1、第十六章 神经系统遗传病Genetic Disease of the Nervous SystemDepartment of Neurology Second Affiliated Hospital Harbin Medical UniversityGenetic disease of nervous system 1、Introduction 2、Friedreich Ataxia 3、Spinocerebellar Ataxia(SCA)4、Charcot-Marie-Tooth Disease掌握：掌握：1、Friedreich型共济失调的主要临床特征、临床表现。2、脊髓小脑性共济失调的
2、临床表现、诊断及鉴别诊断。熟悉：熟悉：1、Friedreich型共济失调的病因、发病机制。2、脊髓小脑性共济失调的病因、发病机制。3、腓骨肌萎缩症(CMT)的临床表现、诊断及鉴别诊断。第一节 General Introduction 1.Conception Genetic disease of the nervous system 是指由于生殖细胞（germ cell）或受精卵（zygote）中的遗传物质在数量、结构或功能上发生改变，使发育的个体出现以神经系统缺欠(deficiency)为主要临床表现的疾病。Congenital Disease Family DiseaseClassific
3、ation and Genetic patternlMonogenic DisorderslPolygenic DisorderslMitochondrial DisorderslChromosome Disorders1.Monogenic disorders：The base replacement,Insert,Deletion,repeat or abnormal expansion of single gene.Autosomal dominant disorders Autosomal recessive disorders X-linked dominant disorders
4、X-linked recessive disorders 动态突变性遗传Common Diseases:Charcot-Marie-Tooth,Duchenne muscular dystrophy,Wilson Disease,Hereditary Ataxia2.polygenic disorders:are influenced by genes in complex ways which are poorly understood but involve the interaction of multiple genes and interactions between genes a
5、nd environmental factors The common polygenic disorders:Epilepsy,migraine and arteriosclerosis.3.线粒体遗传病(mitochondrial disorders)Mitochondrial disorders are caused by mutation of mitochondrion(number or structure)，They are maternal inheritance.optic atrophy and mitochondrial encephalomyopathy.4.Chrom
6、osome disordersChromosome disorders are caused by the number or construction abnormalities of chromosome.for example：Downsyndrome Symptoms and physical signsClinical features are of diversity,include common and specific symptoms Common symptoms:Specific symptoms 1.Common symptoms:Mental retardation
7、and Disturbance of behavior Language dysfunction,dementia Seizure、Nystagmus,Paraesthesia(感觉异常)Involuntary movement(不自主运动)、Ataxia and Dystonia(肌张力障碍)Muscle atrophy还可有五官畸形、脊柱裂、弓型足、指（趾）畸形、皮肤毛发异常和肝脾肿大；2.Specific symptom：肝豆状核变性K-F环、共济失调毛细血管扩张症结合膜毛细血管扩张 结节性硬化症面部皮脂腺瘤 神经纤维瘤皮肤牛奶咖啡斑 4.Diagnosis:(1).临床资料的搜集：尤其
8、是发病年龄、性别、独特的症状和体征，如牛奶咖啡斑(2).系谱分析(pedigree analysis)可判断有无遗传病和区分类型(3).常规辅助检查:Include biochemistry,Electrophysiology,Imaging studies and Pathology对诊断和鉴别诊断具有重要意义，如：假肥大型肌营养不良血清学；肝豆状核变性血清铜兰蛋白、血清铜和尿铜;腓骨肌萎缩症神经活检;脊髓小脑性共济失调,橄榄脑桥小脑萎缩的头颅MRI;(4).genetic diagnosis：1)染色体检查(karyotype analysis)：染色体数目异常；染色体结构畸变(const
