In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling ...blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families.
Alleviating the burden of rare diseases requires research into new diagnostic and therapeutic strategies. We undertook a systematic review to identify and compare the impact of stand-alone ...registries, registries with biobanks, and rare disease biobanks on research outcomes in rare diseases.
A systematic review and meta-aggregation was conducted using the preferred reporting items for systematic reviews and meta-analyses (the PRISMA statement). English language publications were sourced from PubMed, Medline, Scopus, and Web of Science. Original research papers that reported clinical, epidemiological, basic or translational research findings derived from data contained in stand-alone registries, registries with biobanks, and rare disease biobanks were considered. Articles selected for inclusion were assessed using the critical appraisal instruments by JBI-QARI. Each article was read in its entirety and findings were extracted using the online data extraction software from JBI-QARI.
Thirty studies including 28 rare disease resources were included in the review. Of those, 14 registries were not associated to biobank infrastructure, 9 registries were associated with biobank infrastructure, and 6 were rare disease biobank resources. Stand-alone registries had the capacity to uncover the natural history of disease and contributed to evidence-based practice. When annexed to biobank infrastructure, registries could also identify and validate biomarkers, uncover novel genes, elucidate pathogenesis at the Omics level, and develop new therapeutic strategies. Rare disease biobanks in this review had similar capacity for biological investigations, but in addition, had far greater sample numbers and higher quality laboratory techniques for quality assurance processes.
We examined the research outcomes of three specific populations: stand-alone registries, registries with biobanks, and stand-alone rare disease biobanks and demonstrated that there are key differences among these resources. These differences are a function of the resources' design, aims, and objectives, with each resource having a distinctive and important role in contributing to the body of knowledge for rare disease research. Whilst stand-alone registries had the capacity to uncover the natural history of disease, develop best practice, replace clinical trials, and improve patient outcomes, they were limited in their capacity to conduct basic research. The role of basic research in rare disease research is vital; scientists must first understand the pathways of disease before they can develop appropriate interventions. Rare disease biobanks, on the other hand (particularly larger biobanks), had the key infrastructure required to conduct basic research, making novel Omics discoveries, identify and validate biomarkers, uncover novel genes, and develop new therapeutic strategies. However, these stand-alone rare disease biobanks did not collect comprehensive data or impact on clinical observations like a rare disease registry. Rare disease research is important not only for rare diseases, but also for also common diseases. For example, research of low-density lipoprotein (LDL)-receptors in the rare disease known as familial hypercholesterolemia led to the discovery of statins, a drug therapy that is now used routinely to prevent heart disease.
Rare diseases are still under-researched worldwide. This review made the important observation that registries with biobanks had the function of both stand-alone registries (the capacity to collect comprehensive clinical and epidemiological data) and stand-alone rare disease biobanks (the ability to contribute to Omics research). We found registries with biobanks offer a unique, practical, cost-effective, and impactful solution for rare disease research. Linkage of stand-alone registries to rare disease biobanks will provide the appropriate resources required for the effective translation of basic research into clinical practice. Furthermore, facilitators such as collaboration, engagement, blended recruitment, pro-active marketing, broad consent, and "virtual biobank" online catalogues will, if utilised, add to the success of these resources. These important observations can serve to direct future rare diseases research efforts, ultimately improve patient outcomes and alleviate the significant burden associated with rare disease for clinicians, hospitals, society, and most importantly, the patients and their families.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder caused by a duplication of the methyl-CpG-binding protein 2 (MECP2) gene-a gene in which loss-of-function mutations ...lead to Rett syndrome (RTT). MDS has an estimated live birth prevalence in males of 1/150,000. The key features of MDS include intellectual disability, developmental delay, hypotonia, seizures, recurrent respiratory infections, gastrointestinal problems, behavioural features of autism and dysmorphic features-although these comorbidities are not yet understood with sufficient granularity. This review has covered the past two decades of MDS case studies and series since the discovery of the disorder in 1999. After comprehensively reviewing the reported characteristics, this review has identified areas of limited knowledge that we recommend may be addressed by better phenotyping this disorder through an international data collection. This endeavour would also serve to delineate the clinical overlap between MDS and RTT.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Rett syndrome is caused by a pathogenic mutation in the MECP2 gene with major consequences for motor and cognitive development. One of the effects of impaired MECP2 function is reduced production of ...Brain Derived Neurotrophic Factor (BDNF), a protein required for normal neuronal development. When housed in an enriched environment, MECP2 null mice improved motor abilities and increased levels of BDNF in the brain. We investigated the effects of environmental enrichment on gross motor skills and blood BDNF levels in girls with Rett syndrome.
A genetically variable group of 12 girls with a MECP2 mutation and younger than 6 years participated in a modified individually randomised stepped wedge design study. Assessments were conducted on five occasions, two during the baseline period and three during the intervention period. Gross motor function was assessed using the Rett Syndrome Gross Motor Scale (maximum score of 45) on five occasions, two during the baseline period and three during the intervention period. Blood levels of BDNF were measured at the two baseline assessments and at the end of the intervention period. The intervention comprised motor learning and exercise supplemented with social, cognitive and other sensory experiences over a six-month period.
