Altered Carbon Dioxide Metabolism and Creatine Abnormalities in Rett Syndrome

Halbach, Nicky S. J.; Smeets, Eric; Bierau, Jörgen; Keularts, Irene M. L. W.; Plasqui, Guy; Julu, Peter O.O.; Engerström, Ingegerd Witt; Bakker, J.; Curfs, Leopold

doi:10.1007/8904_2011_76

Cited by 7 publications

(8 citation statements)

References 29 publications

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“…Typical noticeable laboratory results are EEG (and EKG) abnormalities, atypical brain glycolipids, altered neurotransmitter, creatine and growth factor levels, and alkalosis. Most of the symptoms can be related to disturbed neuronal function but some of them are caused or influenced by alterations which are not yet elucidated [4, 21, 22]. It is also unknown whether it is the often in RTT observed changes of carbon dioxide metabolism that cause respiratory problems or that dysfunctional brain stem neurons are responsible for breathing abnormality [4].…”

Section: Rett Syndrome Phenotype Development Within Lifementioning

confidence: 99%

“…The BDNF molecular pathway and its influence on neuronal development and function is currently the best investigated. For GAMT it is known that this gene is involved in creatine metabolic and biosynthetic process which was found to be dysregulated in some (not all) Rett females and may cause or consequence to breathing problems [4]. DLX5 and DLX6 are homeobox genes and involved in regulation of gene expression in general.…”

Section: The Most Important Metabolites Genes and Pathways Affected mentioning

confidence: 99%

“…1) Breathing patterns: breathing is regulated by brain stem function which gets its signals from receptors for blood pH, carbon dioxide and (to a lower amount) oxygen levels. Abnormal RTT breathing patterns could be caused by neuronal dysfunction of the brain stem or neuronal pathways but metabolic dysregulation involving abnormal creatine levels due to GAMT over/under expression is also an influencing factor [4]. GAMT is one of the MECP2 downstream activated genes.…”

Section: Current Gaps In Understanding Rtt Pathwaysmentioning

confidence: 99%

“…It is considered a rare disease since it affects fewer than 1 in 2000 individuals [2], but it is still one of the most abundant causes for intellectual disability in females. RTT was first described in 1966 by the Viennese pediatric Andreas Rett, who observed the typical hand movements (“hand washing”) of his patients [3, 4]. Cause of RTT is in most cases a de novo mutation of MECP2 (methyl-CpG-binding protein 2) gene; which was discovered by Amir et al [5].…”

Section: Introductionmentioning

confidence: 99%

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Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

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Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6–18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.

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Section: Rett Syndrome Phenotype Development Within Lifementioning

confidence: 99%

Section: The Most Important Metabolites Genes and Pathways Affected mentioning

confidence: 99%

Section: Current Gaps In Understanding Rtt Pathwaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

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“…It may be a major determinant of the quality of daily life of the female and her family [Julu and Witt Engerström, ; Smeets et al, ; Halbach et al, , ; Julu et al, ; Tarquinio et al, ]. Neurophysiological research has established three cardiorespiratory phenotypes in RTT (forceful, feeble, and apneustic breathers), and their clinical relevance [Julu and Witt Engerström, ; Smeets et al, ; Julu et al, ; Halbach et al, ].…”

Section: Introductionmentioning

confidence: 99%

Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study

Halbach

Smeets

Julu

et al. 2016

American J of Med Genetics Pt A

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Many studies have attempted to establish the genotype–phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well‐defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype–phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non‐invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence‐based management in RTT. © 2016 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

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