1、第十六章 神經系統遺傳病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： 1、Friedreich型共濟失調的主要臨床特征、臨床表現。 2、脊髓小腦性共

2、濟失調的臨床表現、診斷及鑒別診斷。熟悉： 1、Friedreich型共濟失調的病因、發病機制。 2、脊髓小腦性共濟失調的病因、發病機制。 3、腓骨肌萎縮癥(CMT)的臨床表現、診斷及鑒別診斷 。第一節 General Introduction1. Conception Genetic disease of the nervous system 是指由于生殖細胞（ germ cell）或受精卵（ zygote）中的遺傳物質在數量、結構或功能上發生改變，使發育的個體出現以神經系統缺欠(deficiency)為主要臨床表現的疾病。 Congenital Disease Family DiseaseC

3、lassification and Genetic patternMonogenic DisordersPolygenic DisordersMitochondrial DisordersChromosome Disorders1.Monogenic disorders：The base replacement, Insert, Deletion, repeat or abnormal expansion of single gene. Autosomal dominant disorders Autosomal recessive disorders X-linked dominant di

4、sorders X-linked recessive disorders 動態突變性遺傳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 b

5、etween genes and environmental factors The common polygenic disorders: Epilepsy, migraine and arteriosclerosis. 3. 線粒體遺傳病(mitochondrial disorders ) Mitochondrial disorders are caused by mutation of mitochondrion (number or structure)，They are maternal inheritance.optic atrophy and mitochondrial ence

6、phalomyopathy.4.Chromosome 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 symptomsCommon symptoms:Specific symptoms 1.Common sympto

7、ms:Mental retardation and Disturbance of behaviorLanguage dysfunction, dementiaSeizure、Nystagmus, Paraesthesia (感覺異常)Involuntary movement(不自主運動)、Ataxia and Dystonia(肌張力障礙) Muscle atrophy還可有五官畸形、脊柱裂、弓型足、指（趾）畸形、皮膚毛發異常和肝脾腫大； 2.Specific symptom：肝豆狀核變性K-F環、共濟失調毛細血管擴張癥結合膜毛細血管擴張結節性硬化癥面部皮脂腺瘤神經纖維瘤皮膚牛奶咖啡斑 4.

8、Diagnosis:(1). 臨床資料的搜集：尤其是發病年齡、性別、獨特的癥狀和體征，如牛奶咖啡斑(2). 系譜分析(pedigree analysis)可判斷有無遺傳病和區分類型(3). 常規輔助檢查: Include biochemistry, Electrophysiology, Imaging studies and Pathology對診斷和鑒別診斷具有重要意義， 如：假肥大型肌營養不良血清學；肝豆狀核變性血清銅蘭蛋白、血清銅和尿銅; 腓骨肌萎縮癥神經活檢; 脊髓小腦性共濟失調,橄欖腦橋小腦萎縮的頭顱MRI; (4). genetic diagnosis： 1) 染色體檢查(kary

9、otype analysis)：染色體數目異常；染色體結構畸變(constructive aberration): 2) 基因診斷(gene detection)： 方法包括: Southern Hybridization，PCR 3) Gene production detection：假性肥大肌營養不良-測定肌細胞膜上抗肌萎縮蛋白(dystrophin) 5. treatment and Prevention No effective treatment基因治療(gene therapy)是指應用基因工程技術來更換、校正或增補基因，以達到治療遺傳病的目的，但目前基因治療還很不成熟；其他治療

10、包括：Operation; medicine therapy；Diet therapy；symptom therapy; rehabilitation。Prevention：important 遺傳咨詢（genetic counseling)； 避免近親結婚； 攜帶者檢測(carrier detection)； 產前診斷； 選擇性人工流產(selective abortion)；第二節 hereditary ataxia1. Conception：Hereditary ataxia is a group of inherited and degenerative disorders of CN

11、S.Characterized by slowly progressive ataxia.These 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 At

