Pathophysiology and Treatment of Syringomyelia

脊髓空洞症的病理生理学和治疗

基本信息

批准号：
10018687
负责人：
John Heiss
金额：
$ 71.75万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10018687
关键词：
AQP1 gene Affect Anatomy Appearance Automobile Driving Brain Brain imaging Candidate Disease Gene Caring Cerebellar tonsil Cerebellum Cerebrospinal Fluid Cerebrospinal Fluid Pressure Characteristics Chromosomes Clinical Research Collaborations Communication Computer software Congenital Disorders Cyst DNA Data Data Set Development Diagnosis Dideoxy Chain Termination DNA Sequencing Disease Doctor of Medicine Doctor of Philosophy Dyes Dysplasia Enrollment Ependymal Cyst Etiology Extended Family Family Family Study Family member Functional disorder Funding Future Gene Frequency Genetic Genetic Models Genotype Individual Infection Laboratories Lead Link Magnetic Resonance Imaging Maps Measures Medulla Oblongata Monitor Morphology Myelography National Human Genome Research Institute Natural History Neurologic Dysfunctions Neurologic Examination Neurology Obstruction Operative Surgical Procedures Pain Paper Paralysed Pathway interactions Patient-Focused Outcomes Patients Penetrance Phenocopy Phenotype Physiological Posterior Fossa Prevalence Process Proteins Protocols documentation Published Comment Publishing Reporting Research Personnel Role Russia Sampling Shapes Signal Transduction Software Tools Specimen Spinal Spinal Cord Structure Subarachnoid Space Subgroup Syndrome Syringes Syringomyelia Trauma United States Variant Venous Vertebral column Work aquaporin 4 causal variant cerebrospinal fluid flow epidemiology study exome follow-up foramen magnum genetic linkage analysis genetic pedigree genome-wide interest malformation member programs rare variant relating to nervous system skull base trait tumor

