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Orphanet Journal of Rare Diseases Jun 2023We refine the clinical spectrum of FOXG1 syndrome and expand genotype-phenotype correlations through evaluation of 122 individuals enrolled in an international patient...
BACKGROUND
We refine the clinical spectrum of FOXG1 syndrome and expand genotype-phenotype correlations through evaluation of 122 individuals enrolled in an international patient registry.
METHODS
The FOXG1 syndrome online patient registry allows for remote collection of caregiver-reported outcomes. Inclusion required documentation of a (likely) pathogenic variant in FOXG1. Caregivers were administered a questionnaire to evaluate clinical severity of core features of FOXG1 syndrome. Genotype-phenotype correlations were determined using nonparametric analyses.
RESULTS
We studied 122 registry participants with FOXG1 syndrome, aged < 12 months to 24 years. Caregivers described delayed or absent developmental milestone attainment, seizures (61%), and movement disorders (58%). Participants harbouring a missense variant had a milder phenotype. Compared to individuals with gene deletions (0%) or nonsense variants (20%), missense variants were associated with more frequent attainment of sitting (73%). Further, individuals with missense variants (41%) achieved independent walking more frequently than those with gene deletions (0%) or frameshift variants (6%). Presence of epilepsy also varied by genotype and was significantly more common in those with gene deletions (81%) compared to missense variants (47%). Individuals with gene deletions were more likely to have higher seizure burden than other genotypes with 53% reporting daily seizures, even at best control. We also observed that truncations preserving the forkhead DNA binding domain were associated with better developmental outcomes.
CONCLUSION
We refine the phenotypic spectrum of neurodevelopmental features associated with FOXG1 syndrome. We strengthen genotype-driven outcomes, where missense variants are associated with a milder clinical course.
Topics: Humans; Rett Syndrome; Genotype; Seizures; Frameshift Mutation; Registries; Nerve Tissue Proteins; Forkhead Transcription Factors
PubMed: 37308910
DOI: 10.1186/s13023-023-02745-y -
European Journal of Paediatric... Jul 2022The aim of the study was to identify and characterize outcome measures for objective and subjective assessment in persons with Rett syndrome (RS). (Review)
Review
OBJECTIVE
The aim of the study was to identify and characterize outcome measures for objective and subjective assessment in persons with Rett syndrome (RS).
METHODS
A systematic review was conducted consulting the EBSCO, Cochrane, Web of Science, Scielo, MEDLINE and PsycINFO databases for published studies describing the use of patient-reported outcome measures (PROMs) and other outcome measures in persons with RS. Validation studies and observational studies were included. The PROMs were first described, and then the measurement properties were evaluated using predefined criteria according to the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN). The outcome measures were then grouped according to the International Classification of Functioning, Disability and Health (ICF) to establish a relationship between outcome measures and ICF domains.
RESULTS
Twenty out of 2327 articles were appraised, and seventeen different outcome measures were identified and described. Ten outcome measures corresponded to evaluation questionnaires, while the remaining seven assessed functional outcomes: walking distance, physical activity level and ability to interact visually. A relation between these outcome measures that assess RS and the ICF allows understanding that most of the instruments (fifteen) include the assessment of activity limitations.
CONCLUSIONS
The findings of this study seem to be promising for their use by clinicians and researchers, although they have methodological limitations. The accuracy and quality of these individual outcome measures should continue to be assessed in an attempt to gather a consensus on the best tools used in RS.
Topics: Consensus; Humans; Outcome Assessment, Health Care; Psychometrics; Quality of Life; Rett Syndrome; Surveys and Questionnaires
PubMed: 35717810
DOI: 10.1016/j.ejpn.2022.06.003 -
Human Molecular Genetics Dec 2023MeCP2 (Methyl CpG binding protein 2) is an intrinsically disordered protein that binds to methylated genome regions. The protein is a critical transcriptional regulator... (Review)
Review
MeCP2 (Methyl CpG binding protein 2) is an intrinsically disordered protein that binds to methylated genome regions. The protein is a critical transcriptional regulator of the brain, and its mutations account for 95% of Rett syndrome (RTT) cases. Early studies of this neurodevelopmental disorder revealed a close connection with dysregulations of the ubiquitin system (UbS), notably as related to UBE3A, a ubiquitin ligase involved in the proteasome-mediated degradation of proteins. MeCP2 undergoes numerous post-translational modifications (PTMs), including ubiquitination and sumoylation, which, in addition to the potential functional outcomes of their monomeric forms in gene regulation and synaptic plasticity, in their polymeric organization, these modifications play a critical role in proteasomal degradation. UbS-mediated proteasomal degradation is crucial in maintaining MeCP2 homeostasis for proper function and is involved in decreasing MeCP2 in some RTT-causing mutations. However, regardless of all these connections to UbS, the molecular details involved in the signaling of MeCP2 for its targeting by the ubiquitin-proteasome system (UPS) and the functional roles of monomeric MeCP2 ubiquitination and sumoylation remain largely unexplored and are the focus of this review.
