HEREDITARY SPASTIC PARAPLEGIA--CLINICAL, HISTOCHEMICAL,

遗传性痉挛截瘫(HSP)指的是一组 以进行性下肢痉挛为特征的疾病 软弱。从童年、青春期或成年开始， 行走能力逐渐受损，轮椅经常 需要，以及膀胱和其他神经功能障碍 赤字可能会出现。神经病理学研究显示 中枢神经中最长轴突的远端 系统：皮质脊髓束的下行终末和 纤细束的上升顶端。热休克蛋白可被继承 作为常染色体显性、隐性或X连锁性状， 这在基因上是异质性的。 直到最近，常染色体显性遗传和常染色体的原因 隐性HSP完全未知。在初步数据中，我们 发现常染色体隐性遗传性痉挛的基因 截瘫。联合调查员巴拉比奥博士和他的同事们 在染色体上发现一种新基因(截瘫基因)的突变 常染色体隐性遗传病患者的16q基因 HSP以及许多“明显散发性HSP”的患者也是如此。 这一里程碑式的发现极大地促进了我们对 这种退行性脊髓疾病。我们将在预赛中介绍 例如，有数据表明，Parplegin与酵母同源 线粒体金属蛋白酶AFG3、RCA1和YME1 肌肉活检中明显的线粒体组织化学异常 在截瘫基因突变患者中。巴拉比奥医生和他的 同事们也发现了结构上的相似 截瘫相关基因。这些都是候选基因 常染色体隐性遗传性热休克蛋白不与16q染色体连锁 “显然是零星的过敏性紫杉醇”。 我们将通过解决以下问题来扩展这些发现 问题。1)截瘫基因突变的频率在 常染色体隐性遗传和“明显的散发性热休克”？2) 不同的截瘫基因突变导致不同的临床 模式？3)截瘫相关基因是否存在突变 常染色体隐性遗传和明显散发的热休克蛋白？4)异常 线粒体结构或功能：线粒体的共同特征 遗传类型多样的过敏性紫杉醇？ 这项提议将三组不同的调查人员联合起来 专业知识。首席调查员约翰·芬克博士 丰富的HSP评估经验，已确定超过 140个HSP家族，并具有识别HSP基因突变的专业知识 导致遗传性神经疾病的基因。 合作研究员巴拉比奥博士不仅发现了截瘫 但该基因的其他3个结构上同源的成员 一家人。巴拉比奥博士将确定精确的基因 的定位、完整的cdna序列和基因组结构 这些候选基因。芬克博士将确定是否存在 过敏性紫斑狼疮患者截瘫及其相关基因突变的研究 并将这些突变与表型模式相关联。 联合研究员塞尔瓦托·迪莫罗博士，临床和医学专家 线粒体异常的生化分析，将执行 生化、组织学和超微结构分析 热休克患者皮肤成纤维细胞和肌肉组织中的线粒体 病人。这些发现将与截瘫和 截瘫相关基因分析及其表型分析 热休克蛋白。通过这个合作项目，我们不仅将了解到 截肢素及其相关基因突变的频率 在HSP中，线粒体紊乱是否常见 遗传多样性的过敏性紫斑狼疮的发病机制。这 洞察力将有助于识别候选基因 其他遗传形式的过敏性紫杉醇。目前，截瘫基因分析 可用于诊断某些形式的常染色体隐性遗传性过敏性紫斑狼疮。 我们的研究将扩展这种诊断HSP的能力(通过肌肉 活检和/或通过存在截瘫相关基因 突变)。更好地了解过敏性紫斑狼疮的病理生理学将 提供对这种麻痹的可能治疗方法的见解 无序，有希望进入分子基础，最终 其他退行性神经疾病的治疗包括 肌萎缩侧索硬化症。

Hereditary Spastic Paraplegia (HSP) refers to a group of disorders characterized by progressive lower extremity spastic weakness. Beginning in childhood, adolescence, or adulthood, walking becomes progressively impaired, wheelchairs are often required, and urinary bladder disturbance and other neurologic deficits may occur. Neuropathologic studies show degeneration at the distal ends of the longest axons in the central nervous system: the descending terminals of the corticospinal tracts and ascending terminals of fasciculus gracilus. HSP may be inherited as an autosomal dominant, recessive, or X-linked trait, each of which is genetically heterogeneous. Until recently, the cause of autosomal dominant and autosomal recessive HSP was completely unknown. In Preliminary Data, we present the discovery of a gene for autosomal recessive spastic paraplegia. Co-Investigator, Dr. Ballabio and his colleagues discovered mutations in a novel gene (paraplegin) on chromosome l6q in patients with "pure" and "complicated" autosomal recessive HSP as well as in many patients with "apparently sporadic HSP". This landmark discovery greatly advances our understanding of this degenerative spinal cord disease. We present in Preliminary Data, for example, that paraplegin is homologous to yeast mitochondrial metalloproteases AFG3, RCA1, and YME1 and that abnormal mitochondrial histochemistry is evident in muscle biopsy in patients with paraplegin gene mutations. Dr. Ballabio and his colleagues also identified structurally similar paraplegia-related genes. These are candidate genes for autosomal recessive HSP not linked to chromosome 16q and for "apparently sporadic HSP". We will extend these discoveries by addressing the following questions. 1) How frequent are paraplegin gene mutations in autosomal recessive and "apparently sporadic HSP"? 2) Do different paraplegin gene mutations produce different clinical patterns? 3) Are there mutations in paraplegin-related genes in autosomal recessive and apparently sporadic HSP? 4) Is abnormal mitochondria structure or function a common feature of genetically diverse types of HSP? This proposal unites three groups of investigators with diverse expertise. The Principal Investigator, Dr. John Fink, has extensive experience evaluating HSP, has ascertained more than 140 HSP kindreds, and has expertise identifying mutations in genes responsible for inherited neurologic disorders. Co-investigator Dr. Ballabio identified not only the paraplegin gene but 3 other structurally homologous members of this gene family. Dr. Ballabio will determine the precise genetic location, complete cDNA sequence, and genomic organization of these candidate genes. Dr. Fink will determine the presence of paraplegin and paraplegin-related gene mutations in HSP subjects and correlate these mutations with phenotypic patterns. Co-investigator Dr. Salvatore DiMauro, an expert in clinical and biochemical analysis of mitochondrial abnormalities, will perform biochemical, histologic, and ultrastructural analysis of mitochondria in skin fibroblast and muscle biopsies from HSP patients. These findings will be correlated with paraplegin and paraplegin-related gene analysis and with phenotypic patterns of HSP. Through this collaborative project, we will learn not only the frequency of paraplegin and paraplegin-related gene mutations in HSP, but also whether mitochondrial disturbance is a common mechanism underlying genetically diverse types of HSP. This insight will facilitate identification of candidate genes for other genetic forms of HSP. Currently, paraplegin gene analysis can be used to diagnose some forms of autosomal recessive HSP. Our research will extend this ability to diagnose HSP (by muscle biopsy and/or by the presence of paraplegin-related gene mutation). Greater understanding of HSP's pathophysiology will provide insights into possible therapy for this paralyzing disorder and hopefully into the molecular basis and ultimately treatments for other degenerative neurologic disorders including amyotrophic lateral sclerosis.