Dataset Information

Altered carbon dioxide metabolism and creatine abnormalities in rett syndrome.

ABSTRACT: Despite their good appetite, many females with Rett syndrome (RTT) meet the criteria for moderate to severe malnutrition. Although feeding difficulties may play a part in this, other constitutional factors such as altered metabolic processes are suspected. Irregular breathing is a common clinical feature, leading to chronic respiratory alkalosis or acidosis. We assumed that these changes in intracellular pH cause disturbances in the metabolic equilibrium, with important nutritional consequences. The study population consisted of a group of thirteen well-defined RTT girls with extended clinical, molecular and neurophysiological assessments. Despite normal levels of total dietary energy and protein intakes, malnutrition was confirmed based on significantly low fat-free mass index (FFMI) values. Biochemical screening of multiple metabolic pathways showed significantly elevated plasma creatine concentrations and increased urinary creatine/creatinine ratio in five RTT girls. Four girls, 10 years and older, were forceful breathers, one 13-year-old girl had an undetermined cardiorespiratory phenotype. An isolated increase of the urinary creatine/creatinine ratio was seen in two girls, a 9-year old forceful and a 4-year old feeble breather. Given that the young girls are feeble breathers and the older girls are forceful breathers, it is impossible to determine whether the elevated creatine concentrations are due to increasing age or cardiorespiratory phenotype. Furthermore, MeCP2 deficiency may cause epigenetic aberrations affecting the expression of the creatine-transporter gene, which is located at Xq28. Further studies are required to confirm these findings and to provide greater insight into the pathogenesis of the abnormal creatine metabolism in RTT.

SUBMITTER: Halbach NS

PROVIDER: S-EPMC3509869 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Altered carbon dioxide metabolism and creatine abnormalities in rett syndrome.

Halbach Nicky S J NS Smeets Eric E J EE Bierau Jörgen J Keularts Irene M L W IM Plasqui Guy G Julu Peter O O PO Engerström Ingegerd Witt IW Bakker Jaap A JA Curfs Leopold M G LM

JIMD reports 20110928

Despite their good appetite, many females with Rett syndrome (RTT) meet the criteria for moderate to severe malnutrition. Although feeding difficulties may play a part in this, other constitutional factors such as altered metabolic processes are suspected. Irregular breathing is a common clinical feature, leading to chronic respiratory alkalosis or acidosis. We assumed that these changes in intracellular pH cause disturbances in the metabolic equilibrium, with important nutritional consequences. ...[more]

PMID: 23430883

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Project description:BackgroundThe human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status.ResultsOur findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida. We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles.ConclusionsWe demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology.

Project description:BackgroundRett syndrome (RS) is the leading cause of profound mental retardation of genetic origin in girls. Since RS is mostly caused by mutations in the MECP2 gene, transgenic animal models such as the Mecp2-deleted ("Mecp2-null") mouse have been employed to study neurological symptoms and brain function. However, an interdisciplinary approach drawing from chemistry, biology and neuroscience is needed to elucidate the mechanistic links between the genotype and phenotype of this genetic disorder.Methodology/principal findingsWe performed, for the first time, a metabolomic study of brain extracts from Mecp2-null mice by using high-resolution magnetic resonance spectroscopy. A large number of individual water-soluble metabolites and phospholipids were quantified without prior selection for specific metabolic pathways. Results were interpreted in terms of Mecp2 gene deletion, brain cell function and brain morphology. This approach provided a "metabolic window" to brain characteristics in Mecp2-null mice (n = 4), revealing (i) the first metabolic evidence of astrocyte involvement in RS (decreased levels of the astrocyte marker, myo-inositol, vs. wild-type mice; p = 0.034); (ii) reduced choline phospholipid turnover in Mecp2-null vs. wild-type mice, implying a diminished potential of cells to grow, paralleled by globally reduced brain size and perturbed osmoregulation; (iii) alterations of the platelet activating factor (PAF) cycle in Mecp2-null mouse brains, where PAF is a bioactive lipid acting on neuronal growth, glutamate exocytosis and other processes; and (iv) changes in glutamine/glutamate ratios (p = 0.034) in Mecp2-null mouse brains potentially indicating altered neurotransmitter recycling.Conclusions/significanceThis study establishes, for the first time, detailed metabolic fingerprints of perturbed brain growth, osmoregulation and neurotransmission in a mouse model of Rett syndrome. Combined with morphological and neurological findings, these results are crucial elements in providing mechanistic links between genotype and phenotype of Rett syndrome. Ultimately, this information can be used to identify novel molecular targets for pharmacological RS treatment.

Dataset Information

Altered carbon dioxide metabolism and creatine abnormalities in rett syndrome.

Publications

Altered carbon dioxide metabolism and creatine abnormalities in rett syndrome.

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