linoleic-acid and Friedreich-Ataxia

Diagnosis and classification of the inherited ataxias are reviewed with emphasis on recognizing treatable disorders. Even when basic defects are untreatable, many complications of the degenerative process are amenable to therapy.

Topics: Ataxia; Brain; Cells, Cultured; Fibroblasts; Friedreich Ataxia; Genes, Recessive; Humans; Ketoglutarate Dehydrogenase Complex; Linoleic Acid; Linoleic Acids; Lipoproteins; Malate Dehydrogenase; Pyruvate Carboxylase Deficiency Disease; Pyruvate Dehydrogenase Complex Deficiency Disease

Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial.. Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2.. Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study.. The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Topics: Double-Blind Method; Friedreich Ataxia; Humans; Linoleic Acid; Linoleic Acids; Walking

RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia.. To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients.. We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk.. Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject with a low body mass index experienced steatorrhea taking a high dose and discontinued the study. Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to be present in plasma on day 28. There was an improvement in peak workload in the drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116), and in stride speed (P = 0.15).. RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted. © 2018 International Parkinson and Movement Disorder Society.

Topics: Adolescent; Adult; Arachidonic Acid; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Friedreich Ataxia; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Time Factors; Treatment Outcome; Young Adult

Lecithin and safflower oil brought about the same changes in serum LAD activity and kinetics in patients with Friedreich's Ataxia as in controls when results of this double-blind crossover study were analyzed according to group assignation. According to functional stages, pretrial LAD activity decreased with advancing severity while Km for lipoamide increased. Lecithin and safflower oil supplements corrected the elevated Km for lipoamide but produced a further reduction in LAD activity. These changes may have been due to the increased intake of linoleic acid, a precursor of lipoic acid, which is present in high percentage in both lecithin and safflower oil. Results of the biochemical study thus agreed with the clinical data gathered during the course of the one-year trial in suggesting that linoleic acid may well have been the active factor through which biochemical and clinical improvement was previously observed in patients with Friedreich's Ataxia supplemented with lecithin.

Topics: Administration, Oral; Dihydrolipoamide Dehydrogenase; Friedreich Ataxia; Humans; Kinetics; Linoleic Acid; Linoleic Acids; NAD; Phosphatidylcholines

A clinical and biochemical evaluation of twenty-two patients with Friedreich's Ataxia and ten normal controls was undertaken in 1980 to assess the effect of lecithin and linoleic acid supplements on the course of the disease. The trial consisted of two consecutive six months periods on either supplements in a double-blind crossover fashion. Clinical appraisal was performed with regards to the following parameters: joints mobility, muscle strength, equilibrium, coordination, motor accuracy, speech and numerous day to day activities. Blood samples were obtained at the beginning and in the course of the trial for enzymatic determinations. This paper describes the methodology of the study.

Topics: Administration, Oral; Adolescent; Adult; Child; Clinical Trials as Topic; Double-Blind Method; Female; Friedreich Ataxia; Humans; Linoleic Acid; Linoleic Acids; Locomotion; Male; Motor Skills; Muscle Contraction; Phosphatidylcholines

Twenty-two patients with Friedreich's Ataxia and ten normal controls were followed for one year and assessed as to their clinical performance after two successive six-month periods of lecithin or safflower oil. Results demonstrated no significant difference in performance scores according to group assignation, neither in patients nor in controls. According to stages, two patients in stage I and to a lesser degree, one patient in stage IV showed better scores for muscle strength and some motor accuracy and coordination tests with lecithin. Controls as groups maintained positive scores in all tests. Patients as groups showed negative mean values in nine out of eleven tests. Again as groups, patients receiving safflower oil demonstrated a mean 8% less deterioration than patients receiving lecithin. This study demonstrates that objective clinical tests and the participation of normal controls are a must in a therapeutic trial implicating patients with a progressive disorder such as Friedreich's Ataxia. The possible role of linoleic acid as the active factor from which clinical improvement proceeded in some specific patients and with early functional stages of the disease, has to be considered and reevaluated in the near future.

Topics: Administration, Oral; Clinical Trials as Topic; Double-Blind Method; Friedreich Ataxia; Humans; Linoleic Acid; Linoleic Acids; Motor Skills; Muscle Contraction; Phosphatidylcholines

Topics: Disease Progression; Double-Blind Method; Friedreich Ataxia; Humans; Linoleic Acid; Oxygen Consumption; Walking; Workload

The author reviews the arguments for and against the four etiologic hypotheses in Friedreich's disease that have been proposed since 1974: the "pyruvate hypothesis", the "lipid-membrane hypothesis", the "energy-defect hypothesis" and finally the "taurine hypothesis". While none of these hypotheses are mutually exclusive, the author shows that all of these mechanisms play some role in the pathophysiology of the symptoms, but that only the "taurine hypothesis" appears to be compatible with all the known facts and the biochemical abnormalities reported. The author proposed that the taurine retention defect (possibly due to a block in the high affinity-low capacity transport of taurine - The TH System) is a primary event in Friedreich's disease. Whether it is the primary genetic event still has to be determined.

Topics: Amino Acids; Coenzyme A; Energy Metabolism; Fatty Acids; Friedreich Ataxia; Humans; Intestinal Absorption; Linoleic Acid; Linoleic Acids; Membrane Lipids; Mitochondria; Pyruvate Dehydrogenase Complex; Research; Taurine