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Movement Disorders : Official Journal... May 2024Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets.
BACKGROUND
Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets.
OBJECTIVES
The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet.
METHODS
UX007G-CL301 was a randomized, double-blind, placebo-controlled, phase 3 crossover study. After a 6-week run-in, eligible patients were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open-label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank-sum test.
RESULTS
Forty-three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7-38.3] vs. 11.8; [3.2-28.7]; Hodges-Lehmann estimated median difference: 1.46; 95% confidence interval, -1.12 to 4.36; P = 0.2684). Treatment-emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non-serious adverse events that were predominantly gastrointestinal. The study was closed early during the open-label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately.
CONCLUSION
There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double-blind maintenance period. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PubMed: 38725190
DOI: 10.1002/mds.29822 -
Environmental Research Jun 2024Dioxin-like pollutants (DLPs), such as polychlorinated biphenyl 126 (PCB 126), are synthetic chemicals classified as persistent organic pollutants. They accumulate in...
Dioxin-like pollutants (DLPs), such as polychlorinated biphenyl 126 (PCB 126), are synthetic chemicals classified as persistent organic pollutants. They accumulate in adipose tissue and have been linked to cardiometabolic disorders, including fatty liver disease. The toxicity of these compounds is associated with activation of the aryl hydrocarbon receptor (Ahr), leading to the induction of phase I metabolizing enzyme cytochrome P4501a1 (Cyp1a1) and the subsequent production of reactive oxygen species (ROS). Recent research has shown that DLPs can also induce the xenobiotic detoxification enzyme flavin-containing monooxygenase 3 (FMO3), which plays a role in metabolic homeostasis. We hypothesized whether genetic deletion of Fmo3 could protect mice, particularly in the liver, where Fmo3 is most inducible, against PCB 126 toxicity. To test this hypothesis, male C57BL/6 wild-type (WT) mice and Fmo3 knockout (Fmo3 KO) mice were exposed to PCB 126 or vehicle (safflower oil) during a 12-week study, at weeks 2 and 4. Various analyses were performed, including hepatic histology, RNA-sequencing, and quantitation of PCB 126 and F2-isoprostane concentrations. The results showed that PCB 126 exposure caused macro and microvesicular fat deposition in WT mice, but this macrovesicular fatty change was absent in Fmo3 KO mice. Moreover, at the pathway level, the hepatic oxidative stress response was significantly different between the two genotypes, with the induction of specific genes observed only in WT mice. Notably, the most abundant F2-isoprostane, 8-iso-15-keto PGE2, increased in WT mice in response to PCB 126 exposure. The study's findings also demonstrated that hepatic tissue concentrations of PCB 126 were higher in WT mice compared to Fmo3 KO mice. In summary, the absence of FMO3 in mice led to a distinctive response to dioxin-like pollutant exposure in the liver, likely due to alterations in lipid metabolism and storage, underscoring the complex interplay of genetic factors in the response to environmental toxins.
Topics: Animals; Oxygenases; Polychlorinated Biphenyls; Oxidative Stress; Mice; Mice, Inbred C57BL; Male; Mice, Knockout; Liver; Environmental Pollutants
PubMed: 38373550
DOI: 10.1016/j.envres.2024.118492 -
The Journal of Nutrition Mar 2024Hepatic mitochondrial dysfunction is a major cause of fat accumulation in the liver. Individuals with fatty liver conditions have hepatic mitochondrial structural...
BACKGROUND
Hepatic mitochondrial dysfunction is a major cause of fat accumulation in the liver. Individuals with fatty liver conditions have hepatic mitochondrial structural abnormalities and a switch in the side chain composition of the mitochondrial phospholipid, cardiolipin, from poly- to monounsaturated fatty acids. Linoleic acid (LA), an essential dietary fatty acid, is required to remodel nascent cardiolipin (CL) to its tetralinoleoyl cardiolipin (LCL, CL with 4 LA side chains) form, which is integral for mitochondrial membrane structure and function to promote fatty acid oxidation. It is unknown, however, whether increasing LA in the diet can increase hepatic LCL concentrations and improve mitochondrial respiration in the liver compared with a diet rich in monounsaturated and saturated fatty acids.
OBJECTIVES
The main aim of this study was to test the ability of a diet fortified with LA-rich safflower oil (SO), compared with the one fortified with lard (LD), to increase concentrations of LCL and improve mitochondrial respiration in the livers of mice.
METHODS
Twenty-four (9-wk-old) C57 BL/J6 male mice were fed either the SO or LD diets for ∼100 d, whereas food intake and body weight, fasting glucose, and glucose tolerance tests were performed to determine any changes in glycemic control.
RESULTS
Livers from mice fed SO diet had higher relative concentrations of hepatic LCL species compared with LD diet-fed mice (P value = 0.004). Uncoupled mitochondria of mice fed the SO diet, compared with LD diet, had an increased baseline oxygen consumption rate (OCR) and succinate-driven respiration (P values = 0.03 and 0.01). SO diet-fed mice had increased LA content in all phospholipid classes compared with LD-fed mice (P < 0.05).
CONCLUSIONS
Our findings reveal that maintaining or increasing hepatic LCL may result in increased OCR in uncoupled hepatic mitochondria in healthy mice whereas higher oleate content of CL reduced mitochondrial function shown by lower OCR in uncoupled mitochondria.
Topics: Male; Mice; Animals; Linoleic Acid; Cardiolipins; Mitochondria; Dietary Fats; Fatty Acids; Liver; Diet; Phospholipids; Linoleic Acids; Respiration
PubMed: 38160803
DOI: 10.1016/j.tjnut.2023.12.037