9、ructive aberration):2)基因诊断(gene detection)：方法包括:Southern Hybridization，PCR 3)Gene production detection：假性肥大肌营养不良-测定肌细胞膜上抗肌萎缩蛋白(dystrophin)5.treatment and Prevention No effective treatment 基因治疗(gene therapy)是指应用基因工程技术来更换、校正或增补基因，以达到治疗遗传病的目的，但目前基因治疗还很不成熟；其他治疗包括：Operation;medicine therapy；Diet therapy；
10、symptom therapy;rehabilitation。Prevention：important 遗传咨询（genetic counseling)；避免近亲结婚；携带者检测(carrier detection)；产前诊断；选择性人工流产(selective abortion)；第二节 hereditary ataxia 1.Conception：Hereditary ataxia is a group of inherited and degenerative disorders of CNS.Characterized by slowly progressive ataxia.Thes
11、e disorders show considerable clinic variability.But,genetic background,ataxia and spinocerebellar lesion are mainly clinical features of them.2.Classification:Traditional classification by pathologic findings:Spinal Ataxia;Spinocerebellar Ataxia;Cerebellar ataxia;New classification by the onset of
12、age,clinical features,Genetic pattern and location of gene mutation（参考表16-1）by Harding(1993)p.270 Friedreich 型共济失调 Friedreich report this disease firstly in 1863，Its incidence rate is 2/100000，It is a early-onset ataxia and transmitted by autosomal recessive inheritance 1.Etioligy and Pathogenesis F
13、riedreich ataxia(FRDA)是由位于9号染色体长臂(9q13-21.1)基因缺陷所致。95%以上的病人有该基因第18号内含子(intron)GAA异常扩增（661700次），正常人GAA重复42次以下，扩增的GAA形成的异常螺旋结构可抑制基因转录(gene transcription)。Friedreich共济失调的基因产物Frataxin蛋白主要位于spinal cord、Skeleton muscle、heart and liver 细胞线粒体(mitochondrion)的内膜，可导致线粒体功能障碍而发病。2.Pathology Posterior columns and
14、 lateral column of spinal cord are mainly involved ，the spinal cord is thin，especially in thoracal spinal cord。Microscope can find that cell loss of posterior column,spinocerebellar tract,pyramidal tract degenerate,dorsal root ganglia and Clarkes column；peripheral nerve demyelination and gliosis；bra
15、instem、cerebellum and brain are rarely involved；Cardiomyopathy and heart cell hypertrophy。3.clinical findings(1)The age of onset is 8-15 years older commonly,with more expanded repeats correlating with earlier onset。(2).The initial symptom is progressive gait ataxia,followed by ataxia of all limbs w
16、ithin 2 years.usually,both legs are affected simultaneously,difficulty in standing and walking steadily；the hands usually become clumsy month or years after the gait disorder with intention tremor；Dysarthric speech appears after the arms are involved(rarely is this an early symptom)。(3)Physical exam
