Clinical Study On Etiology & Therapy Of Neurogenetic Dis

病因临床研究

• 批准号: 6843249
• 负责人: RAPHAEL SCHIFFMANN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 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/6843249
• 关键词: Fabry's disease; Gaucher's disease; alpha galactosidase; cerebrosides; clinical research; clinical trials; disease /disorder etiology; enzyme therapy; gene mutation; genetic disorder; histopathology; human subject; human therapy evaluation; immunocytochemistry; immunoelectron microscopy; leukodystrophy; mucopolysaccharidosis type IV; nervous system disorder therapy; neurogenetics; western blottings

Gaucher Disease: In the largest neuropathological investigation of its kind in Gaucher disease, we studied 14 patients with all three phenotypes of this disease. We found a unique pathologic pattern of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex. While this finding was common to all three phenotypes of Gaucher disease, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b, were involved in all patients with this disorder. Immunohistochemical staining with anti-glucocerebrosidase antibody precisely matched the pathologic localization with dense staining of CA4-2. We identified numerous brain stem-type Lewy bodies in hippocampal CA4-2 neurons in two patients with type 1 GD and parkinsonism. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity in Gaucher disease, neuronal cytotoxicity and cytotoxic Lewy body formation. Fabry Disease: One of the major goals of the Branch is to develop effective treatment for patients with hereditary neurometabolic disorders. Second to Gaucher disease, the most prevalent condition in this category is Fabry disease. Patients with this disorder have a severely painful peripheral neuropathy, premature strokes and myocardial infarctions, and ultimately, complete renal failure. During the reporting year, we performed an open-label continuation study of enzyme replacement therapy (ERT) for Fabry disease. The missing enzyme, alpha-galactosidase A, was prepared in a Good Manufacturing Practices Facility using a continuous human cell line as source of the enzyme. Patients receiving the study drug had significant reduction of the painful acroparesthesias associated with this disorder. Patients who had been initially on placebo experienced the same benefit when treated with enzyme. Additional findings revealed that patients receiving the enzyme had an improvement of their ability to sense cold and warm temperature and correction of their sweating deficiency. Using MRI and arterial spin-tagging method we showed that brain damage in Fabry patients is associated with increased cerebral blood flow. ERT reversed the cerebral hyper-perfusion in patients with Fabry disease. ERT has been approved for patients with Fabry disease in the European Union and 15 other countries. Mucolipidosis IV: We invstigated 28 patients with this autosomal recessive neurogenetic disorder and identified mutations the protein called mucolipin in all of them. All of the patients had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had an iron deficiency anemia. MRI of the head showed consistent characteristic findings of a thin corpus callosum. This condition remained unchanged during the follow-up period extending over several years. Prominent abnormalities of speech, hand-usage, and swallowing were also noted. Correlation of the genotype with the neurological handicap and the degree of dysplasia of the corpus callosum was observed. We concluded that mucolipidosis IV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay the correct diagnosis of this condition. Leukodystrophies: We demonstrated mutations in subunits of the eucaryotic initiation factor 2B (eIF2B) in patients with a leukodystrophy that was first identified by DMNB in 1994 which at the time was called Childhood Ataxia with CNS Hypomyelination (CACH). Patients with CACH develop a progressive neurological deterioration in childhood, adolescence and sometimes in adulthood. The clinical decline is often initiated or worsens after stresses such as a mild head trauma or an intercurrent febrile illness. eIF2B is a protein complex that is essential for the regulation of protein synthesis, particularly in response to stress. We discovered that patients with Cree leukoencephalopathy, a very severe genetic disease of infancy, also have mutations in eIF2B. Brains of patients with Cree leukoencephalopathy were found to have the same "foamy" oligodendrocytes that we previously described as a hallmark of CACH. We also found that patients with another leukodystrophy we described in 1997 and termed ovarioleukodystrophy also have mutations in subunits of the protein eIF2B. This neurogenetic complex comprises one of the most common leukodystrophy syndromes. It is likely that these investigations will lead to a better understanding of myelination and maintenance of the myelin sheath, particularly in relationship to stressful situations and conditions.