Topics: Humans; Methyl-CpG-Binding Protein 2; Sumoylation; Proteasome Endopeptidase Complex; Rett Syndrome; Ubiquitination; Ubiquitin
PubMed: 37694858
DOI: 10.1093/hmg/ddad150 -
Cells May 2023Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 () cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to...
Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 () cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a 'Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein-protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes. Functional enrichment analysis of RTT and RTT-L genes identified a number of intuitive biological processes. We also identified transcription factors (TFs) whose binding sites are common across the set of RTT and RTT-L genes and appear as important regulatory motifs for them. Investigation of the most significant over-represented pathway analysis suggests that HDAC1 and CHD4 likely play a central role in the interactome between RTT and RTT-L genes.
Topics: Humans; Rett Syndrome; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Transcription Factors; Neurodevelopmental Disorders
PubMed: 37408271
DOI: 10.3390/cells12101437 -
International Journal of Molecular... Aug 2019In this narrative review, we summarize recent pieces of evidence of the role of microbiota alterations in Rett syndrome (RTT). Neurological problems are prominent... (Review)
Review
In this narrative review, we summarize recent pieces of evidence of the role of microbiota alterations in Rett syndrome (RTT). Neurological problems are prominent features of the syndrome, but the pathogenic mechanisms modulating its severity are still poorly understood. Gut microbiota was recently demonstrated to be altered both in animal models and humans with different neurodevelopmental disorders and/or epilepsy. By investigating gut microbiota in RTT cohorts, a less rich microbial community was identified which was associated with alterations of fecal microbial short-chain fatty acids. These changes were positively correlated with severe clinical outcomes. Indeed, microbial metabolites can play a crucial role both locally and systemically, having dynamic effects on host metabolism and gene expression in many organs. Similar alterations were found in patients with autism and down syndrome as well, suggesting a potential common pathway of gut microbiota involvement in neurodevelopmental disorders.
Topics: Animals; Biodiversity; Dysbiosis; Gastrointestinal Microbiome; Humans; Metagenome; Metagenomics; Neurodevelopmental Disorders; Phenotype; Rett Syndrome
PubMed: 31454888
DOI: 10.3390/ijms20174160 -
Genes Dec 2023Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders...
Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders underscore the conceptual dose-dependent risk posed by gene therapy for mosaic RTT patients. Recently, a miRNA-Responsive Autoregulatory Element (miRARE) mitigated the dose-dependent toxicity posed by self-complementary adeno-associated viral vector serotype 9 (AAV9) mini gene therapy (scAAV9/mini) in mice. Here, we report an efficacy assessment for the human-ready version of this regulated gene therapy (TSHA-102) in male knockout (KO) mice after intracerebroventricular (ICV) administration at postnatal day 2 (P2) and after intrathecal (IT) administration at P7, P14 (±immunosuppression), and P28 (±immunosuppression). We also report qPCR studies on KO mice treated at P7-P35; protein analyses in KO mice treated at P38; and a survival safety study in female adult mice. In KO mice, TSHA-102 improved respiration, weight, and survival across multiple doses and treatment ages. TSHA-102 significantly improved the front average stance and swing times relative to the front average stride time after P14 administration of the highest dose for that treatment age. Viral genomic DNA and mini mRNA were present in the CNS. MiniMeCP2 protein expression was higher in the KO spinal cord compared to the brain. In female mice, TSHA-102 permitted survivals that were similar to those of vehicle-treated controls. In all, these pivotal data helped to support the regulatory approval to initiate a clinical trial for TSHA-102 in RTT patients (clinical trial identifier number NCT05606614).