At the first assessment, the mean (SD) age of the children was 3 years (1 year 1 month) years ranging from 1 year 6 months to 5 years 2 months. Also at baseline, mean (SD) gross motor scores and blood BDNF levels were 22.7/45 (9.6) and 165.0 (28.8) ng/ml respectively. Adjusting for covariates, the enriched environment was associated with improved gross motor skills (coefficient 8.2, 95%CI 5.1, 11.2) and a 321.4 ng/ml (95%CI 272.0, 370.8) increase in blood BDNF levels after 6 months of treatment. Growth, sleep quality and mood were unaffected.
Behavioural interventions such as environmental enrichment can reduce the functional deficit in Rett syndrome, contributing to the evidence-base for management and further understanding of epigenetic mechanisms. Environmental enrichment will be an important adjunct in the evaluation of new drug therapies that use BDNF pathways because of implications for the strengthening of synapses and improved functioning.
ACTRN12615001286538 .
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•This is the first study to describe the use of VNS in CDKL5 Deficiency Disorder.•One in six of our study population of over 200 patients received VNS treatment.•Improvement in seizure activity was ...reported for over two thirds of those treated.
Variants within the CDKL5 gene result in a severe epileptic encephalopathy now known as the CDKL5 Deficiency Disorder. Phenotypic characteristics include global developmental delay and early seizure onset with poor response to anti-epileptic medications. Vagus nerve stimulation (VNS) has been used in other populations as an adjunct treatment for refractory epilepsy with seizure reduction reported in over half of patients. This study aimed to investigate the role of VNS in the CDKL5 Deficiency Disorder.
The International CDKL5 Disorder Database collects information on individuals with the CDKL5 Deficiency Disorder. Families provide information regarding seizure characteristics and their pharmaceutical and non-pharmaceutical management including VNS use. Descriptive statistics and time to event analyses were performed. Clinical vignettes were also provided from patients attending the CDKL5 Center of Excellence at Children’s Hospital Colorado.
Individuals who had a pathogenic CDKL5 variant and on whom information regarding VNS treatment was available were identified (n = 222). Previous or current use of VNS was reported for 38 (17.1%), with a median age at implantation of 4.9 years. Improvements in seizure control were reported in over two-thirds (25/36, 69%); including reduction in frequency (17/25, 68%), duration (18/25, 72%) and intensity (15/25, 60%) of seizures. Median duration of VNS use before any seizure improvement was 73 days. Behavioural changes such as improved mood and alertness were reported in nine individuals. Early termination of VNS secondary to side effects was reported in three cases. There was no reduction in number of AEDs for those with VNS treatment.
Our study suggests that VNS is a generally safe and effective adjunct treatment for CDKL5-associated epilepsy. Additional benefits such as mood and behavioural improvements provide further support of its use in the CDKL5 Deficiency Disorder. Future studies are required to determine the optimal settings and therapeutic potential for this treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary
Objective
Pathogenic variants involving the CDKL5 gene result in a severe epileptic encephalopathy, often later presenting with features similar to Rett syndrome. Cardinal features of ...epilepsy in the CDKL5 disorder include early onset at a median age of 6 weeks and poor response to antiepileptic drugs. The ketogenic diet (KD) was first introduced in the 1920s as a treatment option for refractory epilepsy in children. This study investigated use of the KD in the CDKL5 disorder and its influences on seizures.
Methods
The International CDKL5 Disorder Database, established in 2012, collects information on individuals with the CDKL5 disorder. Families have provided information regarding seizure characteristics, use, and side effects of the KD treatment. Descriptive statistics and time to event analyses were performed. Clinical vignettes were also provided on patients attending Boston Children's Hospital.
Results
Data regarding KD use were available for 204 individuals with a pathogenic CDKL5 variant. Median age of inclusion in the database was 4.8 years (range = 0.3–33.9 years), with median age of 6 weeks (range = 1 day–65 weeks) at seizure onset. History of KD use was reported for 51% (104 of 204) of individuals, with a median duration of use of 17 months (95% confidence interval = 9–24). Changes in seizure activity after commencing KD were reported for two‐thirds (69 of 104), with improvements in 88% (61 of 69). Nearly one‐third (31.7%) experienced side effects during the diet. At ascertainment, only one‐third (32%) remained on the diet, with lack of long‐term efficacy as the main reason for diet cessation (51%, 36 of 70).
