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Journal of the Formosan Medical... Dec 2019Patients with Rett syndrome (RTT) present characteristic regression in communication and hand skills, which eventually leads to intellectual and physical disability....
BACKGROUND
Patients with Rett syndrome (RTT) present characteristic regression in communication and hand skills, which eventually leads to intellectual and physical disability. Moreover, caregivers of patients with RTT face stressors related to patients' medical and developmental concerns. Given the indications from case reports, this pilot study investigated the effectiveness of music therapy on RTT patients, as well as on parental stress for families of children with RTT.
METHODS
Families in the study group were enrolled in a twice-weekly 120-minute music therapy program for 24 weeks (n = 11), whereas families in the control group did not receive music therapy (n = 12). Participants were administered the Vineland Adaptive Behavior Scales, Rett Syndrome Clinical Severity Scale, Rett Syndrome Motor Behavioral Assessment, and Parenting Stress Index for caregivers of RTT children before and after the music therapy program.
RESULTS
Music therapy improved receptive language, verbal and non-verbal communication skills, and social interaction for RTT patients. In addition, purposeful hand function, breathing patterns, and eye contact were significantly improved. Of note, music therapy also decreased the frequency of epileptic seizures. Lastly, caregivers in the study group exhibited significantly lower stress following the program.
CONCLUSION
The 24-week music therapy program was effective in improving social interaction, communication skills, eye contact, hand function, and reducing seizure frequency among RTT patients. Additionally, music therapy was effective in relieving parenting stress, which may help healthcare providers initiate early intervention strategies that can prevent parenting stress and reduce the risk of depression.
Topics: Adolescent; Adult; Caregivers; Child; Child, Preschool; Epilepsy; Family; Female; Humans; Male; Music Therapy; Neuropsychological Tests; Pilot Projects; Rett Syndrome; Stress, Psychological; Treatment Outcome; Young Adult
PubMed: 30670340
DOI: 10.1016/j.jfma.2019.01.001 -
Neuroscience and Biobehavioral Reviews Mar 2019Rett syndrome (RTT) is an X-linked genetic disorder that occurs predominantly in females. The clinical picture associated with RTT is defined by core and supportive... (Review)
Review
Rett syndrome (RTT) is an X-linked genetic disorder that occurs predominantly in females. The clinical picture associated with RTT is defined by core and supportive consensus criteria, with a period of behavioural regression being a conditio sine qua non. This review sheds light on atypical neurofunctions and potential behavioural biomarkers before the onset of regression. The main focus lies on (a) motor development, especially on purposeful hand movements and the occurrence of stereotypies; and (b) speech-language and socio-communicative development. We outline potentially specific atypical behavioural patterns in these domains (e.g., vocalisations on inspiratory airstream) and different developmental traits of regression: (i) non-achievement of certain milestones: 'regression', here, might point to the fact that the lack of respective behavioural patterns appeared more and more worrisome with increasing age; and (ii) developmental milestones were achieved and functions deteriorate or even get lost during regression. To conclude, we are not quite there yet, but seem to be on the right track towards defining new and reliable neurofunctional markers for early detection of RTT.
Topics: Communication Disorders; Humans; Nonverbal Communication; Phenotype; Rett Syndrome; Social Behavior; Stereotyped Behavior
PubMed: 30832924
DOI: 10.1016/j.neubiorev.2019.01.028 -
Neuropsychopharmacology : Official... Jan 2013Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator of gene expression that is an important epigenetic factor in the maintenance and development of the... (Review)
Review
Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator of gene expression that is an important epigenetic factor in the maintenance and development of the central nervous system. The neurodevelopmental disorders Rett syndrome and MECP2 duplication syndrome arise from loss-of-function and gain-of-function alterations in MeCP2 expression, respectively. Several animal models have been developed to recapitulate the symptoms of Rett syndrome and MECP2 duplication syndrome. Cell morphology, neurotransmission, and cellular processes that support learning and memory are compromised as a result of MeCP2 loss- or gain-of-function. Interestingly, loss-of-MeCP2 function and MeCP2 overexpression trigger diametrically opposite changes in synaptic transmission. These findings indicate that the precise regulation of MeCP2 expression is a key requirement for the maintenance of synaptic and neuronal homeostasis and underscore its importance in central nervous system function. This review highlights the functional role of MeCP2 in the brain as a regulator of synaptic and neuronal plasticity as well as its etiological role in the development of Rett syndrome and MECP2 duplication syndrome.
Topics: Animals; Humans; Methyl-CpG-Binding Protein 2; Neuronal Plasticity; Rett Syndrome; Synapses; Synaptic Transmission
PubMed: 22781840
DOI: 10.1038/npp.2012.116 -
Journal of Pediatric Gastroenterology... Jun 2019We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and...
