MEDICATIONS: LORENZO'S OIL SHOWS PROMISE IN REDUCING RISK OF DEBILITATING DISEASE IN GENETIC DISORDER

July 15, 2005 — Treatment of boys with X-linked adrenoleukodystrophy (ALD) with Lorenzo's oil (LO) reduced their risk of developing the severe debilitating form of the disease, according to a study in the July issue of Archives of Neurology, a journal of the American Medical Association.

Individuals with ALD accumulate high levels of saturated very long-chain fatty acids (VLCFA) in their brains. The course of the disease results in a number of different manifestations [phenotypes], according to background information in the article. The rapidly progressive cerebral ALD (CERALD) type typically begins between ages four and eight and progresses rapidly to total disability within a few years. An adult form is non-inflammatory, progresses slowly and is far less disabling. Children who do not develop abnormalities as measured by magnetic resonance imaging (MRIs) by age seven or clinical symptoms by age 10, have greatly diminished risk of developing cerebral ALD.

In 1989, one of the authors of this study, Augusto Odone, pioneered a treatment (Lorenzo's oil), which was shown to normalize the levels of saturated very long-chain fatty acids within four weeks in most patients with ALD. "The striking effect of LO on plasma C26:0 [a saturated very long-chain fatty acid] levels engendered the hope that it would be of clinical benefit for patients with ALD," the authors write. However, previous clinical trials led to the conclusion that Lorenzo's oil did not alter the rate of progression of the disease in patients who already had neurological symptoms.

Hugo W. Moser, M.D., of the Kennedy Kreiger Institute, Baltimore, and colleagues treated 89 boys with ALD who had no neurological symptoms and normal brain MRIs with moderate dietary fat restriction and Lorenzo's oil between 1989 and 2002. Sixty-four of the patients were younger than seven years old when they began treatment and all were followed up for an average of approximately seven years. Because of the devastating nature of cerebral ALD, and the hope that the striking reduction of very long chain fatty acid levels would lead to clinical benefit, none of the boys were given placebo. Fatty acids blood levels were assessed every month for the first six months after enrollment in the study and every three to six months thereafter. Neurological examinations and MRIs were scheduled every six to 12 months.

Sixty-six patients (74 percent) were well at last follow-up. Twenty-one patients (24 percent) developed MRI abnormalities and 10 patients (11 percent) developed neurological abnormalities. The researchers found a significant association between the development of MRI abnormalities and an increase in the levels of the saturated very long chain fatty acid C26:0. "Patients who had a neurological abnormality had significantly higher weighted average C26:0 levels than those who did not have an abnormality, suggesting that an LO-induced decrease in the C26:0 level could protect against the inflammatory cerebral disease," the authors report.

"We recommend that LO therapy be offered to male patients with ALD who are neurologically asymptomatic, have normal brain MRI results, and are at risk of developing CERALD," the authors conclude. "This recommendation is based on strongly suggestive, albeit not fully definitive, evidence of a preventive effect combined with our awareness of the severe prognosis of the untreated patients with CERALD. The patients who are younger than seven years represent prime candidates for this therapy. We hypothesize that intensive LO therapy during the ages at which the risk for CERALD is greatest may protect against this phenotype until they reach the ages at which the risk for CERALD diminishes."

Editor's Note: This study was supported by grants from the Johns Hopkins University School of Medicine General Clinical Research Center, from the National Center for Research Resources/National Institutes of Health, Bethesda, Md., the National Institutes of Health, Bethesda, Md., the Office of Orphan Drug Products of the Food and Drug Administration, Rockville, Md., and the Myelin Project, Dunn Loring, Va.

Editorial: Lorenzo's Oil: Advances in the Treatment of Neurometabolic Disorders

In an editorial accompanying the article, Raymond Ferri, M.D., Ph.D. and Phillip F. Chance, M.D., of the University of Washington, Seattle, write "In recent years, extraordinary progress has also been made in developing effective treatments, and ALD serves as an excellent model for the treatment of neurometabolic diseases. Current treatment includes hematopoietic stem cell transplantation (HSCT) to stabilize neurologic progression, steroid therapy for adrenal insufficiency, and symptomatic treatments. The article by Moser et al in this issue may establish new standards for the treatment of this degenerative disorder."

"Therefore, Moser and colleagues propose LO therapy for all asymptomatic patients with biochemical evidence of ALD to slow the progression of disease and to prevent symptoms until the child is past the age for the development of the childhood cerebral form of the disorder," the authors write. "Successful implementation of this practice requires early identification of at-risk patients. However, because almost 20 percent of the patients are either asymptomatic or have Addison disease only, at-risk children may not be identified. As also mentioned in the article, neonatal screening would identify more at-risk patients at a very early age. This would allow for further studies to examine very early treatment with LO for affected children, and dietary therapy can be studied in other ALD phenotypes [manifestations]. Also, this study can be extended to follow patients for an even greater duration to establish the full treatment effects of LO."

"X-linked ALD is a rare, progressive neurometabolic disorder, but coordinated, worldwide research efforts have made it a treatable disease," the authors conclude. "Dietary therapy started early in life and HSCT have markedly improved the longevity and quality of life for affected people, and new standards for treatment have been established."