Gaucher病：在对Gaucher病的最大神经病理学研究中，我们研究了14例患有该疾病的三种表型的患者。我们发现了涉及海马CA2-4区域和钙化皮层4B的疾病的独特病理模式。尽管这一发现对于高彻氏病的所有三种表型都是共同的，但变化的程度因疾病的严重程度而变化。脑皮质层3和5，海马Ca2-4和4b层参与了所有这种疾病的患者。抗葡萄糖脑化酶抗体的免疫组织化学染色与CA4-2密集的染色完全匹配病理定位。我们在两名1型GD和帕金森氏症患者的海马CA4-2神经元中确定了许多脑干型Lewy体。这些发现表明了一种连接在高刺病，神经元细胞毒性和细胞毒性路易体形成的常见的细胞毒性机制。 法布里病：该分支机构的主要目标之一是为遗传神经代谢疾病患者开发有效的治疗方法。其次是高陈病，这一类别中最普遍的状况是法布里病。这种疾病患者患有严重疼痛的周围神经病，过早中风和心肌梗塞，最终使肾衰竭完全失败。在报告年度，我们对Fabry病的酶替代疗法（ERT）进行了开放标签延续研究。缺少的酶Alpha-galactosidase A是在良好的制造实践中使用连续的人类细胞系作为酶来源制备的。接受该研究药物的患者与该疾病有关的疼痛的杂脂痛显着降低。用酶治疗时，最初曾在安慰剂上曾经在安慰剂上也有同样的好处。其他发现表明，接受该酶的患者有能力感知冷热温度以及纠正出汗缺乏症的能力。使用MRI和动脉自旋方法，我们表明Fabry患者的脑损伤与脑血流增加有关。 ERT逆转了Fabry病患者的大脑高灌注。 ERT已获得欧盟和其他15个国家的Fabry病患者的批准。 粘膜脂蛋白IV：我们侵入了28例这种常染色体隐性神经发病障碍患者，并鉴定了突变。所有患者的血浆胃胃静脉水平升高，有12例患有铁缺乏性贫血。头部的MRI显示出薄型call体的一致特征发现。在几年内延长的随访期间，这种情况保持不变。还注意到言语，手法和吞咽的明显异常。观察到基因型与神经障碍的相关性和call体的发育不良程度。我们得出的结论是，粘膜脂肪性病IV既是发育性和退化性疾病。作为脑瘫样性脑病的表现可能会延迟正确诊断该疾病的情况。 白细胞营养不良：我们在1994年由DMNB最初发现的白细胞营养不良患者的念珠菌起始因子2B（EIF2B）的亚基中发生了突变，当时DMNB被称为CNS降低术（CACH）的儿童共济失调。 CACH患者在儿童期，青春期以及成年期会出现进行性神经系统恶化。在压力（例如轻度头部外伤或界面的高温疾病）之后，临床下降通常会引发或恶化。 EIF2B是一种蛋白质复合物，对于调节蛋白质合成至关重要，尤其是在响应胁迫方面。我们发现患有Cree Liukoencephalopathy的患者是婴儿期非常严重的遗传疾病，在EIF2B中也有突变。发现CREE白细胞脑病患者的大脑具有相同的“泡沫”少突胶质细胞，我们先前将其描述为CACH的标志。我们还发现，我们在1997年描述的另一种白细胞营养不良的患者，称为卵巢核酸植物营养不良，在蛋白质EIF2B的亚基中也有突变。这种神经遗传复合物包括最常见的白细胞营养不良综合征之一。这些调查可能会导致对髓鞘的髓鞘和维持，尤其是与压力大的情况和条件的关系，从而更好地理解髓鞘。