17、ination:可见水平眼震(horizontal nystagmus)，垂直性(vertical)和旋转性(rotatory)眼震较少;双下肢肌无力，肌张力低(muscle tone decreased)，跟膝胫试验(Heel-knee-shin)和闭目难立征(Romberg sign)阳性；下肢音叉震动觉(vibration sense)和关节位置觉(joint position sense)减退是早期体征；后期可有Babinski sign,Muscle atrophy，occasionally,sphincter distubances；约25%患者有视神经萎缩(optic atrop
18、hy);75%有上胸段脊柱侧(kyphoscoliosis)，50%有弓形足(pes cavus)；85%有心律紊乱、心脏杂音；10%20%伴有糖尿病(diabetes)。(4)通常起病15年后卧床（bedridden），多于4050岁死于感染或心脏病。4.investigative studies(1).skeleton film show skeletal abnormalities；CT或MRI示脊髓变细，cerebellum and brainstem are rarely involved；(2).心电图(electrocardiograph):常有T波倒置、心律紊乱及传导阻滞；(3
19、).Echocardiography:Hypertrophy；(4).视诱发电位(visual evoked potential):Amplitude decreased；(5).脑脊液(cerebrospinal fluid):normal protein；(6).DNA分析FRDA基因18号内含子GAA大于66次重复。5.Diagnosis and differential diagnosis (1).Diagnosis:Early onset;Slowly Progressive Ataxia from both legs to arms;Dysarthria,Nystagmus,ten
20、don reflex absent and Babinski sign；loss of vibratory and joint position sense;Kyphoscoliosis，Pes vacus，heart lesion;MRI显示脊髓萎缩，则不难诊断;FRDA基因GAA异常扩增，可确定诊断。(2)不典型病例需与其他疾病鉴别 慢性变性疾病和脱髓鞘性疾病(demyelinative disease),Charcot-Marie-Tooth Disease；还应与VitE缺乏和-脂蛋白缺乏引起的共济失调鉴别，后两者可查血清VitE和-脂蛋白的含量以鉴别之。6.treatment no
21、effective treatment is available，轻症病人给予支持疗法，康复(rehabilitation)治疗；重症者可手术矫治弓形足等畸形；用胞二磷胆碱、毒扁豆碱可能有一定的疗效。脊髓小脑性共济失调（Spinocerebellar ataxia SCA）SCA是遗传性共济失调的主要类型，包括SCA1-10.The common feature:onset in middle life、autosomal dominant hereditary and ataxia.H a r d i n g 根 据 有 无 眼 肌 麻 痹(ophthalmoplegia)、锥体外系(ext
22、rapyramidal)症状 及 视 网 膜 色 素 变 性(r e t i n a l p i g m e n t degeneration)归纳为三组十个亚型(表16-1)，SCA的发病与种族有关，SCA1-2在意大利、英国多见，中国、德国和葡萄牙以SCA3最常见。1.etiology and pathogenesis SCA有共同的突变机制，即相应的基因外显子(exon)CAG拷贝数异常扩增,产生多聚谷氨酰胺链(SCA8除外)，产生毒性功能，共同的突变机制也是造成SCA各亚型的临床表现雷同的原因。然而，每一SCA亚型的基因位于不同的染色体，其基因大小及突变部位均不相同（见16-1表），S
23、CA各亚型的临床表现也有差异，如有的伴有眼肌麻痹(ophthalmoplegia)，有的伴有视网膜色素变性，病理损害的部位和程度也有所不同，这提示除了多聚谷氨酰胺毒性作用之外，可能还有其它因素参与发病。2.pathology The common pathological lesion of SCA is in cerebellum、brainstem，with the degenerative spinal cord.但各亚型也有其特点，如：SCA1:loss of neuron in brainstem and cerebellum，spinocerebellar tract and po
24、sterior column are usually involved，很少累及黑质（black matter）、basal ganglia and anterior corn cell；SCA2:nuclei of inferior olivary.Pons and cerebellum；SCA3:pontine and spinocerebellar tract SCA7:Retinal neuron degeneration。3.clinical findings SCA是高度遗传异质性疾病，各亚型的症状相似，交替重叠，其共同临床表现是：(1).一般在3040岁隐袭起病，缓慢进展，但也有
