EFFECT OF GLYCERYL TRIERUCATE THERAPY OF ALD

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. X-linked adrenoleukodystrophy (X-ALD) affects mainly the nervous system white matter and the adrenal gland. It shows a wide range of phenotypic expression. The childhood cerebral form manifests most commonly at 6-8 years of age, and is rapidly progressive, often leading to severe neurological disability before age 10 years. Other forms such as adrenomyloneuropathy (AMN) manifest in adulthood and progress more slowly. The principal biochemical abnormality is the accumulation of saturated very long chain fatty acids (VLCFA), due to a defect in the peroxisomal oxidation of these substances. It is likely, but not proven, that the VLCFA excess contributes to pathogenesis. In 1989 it was shown that the oral administration of a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, also referred to as Lorenzo Oil, can normalize the levels of VLCFA in plasma within 4 weeks. This observation led to the hope administration of this substance to asymptomatic patients could reduce the frequency and severity of subsequent neurologic damage. The present study is designed to assess whether this is the case. Because of the severe nature of the disease, and the striking biochemical effect of Lorenzo Oil on plasma VLCFA levels, a non-randomized study design was adopted. Evaluation of clinical efficacy will be based upon the comparison of clinical course of patients who were placed on oil therapy while they were asymptomatic, with that in a historical control group. Analysis of the age of onset in a large series of historical controls in the US and in Europe, indicate that 31 to 39% of patients with the biochemical defect develop neurologic symptoms by eleven years of age. The present study focuses on the clinical outcome of 125 neurologically X-ALD patients in the US who have been placed on Lorenzo Oil therapy, and is coordinated closely with a similar study in Europe that involves a similar number of patients. The main focus of the study will be on patients who began this therapy before 6 years of age and who have been followed to and beyond their eleventh birthday. We anticipate that between 50 and 60 patients will meet these criteria. The end point will be the proportion of these patients who devleop neurologic symptoms prior to their eleventh birthday. A positive result would be a proportion which is significantly less than 31 to 39%. Power calculations indicate that this sample size will permit detection of a 50% reduction in neurologic involvement by eleven years of age at the 0.05 significance level with 80% power.