GLYCEROL-TRIERUCATE THERAPY OF ADRENOLEUKODYSTROPHY

甘油三芥酸酯治疗肾上腺脑白质营养不良

• 批准号: 3327806
• 负责人: HUGO W MOSER
• 金额: $ 17.85万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3327806
• 关键词: Krabbe's disease; adrenocorticotropic hormone; adult human (21+); corticosteroid receptors; diet route /schedule; diet therapy; dietary control; dietary lipid; disease /disorder prevention /control; erythrocytes; evoked potentials; glycerides; heterozygote; human subject; human therapy evaluation; inborn metabolism disorder diagnosis; leukocytes; longitudinal human study; magnetic resonance imaging; male; myelinopathy; nervous system disorder diagnosis; neuropsychological tests; nutrition related tag; peripheral nervous system disorders; preschool child (1-5); psychological tests; radioimmunoassay; saturated fatty acids; sex linked trait; spinal cord imaging /visualization

The key biochemical abnormality in X-linked adrenoleukodystrophy (ALD) is the accumulation of saturated very long chain fatty acids (VLCFA) in tissues and body fluids, due to a genetic defect of a peroxisomal enzyme that normally degrades these substances. ALD affects mainly the adrenal cortex, nervous system white matter and testis. While the endocrine deficits can be helped by steroid replacement, the neurological disability cannot be treated and often leads to severe disability and premature death. Neurological involvement ranges from rapid cerebral demyelination with mean age of onset at age 7.2 + 1.7 (SD) years, to much more slowly progressive spinal cord and peripheral nerve involvement in adults (adrenomyeloneuropathy). Our laboratory conducts a national program for the diagnosis of X-linked ALD and peroxisomal disorders, and through this program has identified more than 700 males with X-linked ALD, by far the largest group of patients with this disorder anywhere. Recent studies have demonstrated that a new dietary approach can normalize the levels of saturated VLCFA in the plasma of patients with ALD within 2-4 weeks. The regimen involves the oral administration of a glycerol trierucate (GTE) oil together with certain other dietary modifications. Diagnosis ALD can be achieved in the early postnatal period (as well as prenatally), at least several years before the onset of neurological disability in untreated patients. The striking biochemical effect of the new regimen for the first time offers the opportunity to test whether early normalization of saturated VLCFA can prevent or ameliorate the neurological disability in ALD. The proposed study has three components: 1) a double- blinded trial involving adults with adrenomyeloneuropathy and neurologically involved ALD heterozygotes; 2) a prevention trial for neurologically asymptomatic boys with the biochemical defect of ALD; and 3) a study of neurologically symptomatic boys in whom the rate of neurological progression will be compared with that in more than 100 untreated childhood ALD patients who had previously been diagnosed in our laboratory.

X连锁肾上腺脑白质营养不良（ALD）的关键生化异常是 饱和极长链脂肪酸（VLCFA）的积累 组织和体液，由于过氧化物酶体酶的遗传缺陷 通常会降解这些物质。 ALD主要影响肾上腺 皮质、神经系统白质和睾丸。 虽然内分泌 可以通过类固醇替代疗法来缓解神经功能障碍 无法治疗，常常导致严重残疾和过早死亡。 神经系统受累范围从快速脑脱髓鞘到平均 发病年龄 7.2 + 1.7 (SD) 岁，进展缓慢得多 成人脊髓和周围神经受累 （肾上腺脊髓神经病）。 我们的实验室开展了一项国家计划 X 连锁 ALD 和过氧化物酶体疾病的诊断，并通过此 该计划已识别出 700 多名患有 X 连锁 ALD 的男性，迄今为止 世界上最大的患有这种疾病的患者群体。 最近的研究表明，新的饮食方法可以使 ALD患者血浆中饱和VLCFA水平在2-4年内 几周。 该方案包括口服甘油 三芥酸 (GTE) 油与某些其他饮食调整一起。 ALD 的诊断可以在产后早期（以及 产前），至少在神经系统疾病发作前几年 未经治疗的患者的残疾。 显着的生化作用 新的治疗方案首次提供了测试是否早期的机会 饱和 VLCFA 的正常化可以预防或改善神经系统疾病 ALD 中的残疾。 拟议的研究分为三个部分：1）双 涉及患有肾上腺脊髓神经病的成人的盲法试验 神经系统相关的 ALD 杂合子； 2) 预防试验 患有 ALD 生化缺陷、无神经症状的男孩；和 3) 一项针对有神经系统症状的男孩的研究，其中神经系统症状的发生率 将与 100 多个未经治疗的儿童时期的进展进行比较 之前在我们实验室诊断过的 ALD 患者。