25、儿童期及70岁起病者。(2).首发症状多为下肢共济失调，走路摇晃、突然跌倒、发音困难；继而出现双手笨拙及意向性震颤(intention tremor);可见眼震,眼慢扫视运动阳性,dementia and distal muscle atrophy；Dystonia,increased tendon reflex,pathological reflex,spastic gait and sense of vibration and proprioception absent。(3).均有遗传早现现象，即在同一SCA家系中发病年龄逐代提前，症状逐代加重，是SCA非常突出的表现。一般起病后1020
26、年患者不能行走。(4).除了上述共同的症状和体征外，各亚型也具各自的特点而构成不同的疾病。如 SCA1的眼肌麻痹(ophthalmoplegia)，尤其上视不能较突出；SCA2的上肢腱反射减弱或消失，眼慢扫视运动较明显；SCA3的肌萎缩、面肌(facial)及舌肌(glossal)纤颤(fasciculation)、眼睑退缩形成凸眼；SCA5病情进展非常缓慢，症状也较轻；SCA6的早期大腿肌肉痉挛(spasm)、下视震颤、复视(diplopia)和位置性眩晕(vertigo)；SCA7的特征性症状是视力减退或丧失，视网膜色素变性，心脏损害也较突出;SCA8常有发音困难(dysarthria)；
27、SCA10的纯小脑征和癫(epilepsy)发作;4.Lab studies(1).CT or MR show cerebellar and brainstem atrophy，especially pons and the middle peduncle of cerebellum atrophy;(2).brainstem evoked potential may be abnormal;(3).Electromyography show peripheral nerve lesion；(4).normal cerebrospinal fluid；(5).确诊及区分亚型可用外周血白细胞进行
28、PCR分析，检测相应基因CAG扩增的情况;5.diagnosis and differential diagnosis 根据典型的共性症状；结合(magnetic resonance imaging MRI)检查发现小脑、脑干萎缩；排除其它累及小脑和脑干的变性病即可确诊;基因诊断确定其亚型及CAG扩增次数是确诊的golden standard。不典型病例需与多发性硬化(multiple sclerosis)、CJD及感染引起的共济失调鉴别。6.treatment No specific treatment available until now.对症及康复治疗可缓解症状。第三节 腓骨肌萎缩症(
29、Charcot-Marie-Tooth Disease CMT)Introduction:CMT or hereditary motor sensory neuropathy(HMSN).Charcot.Marie and Tooth report it firstly in 1886,It is the most common type of hereditary motor sensory neuropathy.the incidence rate is 1/2500。Classification:I型:nerve conduction velocity less than 38cm/s.
30、include 3 subtypes 1A,1B and 1C by gene location.II型:nerve conduction velocity normal or nearly normal。Include 4 subtypes:2A、2B、2Cand 2D.以CMT1A型最常见。1.etiology and pathologenesis The majority of CMT is autosomal dominant heredity，The minority of it is transmitted by other hereditary patterns.(1).CMT1
31、A：致病基因定位于17p11.2-12，该基因编码周围神经髓鞘蛋白22(PMP22)，它的重复突变导致PMP22基因过度表达(over-expression)，使周围髓鞘蛋白(myelin protein)增加；另有一小部分病人因周围神经髓鞘蛋白PMP22基因的点突变，产生异常PMP22蛋白而致病；(2).CMT2型：autosomal dominant heredity，与其有关的基因至少定位于三个位点,分别位于1,3,7号染色体上.2.Pathology The axon and myelin sheaths of peripheral nerve are involved，the dis
32、tal parts of nerve more than the proximal。I型神经纤维呈对称性节段性脱髓鞘，部分髓鞘再生，Schwann细胞增生与修复，形成“洋葱头”(onion-bulb)样结构，造成运动和感觉神经传导速度减慢 II型为轴突变性(axon degeneration)，运动和感觉神经传导速度改变不明显；前角细胞(anterior horn cell)数量轻度减少，The muscles occur group atrophy(簇状萎缩)。当累及感觉后根纤维时，薄束变性比楔束更严重；the autosomal nervous system remains relativ