12、axia; Cerebellar ataxia;New classification by the onset of age, clinical features, Genetic pattern and location of gene mutation（參考表16-1）by Harding (1993 ) p.270 Friedreich 型共濟失調Friedreich report this disease firstly in 1863，Its incidence rate is 2 /100000，It is a early-onset ataxia and transmitted

13、by autosomal recessive inheritance1. Etioligy and Pathogenesis Friedreich ataxia(FRDA)是由位于9號染色體長臂(9q13-21.1)基因缺陷所致。95%以上的病人有該基因第18號內含子( intron )GAA異常擴增（661700次），正常人GAA重復42次以下，擴增的GAA形成的異常螺旋結構可抑制基因轉錄(gene transcription)。 Friedreich共濟失調的基因產物Frataxin蛋白主要位于spinal cord、 Skeleton muscle、heart and liver 細胞線

14、粒體(mitochondrion )的內膜，可導致線粒體功能障礙而發病。2. Pathology Posterior columns and 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 roo

15、t ganglia and Clarkes column ； peripheral nerve demyelination and gliosis； brainstem、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)

16、. The initial symptom is progressive gait ataxia , followed by ataxia of all limbs within 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 spee

17、ch appears after the arms are involved (rarely is this an early symptom)。(3)Physical examination: 可見水平眼震(horizontal nystagmus)，垂直性(vertical)和旋轉性(rotatory)眼震較少; 雙下肢肌無力，肌張力低(muscle tone decreased)，跟膝脛試驗(Heel-knee-shin)和閉目難立征(Romberg sign)陽性； 下肢音叉震動覺(vibration sense)和關節位置覺(joint position sense)減退是早期體征；

18、 后期可有Babinski sign, Muscle atrophy，occasionally, sphincter distubances； 約25%患者有視神經萎縮(optic atrophy); 75%有上胸段脊柱側(kyphoscoliosis)， 50%有弓形足(pes cavus)； 85%有心律紊亂、心臟雜音； 10%20%伴有糖尿病(diabetes)。(4)通常起病15年后臥床（bedridden），多于4050歲死于感染或心臟病。4. investigative studies(1). skeleton film show skeletal abnormalities；CT

19、或MRI示脊髓變細，cerebellum and brainstem are rarely involved；(2). 心電圖(electrocardiograph): 常有T波倒置、心律紊亂及傳導阻滯；(3). Echocardiography: Hypertrophy；(4). 視誘發電位(visual evoked potential): Amplitudedecreased；(5). 腦脊液(cerebrospinal fluid): normal protein；(6). DNA分析FRDA基因18號內含子GAA大于66次重復。5. Diagnosis and differentia

20、l diagnosis (1). Diagnosis: Early onset; Slowly Progressive Ataxia from both legs to arms; Dysarthria, Nystagmus, tendon reflex absent and Babinski sign； loss of vibratory and joint position sense; Kyphoscoliosis，Pes vacus，heart lesion; MRI顯示脊髓萎縮，則不難診斷; FRDA基因GAA異常擴增，可確定診斷。 (2)不典型病例需與其他疾病鑒別 慢性變性疾病和脫

21、髓鞘性疾病(demyelinative disease), Charcot-Marie-Tooth Disease； 還應與VitE缺乏和-脂蛋白缺乏引起的共濟失調鑒別，后兩者可查血清VitE和-脂蛋白的含量以鑒別之。6. treatment no effective treatment is available ，輕癥病人給予支持療法，康復(rehabilitation)治療；重癥者可手術矯治弓形足等畸形；用胞二磷膽堿、毒扁豆堿可能有一定的療效。脊髓小腦性共濟失調（Spinocerebellar ataxia SCA） SCA是遺傳性共濟失調的主要類型，包括SCA1-10. The comm