项目摘要

Genetics of Chiari I Malformation. Syringomyelia is most often associated with Chiari I malformation. Chiari I malformation develops by an unknown process. Ectopia of the cerebellar tonsils (through the foramen magnum at the base of the skull), the defining characteristic of the Chiari I malformation, may result from abnormal development of the posterior fossa. In a clinical study of families with multiple members affected by the Chiari I malformation, we are using magnetic resonance imaging of the brain to evaluate for Chiari I malformation and measure the size of the osseous structures and volume of the posterior fossa. After phenotyping family members as being affected or unaffected by these traits, we collect DNA specimens from them for genotyping. In collaboration with our Associate Investigator Joan Bailey-Wilson, M.D., Ph.D., we submitted DNA samples of affected and control individuals for Whole Exome Sequence (WES) under the NHGRI NISC-funded flagship project. The samples originated from families in Russia and the United States with multiple members affected by Chiari I malformation. This data set consisted of whole exome data from 10 extended families with a total of 132 individuals (including samples that were previously sequenced). Preliminary filtering was performed by removing markers with a depth of less than 10, a quality score of less than 10, or a ratio of quality score to depth of less than 0.5 using the Golden Helix software. Further filtering was performed using p-link; markers that were only genotyped in two people or less were removed, as were monomorphic markers. Sib-pair was used to remove any markers with Mendelian errors. All cleaning resulted in a total of 560,134 markers. Several dummy individuals were added to connect disjointed pedigrees. To perform multi-point analyses, the markers were mapped onto the Rutgers Map, version 3. Two point linkage analyses were performed using the program TwoPointLods. The genetic model used for the program was a disease allele frequency of 0.01 with a penetrance of 0.01/0.01/0.0 (meaning no phenocopies). Multi-point analyses will be performed using SimWalk2 and annotation will be performed with the ANNOVAR software tool. This year we published our findings of a genome-wide significant signal on chromosome 1q43-44 (HLOD = 3.5) and 12q23 (HLOD = 3.3) in both sets of linkage analyses. Most interesting was that both signals were driven by a single (different) family. Both regions contain several linked exonic variants, including rare variants located in good candidate genes. The two significantly linked regions for small posterior fossa are the respective driving signal in two families and are potentially causal. Further laboratory work is needed to confirm the causality of the signals. Sanger sequencing will be performed by laboratories at the Surgical Neurology Branch to confirm the variant identified on WES. We then anticipate performing functional studies of the protein of interest to further elucidate if it is the causative variant. Finding one or more genetic loci that are associated with the Chiari I malformation would lead to a better understanding of the etiology of the Chiari I malformation. Treatment of Syringomyelia. A natural history study of patients with syringomyelia was initiated 9 years ago in which patients will be monitored annually for 5 years with neurological examinations, standard scales of pain and function, and MRI of the brain and spine. Patients receive specialized care for their condition, including surgery if necessary. This study will better define the outcome of patients with syringomyelia and will provide preliminary data to generate hypotheses for future hypothesis-driven studies. This study was amended to increase the protocol enrollment ceiling to 180 from the previous 120 subjects. Additional subjects were necessary because 17 of 120 subjects had withdrawn from the study and needed to be replaced and because more patients were needed to evaluate the natural history of various subgroups in the study, which now include: a) Chiari I malformation alone, observation subgroup; b) Chiari I malformation alone, surgical treatment subgroup; c) Chiari I malformation with syringomyelia, observation subgroup; d) Chiari I malformation with syringomyelia, surgery subgroup; e) non-Chiari related syringomyelia, observation subgroup; and f) non-Chiari related syringomyelia, surgery subgroup. The study finished enrollment this year and will be completed when all subjects finish 5 years of follow-up. We previously reported a study evaluating the morphologic features of the cerebellum and medulla oblongata before and 3-6 months after surgery in patients with Chiari I malformation and syringomyelia. After surgically expanding the posterior fossa, the abnormal shape of the cerebellum and medulla oblongata characteristic of the Chiari I malformation changed to a more normal appearance. These findings support the concept that the Chiari I malformation arises from lack of development of the posterior fossa rather than a primary neural abnormality. We subsequently published a paper with Linge et al. describing the physiologic changes in CSF flow at the foramen magnum that occur after surgical treatment in patients with Chiari I malformation. We also published a clinical study of the pathophysiology of primary spinal syringomyelia, a type of syringomyelia not associated with Chiari I malformation. A preliminary finding was that obstruction of the spinal subarachnoid space in primary spinal syringomyelia was associated with enlarged cerebrospinal fluid (CSF) pressure waves superior to the obstruction. Successful surgery for primary spinal syringomyelia opened CSF pathways, reduced CSF pressure waves to normal and resolved syringomyelia, as had successful surgery in our studies of Chiari I-type syringomyelia. This association suggests that primary spinal syringomyelia and Chiari I-type syringomyelia arise from a similar mechanism. We published a study of CT-myelography that showed that syringes associated with obstruction of the spinal subarachnoid space had greater accumulation of myelography dye than syringes associated with intramedullary tumors, supporting greater communication of the subarachnoid space with the syrinx when the subarachnoid is obstructed than when an intramedullary tumor is present. We co-authored an epidemiologic study with colleagues in Russia confirming increased prevalence of Chiari I malformation in a region of Tatarstan, Russia. We also co-authored a study that found an association of fibrous dysplasia and Chiari I malformation. We discovered aquaporin-1 and aquaporin-4 expression in an intramedullary spinal cord ependymal cyst, a condition that may be mistakenly diagnoses as "idiopathic syringomyelia." This year we joined with collaborators in publishing a report of the association of Chiari I malformation and EPAS1-associated syndrome, commenting on the role of abnormal posterior fossa development in the development of Chiari I malformation in that syndrome. We also collaborated on a project describing the surgical significance of variations in tentorial venous anatomy.

