脊髓小脑共济失调7型一个家系的临床和基因分析

目的总结脊髓小脑共济失调7型（SCA7）的临床表现，开展基因检测。方法对1个表现为视力下降、辨色力异常和行走不稳的家系完成家系调查及体格检查，部分成员行视网膜形态学及电生理检查；19名家系成员及12名健康对照者行SCA7突变基因PCR，测序仪直接检测三核苷酸胞嘧啶-腺嘌呤-鸟嘌呤（CAG）重复数目。结果6例成员存在小脑性共济失调、视力下降和辨色力异常，眼底示黄斑及视网膜周边色素异常，视网膜电图波形熄灭，震荡电位幅值和光闪视觉诱发电位振幅明显下降；正常等位基因CAG重复数目为8～25次，该6例异常等位基因CAG重复数目为50～97次，诊断为SCA7患者；1例无异常临床表现的成员CAG重复数目分别为18次和56次，后者超出正常范围，诊断为未到发病年龄的症状前患者。结论SCA7患者的临床表现具有异质性，CAG重复数目检测可以为基因诊断和症状前诊断提供依据。     

两遗传性脊髓小脑型共济失调7型家系的临床特征和基因突变研究

目的 探讨遗传性脊髓小脑型共济失调(SCA)7型(SCA7)的临床特征和基因突变.方法 采用聚合酶链反应(PCR)和琼脂糖凝胶电泳(AGE)等技术,检测临床诊断为SCA的5个家系26例患者和37例表型正常的家系成员的SCA7基因内CAG三核苷酸重复次数,对异常等位基因片段进行DNA测序,分析临床表现和基因突变的关系. 结果 2个SCA7家系患者的SCA7等位基因内CAG重复数目为44～50次;临床表现主要为共济失调、视力下降及视网膜色素变性.该家系内表型正常的家系成员SCA7等位基因CAG重复数目为10～30. 结论 CAG过度扩增为SCA7的致病原因,分子遗传学分析有助于SCA7的诊断.     

遗传性脊髓小脑型共济失调7型遗传学诊断及临床特征

目的研究中国人遗传性脊髓小脑型共济失调(SCA)7型(SCA7)的基冈突变和临床特征。方法应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术对临床表现为SCA的92个家系112例患者和16例散发SCA患者的SCA7基因内CAG三核苷酸重复序列进行检测，对异常等位基因片段进行DNA测序，分析基因型和表型之间的关系，并与表型正常的家系成员和健康人对照。结果在1个SCA7家系的6位成员中检测出2例患者的SCA7等化基因内CAG重复数目为71；临床表现主要为共济失调、视力下降、黄蓝色盲及视网膜色素变性。该家系内表型正常的4位成员SCA7等位基因CAG重复数目为7～9，另126例临床表现为SCA的患者、71名表型正常的家系成员及60名健康对照者SCA7等位基因内CAG三核甘三酸重复数为6—21。结论CAG过度扩增为SCA7的致病原因，分子遗传学分析有助于SCA7的诊断；视网膜色素变性为SCA7的重要特征。     

脊髓小脑性共济失调3型的临床与分子生物学特征

目的探讨脊髓小脑性共济失调(SCA)3型的临床与分子生物学特征。方法对2个SCA家系中12例患者的临床表现、头颅影像学资料进行分析,并与15名家系中未发病成员(家系对照组)及12名非血缘关系的健康对照者(健康对照组)的SCA3、SCA1及SCA7基因目的片段CAG重复数目进行比较。结果2个家系4代27名成员中共有12例发病,每代均有患者,男女均受累,起病年龄平均32岁,以行走不稳、动作笨拙和言语含糊为突出表现;头颅MRI示小脑、脑干明显萎缩;各组SCA1及SCA7基因CAG检测均在正常范围;SCA3目的片段CAG两对照组重复11～39次,10例患者为65～87次,确诊为SCA3;家系1的Ⅳ2现年8岁,临床无异常表现,CAG重复数目分别为21次和64次,可能是未到发病年龄的症状前患者。结论SCA3为常染色体显性遗传性疾病,临床均以共济失调和构音障碍为突出表现,CAG重复数目检测可为基因诊断和症状前诊断提供依据。     

脊髓小脑性共济失调2型的分子遗传学诊断及临床分析

目的:研究分析脊髓小脑性共济失调2型(SCA2)的分子遗传学诊断、应用以及临床表现特征。方法:对来自广西地区临床诊断为SCA的1个家系2例患者和8名"健康"家系成员,以及35名正常对照人员,通过聚合酶链式反应、琼脂糖电泳等技术检测SCA2基因位点内CAG三核苷酸重复扩增次数,并对异常等位基因片段进行DNA测序。结果:我国广西正常人群SCA2等位基因CAG重复数为20～29次,1家系中2例患者与1例症状前患者存在SCA2(CAG)n扩展突变,拷贝数分别为42、45、55次。结论:首次发现广西SCA2,利用分子遗传学分析可进行SCA2基因诊断,为症状前诊断及遗传咨询提供依据。     

