第十六章 神经系统遗传病15

(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(constructive 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)
• • • • • • Mental retardation 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；
• 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；symptom therapy; rehabilitation。
• 1. Etioligy and Pathogenesis Friedreich 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（66~1700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。
• 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 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 speech appears after the arms are involved (rarely is this an early symptom)。
• 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. These disorders show considerable clinic variability. But, genetic background, ataxia and spinocerebellar lesion are mainly clinical features of them.
2. polygenic disorders: are influenced by genes in complex ways which are poorly understood but involve the interaction of multiple genes and interactions between genes and environmental factors The common polygenic disorders: Epilepsy, migraine and arteriosclerosis.
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;
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.Chromosome disorders Chromosome disorders are caused by the number or construction abnormalities of chromosome. for example： Down’syndrome
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Symptoms and physical signs
Clinical features are of diversity, include common and specific symptoms • Common symptoms: • Specific symptoms
1.Common symptoms:
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、பைடு நூலகம்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 Disease
第十六章 神经系统遗传病
Genetic Disease of the Nervous System
Genetic 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临床表现、 诊断及鉴别诊断。
• 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 root ganglia and Clarke’s column ； peripheral nerve demyelination and gliosis； brainstem、cerebellum and brain are rarely involved； Cardiomyopathy and heart cell hypertrophy。
• 2. Classification : • Traditional classification by pathologic findings: Spinal Ataxia ; • Spinocerebellar Ataxia; • Cerebellar ataxia; • New classification by the onset of age, clinical features, Genetic pattern and location of gene mutation（参考表16-1） by Harding (1993 ) p.270
Classification and Genetic pattern Monogenic Disorders Polygenic Disorders Mitochondrial Disorders Chromosome Disorders
1.Monogenic disorders：The base replacement, Insert, Deletion, repeat or abnormal expansion of single gene. Autosomal dominant disorders Autosomal recessive disorders X-linked dominant disorders X-linked recessive disorders 动态突变性遗传 Common Diseases: Charcot-Marie-Tooth, Duchenne muscular dystrophy, Wilson Disease, Hereditary Ataxia
• 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
• (3)．Physical examination: • 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；