Mariam A Ahmed1,2,3, Reena V Kartha1,2, Richard C Brundage1,2, James Cloyd1,2, Cynthia Basu4, Bradley P Carlin4, Richard O Jones5, Ann B Moser6, Ali Fatemi7, Gerald V Raymond8. 1. Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN. 2. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA. 3. Department of Pharmacy Practice, Helwan University, Cairo, Egypt. 4. Division of Biostatistics, University of Minnesota, Minneapolis, MN. 5. Division of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD. 6. Peroxisomal Diseases Laboratory, Kennedy Krieger Institute, Baltimore, MD. 7. Genetics Laboratories, Kennedy Krieger Institute, Baltimore, MD. 8. Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
Abstract
AIMS: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. METHODS: Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. RESULTS: The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). CONCLUSIONS: LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALD patients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.
AIMS: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic anderucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. METHODS: Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. RESULTS: The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). CONCLUSIONS:LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALDpatients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.
Authors: Hugo W Moser; Gerald V Raymond; Shou-En Lu; Larry R Muenz; Ann B Moser; Jiahong Xu; Richard O Jones; Daniel J Loes; Elias R Melhem; Prachi Dubey; Lena Bezman; N Hong Brereton; Augusto Odone Journal: Arch Neurol Date: 2005-07
Authors: P Aubourg; C Adamsbaum; M C Lavallard-Rousseau; F Rocchiccioli; N Cartier; I Jambaqué; C Jakobezak; A Lemaitre; F Boureau; C Wolf Journal: N Engl J Med Date: 1993-09-09 Impact factor: 91.245
Authors: D J Loes; S Hite; H Moser; A E Stillman; E Shapiro; L Lockman; R E Latchaw; W Krivit Journal: AJNR Am J Neuroradiol Date: 1994-10 Impact factor: 3.825
Authors: Mariam A Ahmed; Reena V Kartha; Richard C Brundage; James Cloyd; Cynthia Basu; Bradley P Carlin; Richard O Jones; Ann B Moser; Ali Fatemi; Gerald V Raymond Journal: Br J Clin Pharmacol Date: 2016-04-03 Impact factor: 4.335
Authors: Marcia R Terluk; Julianne Tieu; Siddhee A Sahasrabudhe; Ann Moser; Paul A Watkins; Gerald V Raymond; Reena V Kartha Journal: Neurotherapeutics Date: 2022-04-04 Impact factor: 6.088
Authors: Mariam A Ahmed; Reena V Kartha; Richard C Brundage; James Cloyd; Cynthia Basu; Bradley P Carlin; Richard O Jones; Ann B Moser; Ali Fatemi; Gerald V Raymond Journal: Br J Clin Pharmacol Date: 2016-04-03 Impact factor: 4.335