遗传性脊髓小脑型共济失调6型两个家系的临床特征及基因突变研究

目的 研究中国人遗传性脊髓小脑型共济失调6型(SCA6)的基因突变和临床特征。方法 应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术，检测临床诊断脊髓小脑型共济失调(SCA)的120个家系210例患者和47例散发SCA患者的SCA6基因内CAG三核苷酸重复序列，并对异常等位基因片段进行DNA测序。结果 检出2个家系(4例患者)为SCA6，阳性率为1，7％，测序证实其异常等位基因的CAG重复数目为25和26。另253例SCA患者的SCA6等位基因CAG重复数目为7-17，健康人SCA6等位基因CAG重复数目为5-16。2个家系均存在遗传早现现象，异常扩展的CAG序列呈代间稳定性。结论 从临床及基因诊断方面首次确认中国大陆存在SCA6家系；CAG过度扩增为SCA6的致病原因。     

脊髓小脑性共济失调一家系的基因诊断

目的 对1个常染色体显性遗传的脊髓小脑性共济失调(SCA)家系进行基因诊断.方法 采用PCR技术,对一汉族SCA家系(包括3例患者及3位无症状成员)及50名正常对照者的SCA1 ～3基因进行检测,通过琼脂糖凝胶电泳和产物直接测序法计数等位基因内CAG三核苷酸重复次数.结果 该家系中所有成员SCA1、SCA2基因CAG三核苷酸重复次数在正常范围;3例患者SCA3 CAG重复次数分别为67、68和66次,1位无症状成员为71次.结论 该家系为SCA3,基因检测诊断出1例症状前患者.     

脊髓小脑性共济失调6型的分子遗传学诊断及临床特点

目的 研究脊髓小脑性共济失调6型(SCA6)的基因诊断方法及临床特点。方法 对临床诊断为脊髓小脑性共济失调(SCA)的36个家系43例患者及38例散发患者，应用聚合酶链反应对SCA6基因含有CAG三核苷酸重复片段进行扩增，并对异常等位基因片段进行DNA测序，计算CAG重复次数；对2例SCA6患者临床资料进行分析。结果 正常人的SCA6等位基因CAG重复数目为10～13。本组检出家族性患者1例，散发患者1例，其异常等位基因内CAG重复数目分别为25、24。患者临床基本特征为缓慢进展的小脑性共济失调、眼震、构音障碍。结论 致病基因内CAG三核苷酸重复异常扩增是SCA6的确诊依据。SCA6的临床表现与其他SCA亚型无明显差别。     

遗传性脊髓小脑性共济失调7型的基因突变及临床特征分析

目的 研究遗传性脊髓小脑性共济失调7型（SCA7）的基因突变和临床特征。方法 对临床诊断为脊髓小脑性共济失调（SCA）的15个家系24例患者、20例散发SCA患者、41名家系“正常人”及30名非序列的突变,并利用ABI373例序仪对异常等位基因片段进行DNA测序。结果 24例SCA患者的SCA7等位基因CAG重复数目为9－18。正常人SCA7等位基因CAG重复数目为9－19。检出1例散发患者为SCA7,经基因测序证实,其异常等位基因的CAG重复数目为63。结论 CAG过度扩增是SCA7的致病原因,利用基因突变分析可进行基因诊断,提供症状前诊断及遗传咨询的依据,为基因分型奠定基础。     

遗传性脊髓小脑型共济失调7型一家系的临床及基因突变分析

目的研究中国人遗传性脊髓小脑型共济失调7型(SCA7)的基因突变和临床特征。方法应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术对一个表现为共济失调、视力下降、视网膜变性的家系(6位成员,包括2个患者)的SCA7基因内CAG三核苷酸重复序列进行检测,并对异常等位基因片段进行DNA直接测序,分析基因型和表型之间的关系。结果检测出该家系内2个患者的SCA7等位基因CAG重复数目为71,而该家系内其他表型正常的SCA7等位基因CAG重复数目为7～9。结论CAG过度扩增为SCA7的致病原因,分子遗传学分析有助于SCA7的诊断以及症状前患者的预测。     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

Pediatric Epilepsy Surgery

Summary: The use of implantable arrays of epidural electrodes has made it possible to carry out extraoperative electrocorticography (ECoG) and functional localization in the awake child. This has permitted cortical excisions that are determined by criteria similar to those obtained during surgical procedures performed under local anesthesia in adults. In addition, the method also permits simultaneous ECoG and video monitoring during the child's symptomatic seizures, providing additional important localizing information that is impractical to obtain in operations under local anesthesia. We report our experience with 75 children, ages 5 months to 15 years, whom we have managed with epidural electrode arrays. The method of extraoperative ECoG is described and illustrative cases are presented to demonstrate its feasibility and utility in children. In addition, we call attention to gliomas as a common cause of chronic focal seizures in children. Of 49 children undergoing resection and followed for from 1 to 14 years (mean of 5.8 years), 32 (65%) are either seizure free or have had a significant reduction in seizure frequency that has unambiguously improved their quality of life. The results are analyzed further by relating the surgical outcome to each of the pathologic entities that caused the seizures. This analysis reveals the variety of neurological conditions that commonly cause intractable focal seizure disorder in children and distinguishes those pathologic entities in which the seizure disorder is apt to respond to surgical intervention from those that will not.