22、on feature: onset in middle life、autosomal dominant hereditary and ataxia. Harding根據有無眼肌麻痹(ophthalmoplegia )、錐體外系(extrapyramidal)癥狀及視網膜色素變性(retinal pigment degeneration)歸納為三組十個亞型(表16-1)，SCA的發病與種族有關，SCA1-2在意大利、英國多見，中國、德國和葡萄牙以SCA3最常見。1. etiology and pathogenesis SCA有共同的突變機制，即相應的基因外顯子(exon)CAG拷貝數異常擴增,產

23、生多聚谷氨酰胺鏈(SCA8除外)，產生毒性功能，共同的突變機制也是造成SCA各亞型的臨床表現雷同的原因。 然而，每一SCA亞型的基因位于不同的染色體，其基因大小及突變部位均不相同（見16-1表），SCA各亞型的臨床表現也有差異，如有的伴有眼肌麻痹(ophthalmoplegia)，有的伴有視網膜色素變性，病理損害的部位和程度也有所不同，這提示除了多聚谷氨酰胺毒性作用之外，可能還有其它因素參與發病。2. pathology The common pathological lesion of SCA is in cerebellum、brainstem，with the degenerative

24、spinal cord. 但各亞型也有其特點，如： SCA1: loss of neuron in brainstem and cerebellum，spinocerebellar tract and posterior column are usually involved，很少累及黑質（black matter）、basal ganglia and anterior corn cell ； SCA2: nuclei of inferior olivary. Pons and cerebellum； SCA3 : pontine and spinocerebellar tract SCA7:

25、 Retinal neuron degeneration。3. clinical findings SCA是高度遺傳異質性疾病，各亞型的癥狀相似，交替重疊，其共同臨床表現是： (1). 一般在3040歲隱襲起病，緩慢進展，但也有兒童期及70歲起病者。 (2). 首發癥狀多為下肢共濟失調，走路搖晃、突然跌倒、發音困難；繼而出現雙手笨拙及意向性震顫(intention tremor);可見眼震, 眼慢掃視運動陽性, dementia and distal muscle atrophy；Dystonia, increased tendon reflex, pathological reflex, s

26、pastic gait and sense of vibration and proprioception absent。(3). 均有遺傳早現現象，即在同一SCA家系中發病年齡逐代提前，癥狀逐代加重，是SCA非常突出的表現。一般起病后1020年患者不能行走。(4). 除了上述共同的癥狀和體征外，各亞型也具各自的特點而構成不同的疾病。如 SCA1的眼肌麻痹(ophthalmoplegia)，尤其上視不能較突出； SCA2的上肢腱反射減弱或消失，眼慢掃視運動較明顯； SCA3的肌萎縮、面肌(facial)及舌肌(glossal)纖顫(fasciculation)、眼瞼退縮形成凸眼； SCA5病情

27、進展非常緩慢，癥狀也較輕； SCA6的早期大腿肌肉痙攣(spasm)、下視震顫、復視(diplopia)和位置性眩暈(vertigo)； SCA7的特征性癥狀是視力減退或喪失，視網膜色素變性，心臟損害也較突出; SCA8常有發音困難(dysarthria)； SCA10的純小腦征和癲(epilepsy)發作;4. Lab studies(1). CT or MR show cerebellar and brainstem atrophy，especially pons and the middle peduncle of cerebellum atrophy; (2). brainstem e

28、voked potential may be abnormal;(3). Electromyography show peripheral nerve lesion；(4). normal cerebrospinal fluid；(5). 確診及區分亞型可用外周血白細胞進行PCR分析，檢測相應基因CAG擴增的情況;5. diagnosis and differential diagnosis 根據典型的共性癥狀； 結合(magnetic resonance imaging MRI)檢查發現小腦、腦干萎縮； 排除其它累及小腦和腦干的變性病即可確診; 基因診斷確定其亞型及CAG擴增次數是確診的go

