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.

戈谢病：在戈谢病同类最大规模的神经病理学研究中，我们研究了 14 名具有该疾病所有三种表型的患者。我们发现了一种涉及海马 CA2-4 区域和距状皮质第 4b 层的独特疾病病理模式。虽然这一发现对于戈谢病的所有三种表型来说都很常见，但变化的程度根据疾病的严重程度而有所不同。所有患有这种疾病的患者均累及大脑皮质第 3 层和第 5 层、海马 CA2-4 和第 4b 层。使用抗葡萄糖脑苷脂酶抗体进行的免疫组织化学染色与 CA4-2 的密集染色精确匹配病理定位。我们在两名患有 1 型 GD 和帕金森病的患者的海马 CA4-2 神经元中发现了许多脑干型路易体。这些发现提出了一种常见的细胞毒性机制，该机制将戈谢病中异常的葡萄糖脑苷脂酶活性、神经元细胞毒性和细胞毒性路易体形成联系起来。 法布里病：该分支的主要目标之一是为患有遗传性神经代谢疾病的患者开发有效的治疗方法。法布里病是此类疾病中仅次于戈谢病的最常见疾病。患有这种疾病的患者会出现严重疼痛的周围神经病变、过早中风和心肌梗塞，并最终导致完全肾衰竭。在报告年度，我们进行了一项针对法布里病的酶替代疗法（ERT）的开放标签持续研究。缺失的酶，α-半乳糖苷酶 A，是在良好生产规范设施中使用连续人类细胞系作为酶源制备的。接受研究药物的患者与这种疾病相关的疼痛性肢端感觉异常明显减轻。最初服用安慰剂的患者在接受酶治疗后也获得了同样的益处。其他研究结果显示，接受这种酶的患者感知冷热温度的能力得到了改善，并纠正了出汗不足的情况。使用 MRI 和动脉自旋标记方法，我们发现 Fabry 患者的脑损伤与脑血流量增加有关。 ERT 逆转了法布里病患者的脑过度灌注。 ERT 已在欧盟和其他 15 个国家被批准用于治疗法布里病患者。 粘脂沉积症 IV：我们对 28 名患有这种常染色体隐性神经遗传疾病的患者进行了调查，并在所有患者中发现了称为粘脂蛋白的蛋白质的突变。所有患者均患有胃酸缺乏且血浆胃泌素水平升高，其中 12 名患者患有缺铁性贫血。头部 MRI 显示胼胝体薄的一致特征性发现。在长达数年的随访期间，这种情况一直没有改变。还注意到言语、手部使用和吞咽方面的显着异常。观察基因型与神经障碍和胼胝体发育不良程度的相关性。我们得出的结论是，IV 型粘脂沉积症既是一种发育性疾病，又是一种退行性疾病。表现为脑瘫样脑病可能会延迟对该病的正确诊断。 脑白质营养不良：我们证明了脑白质营养不良患者的真核起始因子 2B (eIF2B) 亚基发生突变，这种脑白质营养不良是 DMNB 于 1994 年首次发现的，当时称为儿童共济失调伴中枢神经系统髓鞘形成不足 (CACH)。 CACH 患者在儿童期、青春期，有时甚至在成年期会出现进行性神经功能恶化。临床衰退通常在轻微头部外伤或并发发热性疾病等压力后开始或恶化。 eIF2B 是一种蛋白质复合物，对于蛋白质合成的调节至关重要，特别是在应对压力时。我们发现患有克里脑白质病（一种非常严重的婴儿期遗传病）的患者也有 eIF2B 突变。克里族白质脑病患者的大脑被发现具有与我们之前描述的 CACH 标志相同的“泡沫状”少突胶质细胞。我们还发现，我们在 1997 年描述的另一种脑白质营养不良患者（称为卵巢脑白质营养不良）的蛋白质 eIF2B 亚基也存在突变。这种神经遗传复合体包括最常见的脑白质营养不良综合征之一。这些研究可能会导致人们更好地了解髓鞘形成和髓鞘的维持，特别是与压力情况和条件的关系。