发生于生殖细胞).
  • 他的姥姥有一个新发的 致病变异.

先证者同胞 

• 其同胞患病风险取决于 先证者母亲的基因状态。
• 如果先证者母亲有一个致病性变异,则每次怀孕传递此变异的几率是50%。遗传此变异的儿子将受累; 遗传此变异的女儿是携带者并不受累。
• 同一家庭成员、拥有相同致病性变异的不同家庭、或HSP不同基因型之间的起病年龄, 外显率,和受累程度均不可预测。

先证者子女. 受累的男性的所有女儿均是携带者;他的儿子均不会受累。

先证者的其他家庭成员 . 先证者的姨妈以及他们的子女有成为携带者或受累的风险 (取决于他们的年龄, 家庭关系, 和先证者母亲的携带者状态)

遗传咨询相关问题

当一个患者有HSP的所有症状体征但却无其他相似受累的亲戚是需谨慎。这些个体可能被诊断为原发性侧索硬化(PLS)。但这些没有已知HSP家族史的患者可能是常染色体隐性HSP (并因此传递给下一代的几率低）, 也可能是X-连锁HSP, 外显率降低的常染色体显性HSP，一个新发的 致病性变异, 非生物学父亲, 或者是环境导致。

计划生育. 最佳决定基因风险、阐明携带者状态、并讨论产前检查可行性的时机是在怀孕前。

DNA银行是贮存DNA以备将来之需(典型地从白细胞中提取)。因为检测方法和我们对基因、等位基因变异和疾病的认识很可能会随着时间发展逐步深入，所以应考虑受累患者的DNA银行。

产前检查和植入前遗传学诊断

一旦家庭中受累的成员致病性变异被确认,对增高患病风险的怀孕需要进行产前检查和痉挛性截瘫的 植入前遗传诊断。

对症治疗

目前，没有能阻止或逆转HSP神经变性的特殊治疗。治疗是针对减轻症状和改善平衡、力量和灵活性的。 目前的建议：

• 推荐改善心血管功能，保持并改善肌肉力量和步态，并减轻痉挛状态的日常物理治疗。

• 职业疗法，辅助行走设备和踝-足矫形器经常被使用。

• 减轻肌肉痉挛状态的药物 (如： 巴氯芬^® [口服或鞘内注射], 替扎尼定, 丹曲林, 保妥适^®注射) 和减轻尿急的药(如： 奥昔布宁)

防止继发性并发症 

推荐改善心血管功能，保持并改善肌肉力量和步态，并减轻痉挛状态的日常物理治疗。

监控

患者需做周期性的评估(每年一次或根据需要)，由神经病学医生和物理治疗师评估疾病进展并制定治疗策略以最大可能保留行走功能和减轻症状。

需避免的药剂/环境

尽可能避免暴露于药物或化学物质。

对有患病风险的亲属的评估

见遗传咨询中对有患病风险亲属进行检测以达到遗传咨询目的的部分。

孕期管理

HSP症状通常不会在怀孕期间有显著变化(尽管，如果像巴氯芬这样的药物在孕期减量或停服会加重痉挛状态)。总的来说，单纯型HSP不会增加怀孕和分娩的风险 ，也不会增加产科麻醉风险。

处于研究阶段的治疗方法

搜索ClinicalTrials.gov 来获取更广泛的疾病临床研究信息。注意：也许会没有没有HSP的临床资料。

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Revision History

• 6 February 2014 (me) Comprehensive update posted live
• 3 February 2009 (cd) Revision: 序列分析 for SPG5A available clinically
• 21 May 2008 (cd) Revision: mutations in ZFYVE26 identified as causative of SPG15
• 4 March 2008 (cd) Revision: 序列分析 of entire 编码区 available for SPG8 and SPG33
• 4 October 2007 (cd) Revision: 序列分析 for SPG10 available on a clinical basis
• 11 July 2007 (me) Comprehensive update posted to live Web site
• 21 October 2004 (cd) Revision: arginase deficiency added
• 26 February 2004 (cd) Revision: testing for SPG6 clinically available
• 15 October 2003 (cd) Revision: test availability
• 22 September 2003 (me) Comprehensive update posted to live Web site
• 15 August 2000 (me) Overview posted to live Web site
• 21 March 2000 (jf) Original submission