Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults.

Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions

Characterization of Hacl1 -/- mice, a new animal model for alpha-oxidation deficiency

Phytanic acid is a branched‑chain fatty acid, which is not endogenously synthesized, but it is taken up with the diet, as it is abundant in certain food types such as red meat and dairy products. Its degradation occurs mainly via alpha‑oxidation, a process that takes place in the peroxisomes of cells. Patients with Peroxisome Biogenesis Disorders or Adult Refsum Disease have a deficiency in this process, and they consequently accumulate phytanic acid in their blood and tissues. The accumulation of this FA has toxic consequences, and therefore patients need to follow a regimen poor in phytanic acid. In this work, we characterized a new mouse model for alpha‑oxidation deficiency, namely Hacl1-/- mice. To date, nonbsp;with HACL1 deficiencies have been reported, but we hypothesized to observe a stronger phenotype, as HACL1 is also capable of degrading 2-hydroxy fatty acids, which are particularly abundant in the central nervous system. Based on Northern andnbsp;analysis, Hacl1 expressionnbsp;abolished in our model. However, on a regular diet, these mice did not display any obvious phenotype. This already suggested that the role of HACL1 in the central nervous system might be more limited than we thought, and thatnbsp;fatty acids might be degradednbsp;an alternative pathway. Upon phytol feeding, Hacl1-/- mice displayed anbsp;phenotype, with loss of body weight, liver enlargement and a typical livernbsp;Lipid analyses revealed that phytanic acid was accumulatingnbsp;liver andnbsp;of Hacl1-/- mice, and biochemical and histological analyses showed that lipid metabolism was partially altered. Hepatic triglyceride levels were reduced in phytol‑treatednbsp;mice, and neutral lipids displayed a peculiar distribution pattern, being mainlynbsp;around the portal triad. This was accompanied by a zonal activation ofnbsp;PPARalpha‑target CYP4A1. Additional experiments to verify the occurrence of salvage pathways in the Hacl1-/- mice did not reveal anything interesting, although the main pathway responsible fornbsp;partial rescue of the phenotype likely involves another lyase. Based on its enrichment in a 100000 g pellet and its solubilization by detergents, this lyase is an integral membrane protein of the ER and is likely responsible for thenbsp;activity observed in HACL1 deficient hepatocytes and fibroblasts in vitro. Based on thenbsp;degradation of a 3-methyl-branched fatty acid in HACL1 deficient hepatocytes and fibroblasts, this ER-lyase contributes to alpha-oxidation in vivo as well. This will complicate the detection of HACL1 deficiencies, normally done by human fibroblast oxidation studies. We also hypothesized that the most closely HACL1‑related protein in mammals, ALS, couldnbsp;the microsomal lyase, but we could not demonstrate a lyase activity for ALS. Along with this work, we also developed a quick and robust method for the characterization of enzymatically‑generated aldehydes. This allowed for the reliable quantification of lyase activity in several tissues and cells, but its use can even be enlarged to the quantification of aldehydes in general, as for example plasmalogen‑derived aldehydes.nrpages: 182status: publishe

Phytol-induced pathology in 2-hydroxyacyl-CoA lyase (HACL1) deficient mice. Evidence for a second non-HACL1-related lyase

2-Hydroxyacyl-CoA lyase (HACL1) is a key enzyme of the peroxisomal α-oxidation of phytanic acid. To better understand its role in health and disease, a mouse model lacking HACL1 was investigated. Under normal conditions, these mice did not display a particular phenotype. However, upon dietary administration of phytol, phytanic acid accumulated in tissues, mainly in liver and serum of KO mice. As a consequence of phytanic acid (or a metabolite) toxicity, KO mice displayed a significant weight loss, absence of abdominal white adipose tissue, enlarged and mottled liver and reduced hepatic glycogen and triglycerides. In addition, hepatic PPARα was activated. The central nervous system of the phytol-treated mice was apparently not affected. In addition, 2OH-FA did not accumulate in the central nervous system of HACL1 deficient mice, likely due to the presence in the endoplasmic reticulum of an alternate HACL1-unrelated lyase. The latter may serve as a backup system in certain tissues and account for the formation of pristanic acid in the phytol-fed KO mice. As the degradation of pristanic acid is also impaired, both phytanoyl- and pristanoyl-CoA levels are increased in liver, and the ω-oxidized metabolites are excreted in urine. In conclusion, HACL1 deficiency is not associated with a severe phenotype, but in combination with phytanic acid intake, the normal situation in man, it might present with phytanic acid elevation and resemble a Refsum like disorder.status: publishe

Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome

Funded by a government grant (Odysseus program, G-0905-07) of the Research Foundation-Flanders and by a KU Leuven University Grant (Global Opportunities for Associations GOA 14.011) (G.E.B.); by a Research Foundation-Flanders postdoctoral fellowship (1248513N to M.M.W. and 12C2113N to C.C.); by a Research Foundation-Flanders PhD fellowship (1127415N to D.B.); by a KU Leuven postdoctoral fellowship (Y.A.A.); by Bowel and Cancer Research (UK charity number 1119105 to V.C.G.); and Séverine Vermeire is a senior clinical investigator of Research Foundation-Flanders . Also funded by a Research Foundation-Flanders research grant G-0699-10N (G.E.B. and M.M.W.), G-0501-10 (P.V.d.B.), and by a grant from Research Fund KU Leuven (GOA 14.011 to K.T.) and an European Research Counsil (ERC) Start Grant IMMUNO (A.L.). funded by the Canadian Institutes of Health Research (S.Va.); supported by a joint fellowship from the Canadian Association of Gastroenterology, the Canadian Institutes of Health Research, and Crohn’s and Colitis Canada (Y.N.); supported by a National Council of Science and Technology (CONACyT) grant: 203341 fellowship (E.E.V.M.); and funded by a KU Leuven University grant (PF-TRPLe to K.T.)