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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pediatrics Subcommittee (CHHD)
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Oster-Granite, Mary Lou
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Hugo W. Moser Research Institute Kennedy Krieger
United States
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Paker, A M; Sunness, J S; Brereton, N H et al. (2010) Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial. Neurology 75:826-30
Semmler, Alexander; Bao, Xinhua; Cao, Guangna et al. (2009) Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample. J Neurol 256:1277-80
Mahmood, Asif; Raymond, Gerald V; Dubey, Prachi et al. (2007) Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol 6:687-92
Moser, Hugo W; Mahmood, Asif; Raymond, Gerald V (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3:140-51
Moser, Hugo W (2006) Therapy of X-linked adrenoleukodystrophy. NeuroRx 3:246-53
Zackowski, Kathleen M; Dubey, Prachi; Raymond, Gerald V et al. (2006) Sensorimotor function and axonal integrity in adrenomyeloneuropathy. Arch Neurol 63:74-80
Cox, Christiane S; Dubey, Prachi; Raymond, Gerald V et al. (2006) Cognitive evaluation of neurologically asymptomatic boys with X-linked adrenoleukodystrophy. Arch Neurol 63:69-73
Moser, Hugo W; Raymond, Gerald V; Dubey, Prachi (2005) Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 294:3131-4
Moser, Hugo W; Raymond, Gerald V; Lu, Shou-En et al. (2005) Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil. Arch Neurol 62:1073-80