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Van Geel et al in this issue (pp290–9)1 provide a thorough multidisciplinary analysis of the clinical progression of 22 patients with X-linked adrenoleukodystrophy (X-ALD) who were treated with Lorenzo’s oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate). Four patients remained unchanged. One patient improved, 13 worsened, and in five some indices improved and others worsened. Mild to moderate worsening was the most frequent finding and confirms previous reports.
The introduction of Lorenzo’s oil therapy 10 years ago raised high expectations, heightened by the motion picture of the same name. The expectations were based mainly on the finding that the oil normalises the concentrations of very long chain fatty acids (VLCFA) in plasma. Accumulation of VLCFA is the principal biochemical abnormality in X-ALD and there is evidence that excess of VLCFA contributes to pathogenesis.2 Normalisation of the plasma concentration of the “offending” metabolite is of undisputed benefit in conditions such as phenylketonuria. These considerations, coupled with the tragic course of untreated childhood cerebral X-ALD, led myself and others to conduct non-randomised rather than placebo controlled therapeutic trials. Information obtained since that time highlights drawbacks of this decision and provides a lesson for the future. The drawback is that more than a decade after the first use of Lorenzo’s oil, we still do not know if it is of clinical value. Even though most symptomatic oil treated patients continue to progress, our incomplete knowledge of natural history and the lack of a control group may have masked a moderate benefit. The same concerns limit the power of a current non-randomised international study that involves 250 asymptomatic patients and aims to test whether oil administration diminishes later neurological disability. A lesson relevant to future studies is the realisation that normalisation of plasma VLCFA concentrations is not a valid marker of therapeutic success.Concentrations of VLCFA in plasma do not correlate with the degree of neurological disability,2 and in the study of Van Geel et al patients worsened despite normalisation of plasma concentrations. Furthermore, erucic acid, the active principle of Lorenzo’s oil, does not seem to enter the brain.2 These data diminish the rationale for the therapy.
The continued neurological progression in most patients treated with oil, combined with a 55% incidence of side effects, supports the recommendation of van Geel et al that it should not be offered routinely as a therapy for patients who are already symptomatic. We do recommend continuation and completion of the important study designed to determine whether the oil can prevent later neurological disability. Patients enrolled in this study are monitored to guard against side effects and those who are candidates for bone marrow transplantation are identified. Bone marrow transplantation carries a high risk but has shown remarkable benefit in some patients with early brain involvement.2 Two new promising therapeutic approaches have been proposed recently.4 5The Lorenzo’s oil experience highlights the importance of developing a study design that will permit timely evaluation of their clinical effectiveness.
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