The biochemical abnormality of ALD was first recognized in 1976 (Igarashi et al. 1976). Affected individuals had an elevation of saturated very long-chain fatty acids (VLCFA). The demonstration of this abnormality and the recognition that a part of these fatty acids were of dietary origin prompted early attempts to lower the blood VLCFA levels by changing the diet. This diet was very restricted in food choices since VLCFA are present in many plant and animal products. Unfortunately, dietary restriction of C26:O fatty acid intake failed to lower the plasma VLCFA levels in patients with ALD (Brown et al. 1982).
This failure of dietary effect led to the understanding that there must also be a significant production of VLCFA within the body. Indeed the majority of VLCFA is produced from long-chain fatty acids (Tsuji et al. 1981)(See Origin and Metabolism of VLCFA for more info). There have been a variety of attempts to interfere with long-chain fatty acid elongation. The early focus was on the use of mono-unsaturated long-chain fatty acids. These mono-unsaturated long-chain fatty acids are slightly different than the saturated long chain fatty acids, because they have a single double bond in the fat-chain. It was predicted that the mono-unsaturated fatty acids would compete with the enzymes that are responsible for the elongation of very long-chain fatty acids (elongases) and that their affinity for mono-unsaturated fatty acids would be higher than for saturated fatty acids. Thereby driving the production of saturated VLCFA down (Figure 1). Indeed, the addition of mono- unsaturated fatty acids, especially oleic acid (C18:1), to the tissue culture medium of cultured skin fibroblasts from ALD patients decreased the synthesis of C26:0 by 60% (Rizzo et al. 1984).
The introduction of oleic acid (C18:1) followed by erucic acid (C22:1) when used in combination with a moderately low fat diet resulted in lowering of VLCFA in 6-8 weeks in patients with ALD (Moser et al. 1987; Rizzo et al. 1989) (Figure 2). This oil, which is a 4:1 mixture of glyceryl trioleate (GTO) and glyceryl trierucate (GTE) has been named Lorenzo’s oil. Lorenzo’s oil is taken orally and is generally well tolerated although a moderate reduction of platelets and elevation of liver transaminases has been seen.
From the initial studies examining the role of this mixture in ALD, it was very apparent that it did not alter the progression of cerebral disease in affected individuals. This experience has been demonstrated repetitively. Lorenzo’s oil does not alter the course of childhood or adult cerebral ALD and is never indicated in the cerebral form of the condition. In addition, it has never been studied in the preparation for bone marrow transplantation or in the period of time following that treatment.
Initial studies in the adult form of ALD, adrenomyeloneuropathy (AMN) used the treatment in small populations with variable presentations for short periods of time without definitive effect. These very limited clinical trials led to broad statements of a lack of effect and concerns that the active ingredients did not get into the brain. Indeed, while Lorenzo’s oil lowered the levels of C26:0 in plasma and adipose tissue, it failed to alter the levels of C26:0 in the brain (Rasmussen et al 1994). The authors concluded: “failure of erucic acid to enter the brain in significant quantity may be a factor in the disappointing results of dietary therapy for ALD”. This may be explained by another study that provided experimental evidence that erucic acid does get into the brain, but that it is rapidly metabolized (Golovko and Murphy 2006).
In the 1990’s several groups independently began studying the use of Lorenzo’s oil as a preventative therapy – an agent that would either prevent cerebral disease in boys who were at risk, but unaffected or slow the progression in men with AMN. Two trials (Aubourg et al. 1993; Van Geel et al. 1999) showed that Lorenzo’s oil does not alter progression of disease in men with AMN. In addition, a few males with AMN developed cerebral involvement despite using the oil. All of these trials were open trials (Lorenzo’s oil was not tested against a placebo) and were thus somewhat limited in the ability to be definitive.
In an effort to provide definitive answers concerning the clinical efficacy as a disease-modifying agent in AMN, a phase III trial of Lorenzo’s oil in AMN was initiated in 2007 at the Kennedy Krieger Institute. The 4-year study would include 120 men with AMN who did not have evidence of cerebral involvement, and 120 women with ALD with a myelopathy. The rate of progression would be compared in the Lorenzo’s oil and placebo groups using the Kurtzke EDSS score as the primary outcome and a variety of secondary outcomes. Unfortunately, the study was aborted before completion by the safety monitoring board because of presumed side effects of the placebo treatment. Therefore, there is no scientific evidence to prove that Lorenzo’s oil has a disease modifying effect in AMN.
For cerebral ALD, Moser and colleagues (Moser et al. 2005) reported the experience in a large group of boys who had normal MRI at their entry into the study. In this group, VLCFA were lowered by therapy and a relationship could be demonstrated in a reduction of risk of developing cerebral disease and the reduction of VLCFA. This study, however, has several limitations, for instance the use of historical controls instead of a placebo group, and offers no definitive evidence of the efficacy of Lorenzo’s oil in the prevention of the onset of cerebral ALD in boys with ALD. Based on the results of this study, Lorenzo’s oil is therefore offered to boys with ALD with the aim of reducing risk of the occurrence of cerebral ALD in some countries. It should be noted that the use of Lorenzo’s oil is not without side effects and has considerable impact on quality of life.
We recommend that the use of Lorenzo’s oil should only be undertaken by centers that have the ability to provide monitoring with MRI, nutritional guidance, and the ability to measure VLCFA and other essential fatty acids. Other centers consider the efficacy of Lorenzo’s oil unproven and do not recommend its use.
Lorenzo’s oil must never be undertaken without physician supervision. While serious untoward reactions have not been seen in the monitored use of the oil and diet, individuals on Lorenzo’s oil must be periodically evaluated for safety. Finally, it must be stated firmly that Lorenzo’s oil is only indicated for the biochemical defect of ALD and does not have any role in other demyelinating or progressive neurologic conditions since those individuals will have the ability to metabolize very long-chain fatty acids.