OBJECTIVE
We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and women with Rett syndrome (RTT).
METHODS
Sixty-two individuals with RTT and biliary tract disease were identified from the membership of Rett Syndrome Organization and patient files of the principal investigator. Medical records of 46 individuals were reviewed for presenting features, diagnostic tests, and treatment outcomes of biliary tract disease. We designed a questionnaire that probed the frequency of risk factors and treatment outcomes of biliary tract disease in RTT. The questionnaire was completed by 271 parents whose daughters met the clinical criteria for RTT and/or had MECP2 mutations and participated in the Natural History of Rett Syndrome Study.
RESULTS
Presenting symptoms identified by record review included abdominal pain (94%), irritability (88%), weight loss (64%), and vomiting (52%). Biliary dyskinesia, cholecystitis, and cholelithiasis were identified in 90%, 77%, and 70%, respectively, by cholescintigraphy, surgical pathology, and abdominal ultrasound. The prevalence of biliary tract disease was 4.4% (n = 12) in the RTT cohort. Risk factors included older age (P < 0.001) and a positive family history (P < 0.01). Diagnoses included cholecystitis (n = 5), biliary dyskinesia (n = 6), and cholelithiasis (n = 7). Ten individuals underwent surgery; 7 had resolution of symptoms after surgical intervention.
CONCLUSIONS
Biliary tract disease is not unique to RTT, but may be under-recognized because of the cognitive impairment of affected individuals. Early diagnostic evaluation and intervention may improve the health and quality of life of individuals affected with RTT and biliary tract disease.
Topics: Adolescent; Biliary Tract Diseases; Child; Female; Humans; Methyl-CpG-Binding Protein 2; Mutation; Prevalence; Prospective Studies; Retrospective Studies; Rett Syndrome; Risk Factors; Surveys and Questionnaires; Young Adult
PubMed: 30664568
DOI: 10.1097/MPG.0000000000002273 -
Psychiatry and Clinical Neurosciences Dec 2021This systematic review identified and thematically appraised clinical evidence of movement disorders in patients with Rett syndrome (RTT). (Review)
Review
AIM
This systematic review identified and thematically appraised clinical evidence of movement disorders in patients with Rett syndrome (RTT).
METHOD
Using PRISMA criteria, six electronic databases were searched from inception to April 2021. A thematic analysis was then undertaken on the extracted data to identify potential themes.
RESULTS
Following the thematic analysis, six themes emerged: (i) clinical features of abnormal movement behaviors; (ii) mutational profile and its impact on movement disorders; (iii) symptoms and stressors that impact on movement disorders; (iv) possible underlying neurobiological mechanisms; (v) quality of life and movement disorders; and (vi) treatment of movement disorders. Current guidelines for managing movement disorders in general were then reviewed to provide possible treatment recommendations for RTT.
CONCLUSION
Our study offers an enriched data set for clinical investigations and treatment of fine and gross motor issues in RTT. A detailed understanding of genotype-phenotype relationships of movement disorders allows for more robust genetic counseling for families but can also assist healthcare professionals in terms of monitoring disease progression in RTT. The synthesis also showed that environmental enrichment would be beneficial for improving some aspects of movement disorders. The cerebellum, basal ganglia, alongside dysregulation of the cortico-basal ganglia-thalamo-cortical loop, are likely anatomical targets. A review of treatments for movement disorders also helped to provide recommendations for treating and managing movement disorders in patients with RTT.
Topics: Animals; Humans; Movement Disorders; Mutation; Quality of Life; Rett Syndrome
PubMed: 34472659
DOI: 10.1111/pcn.13299 -
Boletin Medico Del Hospital Infantil de... 2023CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism...
BACKGROUND
CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants.
CASE REPORTS
We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations.
CONCLUSIONS
CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.
Topics: Humans; Female; Autism Spectrum Disorder; Spasms, Infantile; Epilepsy; Rett Syndrome
PubMed: 37490689
DOI: 10.24875/BMHIM.22000100 -
Genes, Brain, and Behavior Jan 2022Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein...
Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Although no disease-modifying therapies exist at this time, some proposed therapeutic strategies aim to supplement the mutant allele with a wild-type allele producing typical levels of functional MeCP2, such as gene therapy. Because MECP2 is a dosage-sensitive gene, with both loss and gain of function causing disease, these approaches must achieve a narrow therapeutic window to be both safe and effective. While MeCP2 supplementation rescues RTT-like phenotypes in mouse models, the tolerable threshold of MeCP2 is not clear, particularly for partial loss-of-function mutations. We assessed the safety of genetically supplementing full-length human MeCP2 in the context of the R294X allele, a common partial loss-of-function mutation retaining DNA-binding capacity. We assessed the potential for adverse effects from MeCP2 supplementation of a partial loss-of-function mutant and the potential for dominant negative interactions between mutant and full-length MeCP2. In male hemizygous R294X mice, MeCP2 supplementation rescued RTT-like behavioral phenotypes and did not elicit behavioral evidence of excess MeCP2. In female heterozygous R294X mice, RTT-specific phenotypes were similarly rescued. However, MeCP2 supplementation led to evidence of excess MeCP2 activity in a motor coordination assay, suggesting that the underlying motor circuitry is particularly sensitive to MeCP2 dosage in females. These results show that genetic supplementation of full-length MeCP2 is safe in males and largely so females. However, careful consideration of risk for adverse motor effects may be warranted for girls and women with RTT.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Female; Genetic Therapy; Humans; Loss of Function Mutation; Male; Mice; Mice, Inbred C57BL; Rett Syndrome
PubMed: 33942492
DOI: 10.1111/gbb.12739 -
Journal of Medical Genetics Jan 2022Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about...
BACKGROUND
Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about the phenotype of adult individuals with Rett syndrome is available, and mainly relies on questionnaires completed by caregivers. Here, we assess the clinical manifestations and management of adult patients with Rett syndrome and present our experience in transitioning from the paediatric to the adult clinic.
METHODS
We analysed the medical records and molecular data of women aged ≥18 years with a diagnosis of classic Rett syndrome and/or pathogenic variants in , and , who were in charge of our clinic.
RESULTS
Of the 50 women with classic Rett syndrome, 94% had epilepsy (26% drug-resistant), 20% showed extrapyramidal signs, 40% sleep problems and 36% behavioural disorders. Eighty-six % patients exhibited gastrointestinal problems; 70% had scoliosis and 90% low bone density. Breathing irregularities were diagnosed in 60%. None of the patients had cardiac issues. CDKL5 patients experienced fewer breathing abnormalities than women with classic Rett syndrome.
CONCLUSION
The delineation of an adult phenotype in Rett syndrome demonstrates the importance of a transitional programme and the need of a dedicated multidisciplinary team to optimise the clinical management of these patients.
Topics: Adult; Epilepsy; Female; Forkhead Transcription Factors; Humans; Methyl-CpG-Binding Protein 2; Middle Aged; Mutation; Nerve Tissue Proteins; Phenotype; Protein Serine-Threonine Kinases; Rett Syndrome; Scoliosis; Sleep Wake Disorders; Young Adult
PubMed: 33106377
DOI: 10.1136/jmedgenet-2020-107333 -
Scientific Data Jan 2021Rett syndrome (RTT) is a rare neurological disorder mostly caused by a genetic variation in MECP2. Making new MECP2 variants and the related phenotypes available...
Rett syndrome (RTT) is a rare neurological disorder mostly caused by a genetic variation in MECP2. Making new MECP2 variants and the related phenotypes available provides data for better understanding of disease mechanisms and faster identification of variants for diagnosis. This is, however, currently hampered by the lack of interoperability between genotype-phenotype databases. Here, we demonstrate on the example of MECP2 in RTT that by making the genotype-phenotype data more Findable, Accessible, Interoperable, and Reusable (FAIR), we can facilitate prioritization and analysis of variants. In total, 10,968 MECP2 variants were successfully integrated. Among these variants 863 unique confirmed RTT causing and 209 unique confirmed benign variants were found. This dataset was used for comparison of pathogenicity predicting tools, protein consequences, and identification of ambiguous variants. Prediction tools generally recognised the RTT causing and benign variants, however, there was a broad range of overlap Nineteen variants were identified that were annotated as both disease-causing and benign, suggesting that there are additional factors in these cases contributing to disease development.
Topics: DNA Mutational Analysis; Data Analysis; Humans; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome
PubMed: 33452270
DOI: 10.1038/s41597-020-00794-7 -
Archives of Neurology Aug 2011The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome or Down... (Comparative Study)
Comparative Study Review
The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome or Down syndrome, suggests the possibility of common neurobiologic mechanisms whose elucidation could fundamentally advance our understanding. This review explores the commonalities and differences between autism and RTT at clinical and molecular levels with respect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in the methyl-CpG-binding protein 2 gene (MECP2), which is responsible for RTT in 95% of individuals with the disorder. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important test beds for evaluating new therapies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances.
Topics: Animals; Autistic Disorder; Comorbidity; Disease Models, Animal; Humans; Methyl-CpG-Binding Protein 2; Phenotype; Rett Syndrome; Transcription, Genetic
PubMed: 21825235
DOI: 10.1001/archneurol.2011.149