Multicenter Therapeutic Trials of X-Linked ALD

描述（由申请人提供）：x -连锁肾上腺脑白质营养不良（X-ALD）主要影响神经系统白质、轴突和肾上腺皮质。其发病率约为1:17 000。在同一家族和男性中，表型表达常常不同，从儿童时期的大脑形式（可能导致10岁前完全残疾和死亡）到肾上腺髓神经病变（AMN）（在20多岁或20多岁时表现为麻痹，在几十年内缓慢进展）。X-ALD杂合的女性可能在中年或以后发展为amn样综合征。大多数男性有原发性肾上腺皮质功能不全，对类固醇替代治疗有反应。长链脂肪酸（VLCFA）的积累是主要的生化异常。缺陷基因编码过氧化物酶体膜蛋白（ALDP）。对于神经系统表现没有一致有效的治疗方法。骨髓移植有利于早期大脑受累的患者，但风险较高。

DESCRIPTION (provided by applicant): X-linked adrenoleukodystrophy (X-ALD) affects mainly the nervous system white matter and axons and the adrenal cortex. Its incidence is approximately 1:17,000. Phenotypic expression varies often within the same family and in males ranges from the childhood cerebral form, which may lead to total disability and death by 10 years of age, to adrenomyeloneuropathy (AMN), which presents in the middle or late twenties as a paraparesis that is slowly progressive over decades. Women heterozygous for X-ALD may develop an AMN-like syndrome in middle age or later. Most males have primary adrenocortical insufficiency which responds to steroid replacement therapy. Accumulation of very long chain fatty acids (VLCFA) is the principal biochemical abnormality. The defective gene codes for a peroxisomal membrane protein (ALDP). There is no consistently effective therapy for the neurologic manifestations. Bone marrow transplantation benefits patients with early cerebral involvement but carries a high risk. The investigators propose a longitudinal cohort study and two Phase II therapeutic trials. Specific Aim 1 will establish a network of five clinical centers: The Kennedy Krieger Institute in Baltimore, the Texas Children's Hospital in Houston, the Massachusetts General Hospital in Boston, the University of Minnesota in Minneapolis, and the University of California at San Francisco. The Program will be coordinated by the Center for Clinical Trials at the Johns Hopkins Bloomberg School of Public Health. Specific Aim 2 will establish a cohort of 300 male X-ALD patients and 100 women heterozygous for X-ALD to permit a longitudinal study of natural history. Follow-up will utilize objective and validated measures of neurologic and neuropsychologic function, and quality of life. Neuroimaging studies have been shown to be valuable surrogate markers of the cerebral disease and will be scored independently by two neuroradiologists using an electronic transmission system developed for this purpose with the support from the National Library of Medicine. Newly developed quantitative tests will be used to aid assessment progression of AMN. Specific Aim 3 will conduct safety-efficacy studies of 4-phenylbutyrate therapy in patients with the cerebral forms of X-ALD, and a placebo controlled trial of insulin-like growth factor-1 in male patients with AMN and heterozygous women with an AMN like syndrome.