33、ely intact。3.clinical findings CMT I型(脱髓鞘型)：(1)the age of onset is late childhood and adolescence.the symmetrical chronic degeneration of peripheral nerve result in distal muscle atrophy，多数患者开始是足和下肢，数月至数年可波及到手肌和前臂肌，extensors are involved early,Flexor is normal,产生马蹄内翻足和爪形足(claw foot)畸形，foot drop及跨阈步态
34、。常伴有脊柱侧弯。(2)检查可见 受累肢体肌肉萎缩，小腿肌肉和大腿的下1/3肌肉(the lower third of the thigh muscle weak and atrophy)，just like stork leg or inverted champagne bottle，手肌萎缩，并波及前臂肌肉，变成爪形手。很少波及肘以上部分;The tendon reflex are absent in the involved limbs；深浅感觉减退可从远端开始，呈手套、袜子样分布；伴有自主神经功能障碍和营养代谢障碍，Rarely,the sensory loss is severe,a
35、nd perforating ulcers may appear。(3)病程非常缓慢，在很长时期内都很稳定，颅神经通常不受累。部分病人虽然存在基因突变，但无肌无力和肌萎缩，仅有弓形足或神经传导速度减慢，有的甚至完全无临床症状。CMT II型(轴索型)：late onset，muscle atrophy occur at adult，clinical features are the same as CMT I型.But lighter than it；CSF:Protein is normal。4.Lab studies (1)检查神经传导速度(Nerve conduction velocit
36、y NCV)对分型至关重要。CMT1型运动NCV从正常的50米/秒减慢为38米/秒以下，CMT2型NCV接近正常。(2)X连锁显性遗传患者脑干听觉诱发电位和视觉诱发电位异常，躯体感觉诱发电位的中枢和周围传导速度减慢。(3)Muscle Biopsy:neurogenic atrophy;(4).Nerve Biopsy:CMT I型的周围神经改变主要是脱髓鞘和雪旺氏细胞增生形成“onion bulb”；CMT II型主要是轴突变性。神经活检还可排除其他遗传性神经病。(5)cerebrospinal fluid:normal，少数病例蛋白含量增高。5.Diagnosis and differen
37、tial diagnosis 临床诊断依据：(1).儿童期或青春期出现缓慢进展的对称性双下肢无力；(2).Stork leg，foot drop,high arches可有脊柱侧弯；(3).tendon reflex decreased or absent，commonly with paresthesia；(4).family history；(5).the slow nerve conduction velocity;nerve biopsy show neurogenic atrophy；(6).Gene detection find CMT1A gene repeat。CMT1型与CM
38、T2型的鉴别：(1).the age of onset：1型12岁左右，2型25岁左右；(2).NCV：1型明显减慢，2型正常或接近正常；(3).基因诊断：1型为17号染色体短臂(17p11.2)1.5Mb长片段(其中包含PMP22基因)的重复或PMP22基因的点突变(1A)；2型为1号染色体短臂(1p3536)的基因突变(2A)。Differential Diagnosis:(1)远端型肌营养不良症(distal muscular dystrophy)：四肢远端肌无力、肌萎缩、渐向上发展，需与CMT鉴别；但该病成年起病，肌电图显示肌源性损害，运动传导速度正常可资鉴别。(2).家族性淀粉样多神
39、经病(family myeloid polyneuropathy)：临床较难区分，需借助神经活检或DNA分析。(3).慢性炎症性脱髓鞘性多发性神经病(chronic inflammatory demyelinating polyneuropathy)：进展相对较快，CSF蛋白含量增多，强的松治疗效果较好。(4)慢性进行性远端型脊肌萎缩症(chronic progressive spinal muscular atrophy)：该病的肌萎缩分布和病程类似CMT病，但感觉一般不受累，EMG显示为前角损害。(5)遗传性共济失调伴肌萎缩(hereditary ataxia with muscular
40、atrophy)：又称Roussy-Lvy综合征。儿童期缓慢起病，表现腓骨肌萎缩、弓形足、脊柱侧凸、四肢腱反射减弱或消失、站立不稳、步态蹒跚、手震颤等共济失调表现，肌电图运动传导速度减慢；与CMT不同或认为是CMT变异型。7.treatment and prevention(1).No specific treatment is known，主要是对症治疗和支持疗法，垂足或足畸形可穿着矫型鞋。(2).预防应首先进行基因诊断，确定先证者(proband)的基因型，然后利用胎儿绒毛、羊水或脐带血，分析胎儿的基因型以建立产前诊断，终止妊娠。8.prognosis This illness progress very slowly.大多数患者可存活数十年，对症处理可提高患者生活质量。