Significance
Benefits of KD in the CDKL5 disorder are in keeping with previous trials on refractory epilepsies. However, poor long‐term efficacy remains as a significant barrier. In view of its side effect profile, KD administration should be supervised by a pediatric neurologist and specialist dietician.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Rett syndrome is associated with severe functional impairments and many comorbidities, each in urgent need of treatments. Mutations in the MECP2 gene were identified as causing Rett syndrome in 1999. ...Over the past 20 years there has been an abundance of preclinical research with some studies leading to human clinical trials. Despite this, few viable therapeutic options have emerged from this investment of effort. Reasons for this lack of success as they relate both to preclinical research and the clinical trial landscape are discussed. Considering what needs to be done to promote further success in the field, we take a positive and constructive approach and introduce the concept of clinical trial readiness and its necessary ingredients for Rett syndrome. These include: listening to the needs of families; support from advocacy groups; optimising use of existing clinic infrastructures and available natural history data; and, finally, the validation of existing outcome measures and/or the development and validation of new measures. We conclude by reiterating the need for a collaborative and coordinated approach amongst the many different stakeholder groups and the need to engage in new types of trial design which could be much more efficient, less costly and much less burdensome on families.
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Initially described as an early onset seizure variant of Rett syndrome, the CDKL5 disorder is now considered as an independent entity. However, little is currently known about the full spectrum of ...comorbidities that affect these patients and available literature is limited to small case series. This study aimed to use a large international sample to examine the prevalence in this disorder of comorbidities of epilepsy, gastrointestinal problems including feeding difficulties, sleep and respiratory problems and scoliosis and their relationships with age and genotype. Prevalence and onset were also compared with those occurring in Rett syndrome.
Data for the CDKL5 disorder and Rett syndrome were sourced from the International CDKL5 Disorder Database (ICDD), InterRett and the Australian Rett syndrome Database (ARSD). Logistic regression (multivariate and univariate) was used to analyse the relationships between age group, mutation type and the prevalence of various comorbidities. Binary longitudinal data from the ARSD and the equivalent cross-sectional data from ICDD were examined using generalized linear models with generalized estimating equations. The Kaplan-Meier method was used to estimate the failure function for the two disorders and the log-rank test was used to compare the two functions.
The likelihood of experiencing epilepsy, GI problems, respiratory problems, and scoliosis in the CDKL5 disorder increased with age and males were more vulnerable to respiratory and sleep problems than females. We did not identify any statistically significant relationships between mutation group and prevalence of comorbidities. Epilepsy, GI problems and sleep abnormalities were more common in the CDKL5 disorder than in Rett syndrome whilst scoliosis and respiratory problems were less prevalent.
This study captured a much clearer picture of the CDKL5 disorder than previously possible using the largest sample available to date. There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics.
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Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale ...was developed to measure gross motor abilities in this population. The current study investigated the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age and genotype were investigated. Clinical assessment scores for 38 girls and women with Rett syndrome who attended the Danish Center for Rett Syndrome were used to assess consistency of measurement. Principal components analysis enabled the calculation of three factor scores: Sitting, Standing and Walking, and Challenge. Motor scores were poorer with increasing age and those with the p.Arg133Cys, p.Arg294* or p.Arg306Cys mutation achieved higher scores than those with a large deletion. The repeatability of clinical assessment was excellent (intraclass correlation coefficient for total score 0.99, 95% CI 0.93-0.98). The standard error of measurement for the total score was 2 points and we would be 95% confident that a change 4 points in the 45-point scale would be greater than within-subject measurement error. The Rett Syndrome Gross Motor Scale could be an appropriate measure of gross motor skills in clinical practice and clinical trials.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate quality of life (QOL) and psychosocial well-being in youth with neuromuscular disorders (NMDs) who are wheelchair users.
MEDLINE, Embase, CINAHL, and PsycINFO (January 2004-April 2016) ...and reference lists of retrieved full-text articles.
Peer-reviewed studies were included when data describing self-reported QOL and psychosocial well-being could be separately understood for those using wheelchairs and 12 to 22 years of age. There were 2058 records independently screened, and potentially eligible articles were obtained and examined by all reviewers. Twelve observational and 3 qualitative studies met the inclusion criteria.
Population representativeness, measurement tools, and outcomes, where possible, with comparison groups. Two reviewers independently appraised studies for risk of bias to internal validity and generalizability.
Heterogeneity of measurement and reporting precluded meta-analysis. Data were cross-sectional only. Compared with same-age typically developing peers, physical QOL was scored consistently and significantly lower in youth with NMDs, whereas psychosocial QOL was not. Psychosocial QOL was highest in youth nonambulant since early childhood and in those recruited via single tertiary specialist clinics. Mental health and social participation could not be compared with same-age populations.
Despite low physical QOL, psychosocial QOL in youth with NMDs appeared comparable with same-age peers. The psychosocial well-being of younger adolescents on degenerative disease trajectories appeared most compromised; however, the longitudinal effects of growing up with a NMD on mental health and social participation are unknown. Interpretation was hampered by poor description of participant age, sex and physical ability; lack of population-based recruitment strategies; and inconsistent use of age-appropriate measures. Understanding of self-reported QOL and psychosocial well-being in youth with NMDs transitioning to adulthood is limited.
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