29、lden standard。 不典型病例需與多發性硬化(multiple sclerosis)、CJD及感染引起的共濟失調鑒別。6. treatment No specific treatment available until now. 對癥及康復治療可緩解癥狀。第三節 腓骨肌萎縮癥(Charcot-Marie-Tooth Disease CMT) Introduction: CMT or hereditary motor sensory neuropathy(HMSN). Charcot. Marie and Tooth report it firstly in 1886, It is t

30、he most common type of hereditary motor sensory neuropathy. the incidence rate is 1/2500。Classification: I型: nerve conduction velocity less than 38cm/s. 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CMT1

31、A型最常見。1. etiology and pathologenesis The majority of CMT is autosomal dominant heredity，The minority of it is transmitted by other hereditary patterns . (1). CMT1A：致病基因定位于17p11.2-12，該基因編碼周圍神經髓鞘蛋白22(PMP22)，它的重復突變導致PMP22基因過度表達(over-expression)，使周圍髓鞘蛋白(myelin protein )增加；另有一小部分病人因周圍神經髓鞘蛋白PMP22基因的點突變，產生

32、異常PMP22蛋白而致病； (2). CMT2型：autosomal dominant heredity，與其有關的基因至少定位于三個位點,分別位于1,3,7號染色體上.2. Pathology The axon and myelin sheaths of peripheral nerve are involved，the distal parts of nerve more than the proximal。 I型神經纖維呈對稱性節段性脫髓鞘，部分髓鞘再生，Schwann細胞增生與修復，形成“洋蔥頭”(onion-bulb)樣結構，造成運動和感覺神經傳導速度減慢 II型為軸突變性(axon

33、 degeneration)，運動和感覺神經傳導速度改變不明顯；前角細胞(anterior horn cell)數量輕度減少，The muscles occur group atrophy (簇狀萎縮)。當累及感覺后根纖維時，薄束變性比楔束更嚴重；the autosomal nervous system remains relatively intact。3. clinical findingsCMT I型(脫髓鞘型)： (1) the age of onset is late childhood and adolescence. the symmetrical chronic degener

34、ation of peripheral nerve result in distal muscle atrophy，多數患者開始是足和下肢，數月至數年可波及到手肌和前臂肌，extensors are involved early, Flexor is normal, 產生馬蹄內翻足和爪形足(claw foot)畸形，foot drop及跨閾步態。常伴有脊柱側彎。 (2) 檢查可見 受累肢體肌肉萎縮，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 inverte

35、d champagne bottle，手肌萎縮，并波及前臂肌肉，變成爪形手。很少波及肘以上部分; The tendon reflex are absent in the involved limbs； 深淺感覺減退可從遠端開始，呈手套、襪子樣分布； 伴有自主神經功能障礙和營養代謝障礙，Rarely, the sensory loss is severe,and perforating ulcers may appear。 (3) 病程非常緩慢，在很長時期內都很穩定，顱神經通常不受累。部分病人雖然存在基因突變，但無肌無力和肌萎縮，僅有弓形足或神經傳導速度減慢，有的甚至完全無臨床癥狀。CMT II

36、型(軸索型)： 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)檢查神經傳導速度(Nerve conduction velocity NCV)對分型至關重要。CMT1型運動NCV從正常的50米/秒減慢為38米/秒以下，CMT2型NCV接近正常。(2)X連鎖顯性遺傳患者腦干聽覺誘發電位和視覺誘發電位異常，軀體感覺誘發電位的中樞和周圍傳導速度減慢。 (3)Muscle Biopsy : neurogenic atrophy;(4). Nerve Biopsy: CMT I型的周圍神經改變主要是脫髓鞘和雪旺氏細胞增生形成“onion bulb”； CMT II型主要是軸突變性。神經活檢還可排除其他遺傳性神經病。 (5)cerebrospinal fluid: normal，少數病例蛋白含量增高。5. Diagnosis and differential diagnosis臨床診斷依據：(1). 兒童期或青春期出現緩慢進展的對稱性雙