GLYCEROL-TRIERUCATE THERAPY OF ADRENOLEUKODYSTROPHY

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）在 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、神经系统白色物质和睾丸。 而内分泌 类固醇替代可以帮助减少神经功能障碍， 无法治疗，往往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，平均 发病年龄为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，并通过这 该项目已经确定了700多名男性X连锁ALD，到目前为止， 最大的一群患有这种疾病的患者。 最近的研究表明，一种新的饮食方法可以使 ALD患者血浆中的饱和VLCFA水平在2-4 周 该方案包括口服甘油 三芥酸酯（GTE）油与某些其他饮食修改。 ALD的诊断可以在出生后早期实现（以及 产前），至少在神经系统疾病发作前几年 未治疗患者的残疾。 这种生物化学效应 新的治疗方案首次提供了一个机会， 饱和VLCFA的正常化可以预防或改善神经系统 ALD中的残疾。 这项研究包括三个部分：1）一个双- 设盲试验，涉及成人肾上腺脊髓神经病和 神经系统受累的ALD杂合子; 2） 具有ALD的生化缺陷的神经学上无症状的男孩;以及3） 一项对有神经系统症状的男孩的研究， 将与100多名未经治疗的儿童进行比较 以前在我们实验室诊断的ALD患者。

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.