Chiari I畸形的遗传学。色疗中心通常与Chiari I畸形有关。 Chiari I畸形通过未知的过程发展。小脑扁桃体（通过颅骨底部的孔巨人）的外观，Chiari I畸形的定义特征可能是由于后孔的异常发育而引起的。在对受Chiari I畸形影响的多个成员家庭的临床研究中，我们使用大脑的磁共振成像来评估Chiari I畸形并测量骨结构的大小和后孔的体积。在将家族成员表现为受这些特征影响或不影响这些特征后，我们从中收集了DNA标本进行基因分型。在与我们的副研究员Joan Bailey-Wilson，医学博士合作的情况下，我们在NHGRI NISC资助的旗舰项目下提交了影响整个外显子序列（WES）的受影响和控制个体的DNA样本。这些样品起源于俄罗斯和美国的家庭，有多个受Chiari I畸形影响的成员。该数据集由来自10个大家庭的整个外显子组数据组成，共有132个个体（包括先前测序的样本）。通过删除深度小于10的标记，质量评分小于10，或使用Golden Helix软件的质量得分与深度小于0.5的比率来进行初步过滤。使用P-Link进行进一步的过滤；仅在两个或更少的人中进行基因分型的标记和单态标记也被删除。 SIB-PAIR用于删除带有Mendelian错误的所有标记。所有清洁总共产生了560,134个标记。添加了几个虚拟人物以连接分离的谱系。为了进行多点分析，将标记映射到Rutgers Map，版本3。使用程序Twopointlods进行了两个点链接分析。该程序使用的遗传模型是疾病等位基因频率为0.01，渗透率为0.01/0.01/0.0（意味着无表现）。将使用SIMWALK2进行多点分析，并将使用Annovar软件工具进行注释。今年，我们在两组链接分析中发表了关于染色体1q43-44（HLOD = 3.5）和12q23（HLOD = 3.3）的全基因组显着信号的发现。最有趣的是，这两个信号都是由一个（不同的）家庭驱动的。这两个区域都包含几种链接的外显子变体，包括位于良好候选基因中的稀有变体。小窝的两个显着连接的区域是两个家族的各个驾驶信号，并且可能是因果关系。需要进一步的实验室工作来确认信号的因果关系。 Sanger测序将由实验室在手术神经病学分支上进行，以确认在WES上确定的变体。然后，我们预计对感兴趣的蛋白质进行功能研究，以进一步阐明它是否是因果变体。找到与Chiari I畸形相关的一个或多个遗传基因座将使人们更好地理解Chiari I畸形的病因。脊髓瘤的治疗。 9年前开始对血管瘤患者进行的自然史研究，其中每年将通过神经系统检查，疼痛和功能的标准尺度以及大脑和脊柱的MRI监测患者5年。患者为自己的病情接受专门护理，包括需要手术。这项研究将更好地定义血管瘤患者的结果，并将提供初步数据，以产生假设驱动的研究的假设。对这项研究进行了修改，以将方案入学式上限提高到前120名受试者的180个。需要其他受试者，因为120名受试者中有17名已从研究中撤回，需要替换，并且需要更多的患者来评估研究中各个亚组的自然历史，现在包括：a）仅Chiari I单独畸形，因此观察子组； b）单独使用Chiari I畸形，手术治疗子组； c）Chiari I与色疗中心，观察亚组的畸形； D）Chiari I与色疗中心，手术亚组的畸形； e）非chiari相关的脊髓念珠菌，观察亚组； f）非chiari相关的脊髓念珠菌，手术亚组。该研究今年完成了入学率，并将在所有受试者完成5年随访时完成。我们此前曾报道过一项研究，该研究评估了小脑和髓质长的形态特征，并在手术后3-6个月对Chiari I畸形和色疗中心的患者进行了3-6个月。在手术扩展后窝后，小脑和髓质的异常形状的chiari i畸形特征变成了更正常的外观。这些发现支持以下概念：Chiari I畸形是由于缺乏后窝而不是主要神经异常而引起的。随后，我们与Linge等人发表了一篇论文。描述了Chiari I畸形患者手术治疗后发生的有孔虫大量疾病室流量的生理变化。我们还发表了一项临床研究，该研究对原发性脊髓瘤的病理生理学，这是一种与Chiari I畸形无关的脊髓念珠菌。一个初步发现是，原发性脊髓脊髓脊髓脊髓脊髓脊髓脊髓杆菌的阻塞与脑脊液增大（CSF）压力波相对于障碍物。原发性脊髓脊髓脊髓疗法的成功手术开放了CSF途径，在我们对Chiari I-I-type肌室的研究中成功手术，CSF压力波降低至正常和已解决的脊椎队。该关联表明，原发性脊髓色疗中心和Chiari I型色疗中心是由类似的机制引起的。我们发表了一项关于CT肌电图的研究，该研究表明，与与鼻内肿瘤相关的注射器相比，脊髓蛛网膜下腔染料的阻塞相比，骨髓肌肌染料的积累更大，在比蛛网膜下母相比，相比，在脑蛛网膜下腔被阻塞时，蛛网膜下腔与Syrinx的交流更大。我们与俄罗斯的同事共同建立了一项流行病学研究，确认俄罗斯塔塔斯坦地区Chiari I畸形的患病率增加。我们还合着了一项研究，该研究发现了纤维发育不良和Chiari I畸形的关联。我们在髓内脊髓膜膜囊肿中发现了Aquaporin-1和Aquaporin-4的表达，这种疾病可能会错误地诊断为“特发性色素肌氏菌”。今年，我们与合作者一起发布了Chiari I畸形和EPAS1相关综合症协会的报告，并评论了异常后窝发展在该综合征中Chiari I畸形发展中的作用。我们还合作了一个项目，描述了纳塔氏静脉解剖学变异的手术意义。