====== Rett syndrome ====== {{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1TAHVG_L--C4I5mkYLxFdHBnGOfUbcjKHIE_g8fNIFvLagCgBZ/?limit=15&utm_campaign=pubmed-2&fc=20230119025252}} ---- ---- Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of methyl CpG-binding protein 2 (MECP2) on the X chromosome in young females. Originally termed cerebroatrophic hyperammonemia, is a rare genetic postnatal neurological disorder of the [[grey matter]] of the brain that almost exclusively affects [[female]]s but has also been found in male patients. The signs of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy and autism. ====Epidemiology==== Rett syndrome occurs in approximately 1:10,000 live female births in all geographies, and across all races and ethnicities. ===== Etiology ===== It was first described by Austrian pediatrician Andreas Rett in 1966. Huda Zoghbi demonstrated in 1999 that Rett syndrome is caused by mutations in the gene [[MECP2]], a protein involved in [[chromatin remodeling]] and modulation of [[RNA splicing]] ((Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56(3):422–437. )). It was removed from the DSM-5 in 2013 because this molecular etiology. ---- RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity. Hao et al show that [[deep brain stimulation of the fornix]] (forniceal DBS) in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT ((Hao S, Tang B, Wu Z, Ure K, Sun Y, Tao H, Gao Y, Patel AJ, Curry DJ, Samaco RC, Zoghbi HY, Tang J. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature. 2015 Oct 14;526(7573):430-434. doi: 10.1038/nature15694. PubMed PMID: 26469053.)). Although much interest has developed in using DBS of the fornix for memory enhancement in Alzheimer disease, this study represents the first extension of this therapeutic possibility to a mouse model of a childhood intellectual disability disorder. In this study, the investigators were able to demonstrate that DBS of the fornix not only enhances contextual memory formation and retrieval in a mouse model of Rett syndrome but also achieves this effect through modulation of synaptic plasticity and neurogenesis, providing additional evidence in support of 2 mechanisms that have been proposed as potential modes of action of DBS in numerous preclinical studies.15,16 Additionally, the stimulation effects seen in this study were achieved with intermittent rather than continuous stimulation, as is generally used in clinical practice, suggesting that therapeutic effects may be achievable for a variety of indications without continuous stimulation, resulting in prolonged battery life and lower risk of unintended stimulation effects. Finally, the findings of this study demonstrate the ability of high-frequency DBS to modulate the activity of complex neural circuits. This finding suggests that DBS may provide a more efficient way of modulating downstream effects of mutated gene products that may not be adequately addressed by available pharmacotherapeutics ((Russo JF, Sheth SA, McKhann GM 2nd. Using Deep Brain Stimulation to Rescue Memory in Rett Syndrome. Neurosurgery. 2016 Feb;78(2):N16-7. doi: 10.1227/01.neu.0000479892.25489.0e. PubMed PMID: 26779794.)) ---- Application of high-frequency deep brain stimulation (DBS) has been shown to have the potential to reverse pathological changes and to rescue contextual memory formation ((Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001;410(6826):372–376.)) ((Stuchlik A. Dynamic learning and memory, synaptic plasticity and neurogenesis: an update. Front Behav Neurosci. 2014;8:106.)) ((Toda H, Hamani C, Fawcett AP, Hutchison WD, Lozano AM. The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg. 2008;108(1):132–138.)) ((Encinas JM, Hamani C, Lozano AM, Enikolopov G. Neurogenic hippocampal targets of deep brain stimulation. J Comp Neurol. 2011;519(1):6–20.)) ((Stone SS, Teixeira CM, DeVito LM, et al.. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci. 2011;31(38):13469–13484.)). ===== Clinical features ===== The clinical features include small [[hand]]s and feet and a deceleration of the rate of head growth (including [[microcephaly]] in some). Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted. People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures. They typically have no verbal skills, and about 50% of affected individuals do not walk. Scoliosis, growth failure, and constipation are very common and can be problematic. ===== Treatment ===== It was found that the 12-month multifaceted neurological physiotherapy intervention had statistically significant improvements in both Gross Motor Function Measure 88 (p = 0.005) and Rett syndrome Gross Motor Scale (p = 0.012). Despite positive improvements, the absence of control group made it difficult for a comparative evaluation to determine what interventions had the best possible outcomes. The quantitative research demonstrates neuro-developmental treatment sessions, hippotherapy, hydrotherapy, physical therapy, a walking program, endurance exercises, active-assisted exercises, and coordination exercises, had a significant impact on improving gross motor function status. Current multifaceted intervention program leads to good improvement of gross motor skills above what can be expected from late motor deterioration ((Kapel A, Kovacic T, Kos N, Velnar T. Impact of a 12-month multifaceted neurological physiotherapy intervention on gross motor function in women with Rett syndrome. J Integr Neurosci. 2022 Mar 22;21(2):59. doi: 10.31083/j.jin2102059. PMID: 35364647.)). ---- Reactivation of the silent wild-type MECP2 allele from the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female patients with RTT. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 from Xi in RTT human embryonic stem cells (hESCs) and derived neurons. Demethylation of the MECP2 promoter by dCas9-Tet1 with target single-guide RNA reactivated MECP2 from Xi in RTT hESCs without detectable off-target effects at the transcriptional level. Neurons derived from methylation-edited RTT hESCs maintained MECP2 reactivation and reversed the smaller soma size and electrophysiological abnormalities, two hallmarks of RTT. In RTT neurons, insulation of the methylation-edited MECP2 locus by dCpf1-CTCF (a catalytically dead Cpf1 fused with CCCTC-binding factor) with target CRISPR RNA enhanced MECP2 reactivation and rescued RTT-related neuronal defects, providing a proof-of-concept study for epigenome editing to treat RTT and potentially other dominant X-linked diseases ((Qian J, Guan X, Xie B, Xu C, Niu J, Tang X, Li CH, Colecraft HM, Jaenisch R, Liu XS. Multiplex epigenome editing of MECP2 to rescue Rett syndrome neurons. Sci Transl Med. 2023 Jan 18;15(679):eadd4666. doi: 10.1126/scitranslmed.add4666. Epub 2023 Jan 18. PMID: 36652535.))