Rett syndrome (RTT) is a disorder that is caused in the majority of cases by mutations in the gene methyl-CpG-binding protein-2 (MeCP2). Children with RTT are generally characterized by normal development up to the first year and a half of age, after which they undergo a rapid regression marked by a deceleration of head growth, the onset of stereotyped hand movements, irregular breathing, and seizures. Animal models of RTT with good construct and face validity are available. Their analysis showed that homeostatic regulation of MeCP2 gene is necessary for normal CNS functioning and that multiple complex pathways involving different neuronal and glial cell types are disrupted in RTT models. However, it is increasingly clear that RTT pathogenetic mechanisms converge at synaptic level impairing synaptic transmission and plasticity. We review novel findings showing how specific synaptic mechanisms and related signaling pathways are affected in RTT models.
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A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome.
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Rett Syndrome Research Trust, Trumbull, CT, USA.
Background: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.
Design: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.
Methods: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment.
Methylmalonic acidaemia masquerading as a neurodegenerative disorder.
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Paediatrics, King George's Medical College, Lucknow, Uttar Pradesh, India.
We present the case of a toddler displaying neuroregression post-acute gastroenteritis, initially suggesting neurodegenerative disorders. Further investigations showed atypical results-neuroimaging was inconsistent with suspected disorders, while fundus evaluation, evoked potentials and nerve conduction velocity were normal. Specialised tests using gas chromatography mass spectrometry and tandem mass spectrometry identified methylmalonic acidaemia (MMA), implicating abnormal neurometabolism.
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Institute of Neurobiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an City 710061, China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an City 710061, China. Electronic address:
Mutations in methyl CpG binding protein 2 (MeCP2) are linked to Rett syndrome, in which epilepsy is one of the most well-described disorders. However, little is known about the specific role of MeCP2 during epileptogenesis. Our previous study has demonstrated that MeCP2 has a unique control on the development of mossy fiber sprouting (MFS) in the epileptic hippocampus.
View Article and Find Full Text PDFIntegrated gene expression and alternative splicing analysis in human and mouse models of Rett syndrome.
Sci Rep
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Institute of Molecular Biology and Pathology, National Research Council, 00185, Rome, Italy.
Mutations of the MECP2 gene lead to Rett syndrome (RTT), a rare developmental disease causing severe intellectual and physical disability. How the loss or defective function of MeCP2 mediates RTT is still poorly understood. MeCP2 is a global gene expression regulator, acting at transcriptional and post-transcriptional levels.
View Article and Find Full Text PDFComprehensive assessment reveals numerous clinical and neurophysiological differences between MECP2-allelic disorders.
Ann Clin Transl Neurol
January 2025
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA.
Objective: Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) result from under- and overexpression of MECP2, respectively. Preclinical studies using genetic-based treatment showed robust phenotype recovery for both MDS and RTT. However, there is a risk of converting MDS to RTT, or vice versa, if accurate MeCP2 levels are not achieved.
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