Heimler Syndrome is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities and occasional or late onset retinal pigmentation. We ascertained eight families with HS, and - using a whole exome sequencing approach - identified biallelic mutations in PEX1 or PEX6 in six of them. Loss of function mutations in both genes are known causes of a spectrum of autosomal recessive peroxisome biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the overlap is minimal and the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define Heimler syndrome as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6

The metabolic footprint of aging in mice

Aging is characterized by a general decline in cellular function, which ultimately will affect whole body homeostasis. Although DNA damage and oxidative stress all contribute to aging, metabolic dysfunction is a common hallmark of aging at least in invertebrates. Since a comprehensive overview of metabolic changes in otherwise healthy aging mammals is lacking, we here compared metabolic parameters of young and 2 year old mice. We systemically integrated in vivo phenotyping with gene expression, biochemical analysis, and metabolomics, thereby identifying a distinguishing metabolic footprint of aging. Among the affected pathways in both liver and muscle we found glucose and fatty acid metabolism, and redox homeostasis. These alterations translated in decreased long chain acylcarnitines and increased free fatty acid levels and a marked reduction in various amino acids in the plasma of aged mice. As such, these metabolites serve as biomarkers for aging and healthspan

Association between nutritional values of hays fed to horses and sensory properties as perceived by human sight, touch and smell

International audienceAlthough hay is the foundation of most equine diets, horse owners rarely ask for biochemical analysis and the routine practice is to choose hay based on its 'perceived' nutritional value. The present study aimed at exploring the relationship between sensory properties as perceived by sight, touch and smell, and the nutritional value of hay measured by biochemical analysis using a 'free sorting task' method. Fifty-four non-expert participants were asked individually to: (1) observe 21 hays samples, (2) group together hays that they perceived as similar for each of the three modalities (hay appearance, odour or texture) and (3) characterize each formed group with a maximum of five descriptive terms. For each modality, results were recorded in a contingency matrix (hays × terms) where only terms cited at the minimum five times for at least one sample, were kept for data analysis. A correspondence analysis (CA) was performed on the contingency matrix to plot both samples and descriptive terms on a χ 2 metric map. Then, a Hierarchical Ascending Classification (HAC) was performed on the coordinates of samples in the CA space. Clusters were identified by truncating the HAC tree-diagrams. The attributes that defined the best resulting clusters were identified by computing their probability of characterizing a cluster. Correlations were computed between each biochemical parameter on one hand, and the first two dimensions of the CA map on the other. Finally, correlations between the values of each hay on the first dimension of the three CA maps (appearance, odour and texture) were computed. Hedonic descriptive terms were primarily used for describing odour and texture modalities. For describing hay appearance, participants spontaneously used visual cues referring to colour or aspect. Based on the tree-diagrams resulting from the HAC, 3, 5 and 2 groups were clustered, respectively for appearance, odour and texture description. Digestible energy was correlated to the first dimension on the three CA maps, whereas CP was correlated to the first dimension of the CA appearance map only. While NDF value was correlated to the first and second dimensions on the CA odour map only, ADF content was correlated to the first dimension on the three CA maps. Non-fibre carbohydrates were correlated to the first dimension of the CA appearance map only. The similarity-based approach which is part of the standard toolbox of food sensory evaluation by untrained consumers was well adapted to animal feeds evaluation by non-experts

Short and Long-term Influence of Phenothiazines On Liver Peroxisomal Fatty-acid Oxidation in Rodents

AbstractEvidence is given that phenothiazines depress hepatic peroxisomal fatty acid oxidation in vivo. After oral administration to rats thioridazine and chlorpromazine inhibit peroxisomal β-oxidation, evaluated by H2O2 production, during 2 weeks. In mice, this effect could not be demonstrated. However, in both species VLCFA are increased after short and long term drug administration. Electron microscopy reveals the presence of membranous structures in liver cytoplasm or lysosomes. The inhibition by thioridazine of peroxisomal β-oxidation does not lead to hepatic peroxisome proliferation. The activities of enzymes related to fatty acid breakdown are not increased and liver peroxisomes are microscopically normal

Altered adrenocortical response under the influence of experimentally increased serum very long chain fatty acids in rats

C 26:0/C 22:0 ratio can be experimentally increased in serum of normal rats by oral administration of hexacosanoic acid (C 26:0) or of thioridazine, an inhibitor of peroxisomal beta-oxidation. This causes a decreased corticosterone response as well as decreased mobilization of cholesterol esters in zona fasciculata interna cells following ACTH administration. Zona fasciculata interna cells and their nuclei are enlarged and contain more Feulgen DNA in thioridazine-fed rats. The similarity of adrenocortical response to inhibition of peroxisomal beta-oxidation and to C 26:0 administration points to raised VLCFA as the common factor which is also operative in many peroxisomal diseases accompanied by adrenocortical function defects