Topics: Adult; Humans; Female; Male; Animals; Mice; Rett Syndrome; MicroRNAs; Mental Retardation, X-Linked; Brain; DNA, Viral; Genetic Therapy; Mice, Knockout
PubMed: 38254921
DOI: 10.3390/genes15010031 -
International Journal of Molecular... May 2023This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies,... (Review)
Review
This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.
Topics: Humans; Rett Syndrome; Gene Editing; Tissue Distribution; Methyl-CpG-Binding Protein 2; Brain; Genetic Therapy
PubMed: 37240368
DOI: 10.3390/ijms24109023 -
Protein & Cell Aug 2021Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W...
Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development.
Topics: Action Potentials; Base Sequence; Cell Differentiation; Fibroblasts; Gene Dosage; Gene Expression; Gene Knockdown Techniques; Genetic Complementation Test; Human Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Methyl-CpG-Binding Protein 2; Neural Stem Cells; Neurons; Phenotype; Primary Cell Culture; Prosencephalon; Rett Syndrome; Severity of Illness Index; Synaptic Transmission
PubMed: 32851591
DOI: 10.1007/s13238-020-00773-z -
Developmental Medicine and Child... Aug 2019To describe a new clinical tool, the Rett Syndrome Motor Evaluation Scale (RESMES) and to assess (loco-)motor function in people with Rett syndrome (RTT).
AIM
To describe a new clinical tool, the Rett Syndrome Motor Evaluation Scale (RESMES) and to assess (loco-)motor function in people with Rett syndrome (RTT).
METHOD
Formal assessment provided by physicians was followed by parents' direct observation at home using the RESMES. Sixty females (mean [SD] age 12y 5mo [8y 9mo], range 3-40y) with a clinical diagnosis and genetically determined RTT participated in the study. Spearman's/Pearson's coefficients assessed the correlation between the clinicians' and caregivers' evaluations, as well as the correlation of RESMES scores with other scales, namely the Pain Assessment in Advanced Dementia, the Rett Assessment Rating Scale, the Modified Ashworth Scale, and hand function (assessed with a scale of evaluation of purposeful hand function). Scores provided by parents and clinicians were tested statistically by Mann-Whitney U test.
RESULTS
Approximately 88% of patients had moderate to severe RTT symptoms and, on average, moderate motor impairment based on the RESMES. RESMES total scores provided by clinicians and caregivers were highly correlated (r=0.91), as were the subscale scores. Postural transition was a critical area of the RESMES, where parents systematically provided lower scores than clinicians, indicating milder degrees of disability. Severity of scoliosis and mutation type emerged as significant predictors of motor function.
INTERPRETATION
The RESMES characterized the (loco-)motor impairments of the patients with RTT well. It also showed a close correlation between the evaluations of clinicians and caregivers, with the possible exception of postural transition tasks, which should be carefully addressed in a clinical setting. The type of mutation and presence of scoliosis should be evaluated, as they predicted the ability to walk.
WHAT THIS PAPER ADDS
Caregivers at home can reliably assess motor function in Rett syndrome using the Rett Syndrome Motor Evaluation Scale (RESMES). RESMES scores provided by clinicians and parents were highly correlated. The severity of scoliosis and the genetic mutation predicted standing and walking abilities.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Motor Skills; Parents; Postural Balance; Rett Syndrome; Severity of Illness Index; Walking; Young Adult
PubMed: 30474854
DOI: 10.1111/dmcn.14109 -
Intellectual and Developmental... Feb 2020There are no published studies describing educational experiences for girls with Rett syndrome. Given the extensive educational needs associated with Rett syndrome, it...
There are no published studies describing educational experiences for girls with Rett syndrome. Given the extensive educational needs associated with Rett syndrome, it is important to understand how families perceive their daughters' educational experiences to inform education service provision. The purpose of this study was to survey parents of school-aged children with Rett syndrome to describe the educational services that they receive and understand parents' perceptions of and satisfaction with the special educational and related services. The majority of parents were satisfied with their daughters' educational services. Communication was the most frequently endorsed priority skill area, and many parents expressed frustration with limited access to augmentative and alternative communication (AAC) devices and staff training in their use. These results suggest there is a need for high-quality speech therapy and an emphasis on AAC support.
Topics: Adolescent; Child; Child, Preschool; Education of Intellectually Disabled; Female; Humans; Parents; Personal Satisfaction; Rett Syndrome
PubMed: 32011225
DOI: 10.1352/1934-9556-58.1.49