Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.

Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders.

Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). FASD is one of the leading preventable forms of neurodevelopmental disorders. In the light of prevention and early intervention, knowledge on how ethanol exposure induces fetal damage is urgently needed. Besides direct ethanol and acetaldehyde toxicity, alcohol increases oxidative stress, and subsequent general effects (e.g., epigenetic imprinting, gene expression, and metabolite levels). The current review provides an overview of the existing knowledge about specific downstream pathways for FASD that affects e.g., the SHH pathway, cholesterol homeostasis, neurotransmitter signaling, and effects on the cytoskeleton. Available human data vary greatly, while animal studies with controlled ethanol exposition are only to a certain limit transferable to humans. The main deficits in knowledge about FASD are the lack of pathophysiological understanding and dose-response relationships, together with the lack of reliable biomarkers for either FASD detection or estimation of susceptibility. In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention.

Extracellular Vesicles in CNS Developmental Disorders.

The central nervous system (CNS) is the most complex structure in the body, consisting of multiple cell types with distinct morphology and function. Development of the neuronal circuit and its function rely on a continuous crosstalk between neurons and non-neural cells. It has been widely accepted that extracellular vesicles (EVs), mainly exosomes, are effective entities responsible for intercellular CNS communication. They contain membrane and cytoplasmic proteins, lipids, non-coding RNAs, microRNAs and mRNAs. Their cargo modulates gene and protein expression in recipient cells. Several lines of evidence indicate that EVs play a role in modifying signal transduction with subsequent physiological changes in neurogenesis, gliogenesis, synaptogenesis and network circuit formation and activity, as well as synaptic pruning and myelination. Several studies demonstrate that neural and non-neural EVs play an important role in physiological and pathological neurodevelopment. The present review discusses the role of EVs in various neurodevelopmental disorders and the prospects of using EVs as disease biomarkers and therapeutics.

Development of consensus-based guidelines for managing communication of individuals with Rett syndrome.

Difficulties with communication have a profound impact on the lives of individuals with Rett syndrome and their caregivers. Globally, many families report difficulty accessing appropriate and timely information and services from professionals with expertise in augmentative and alternative communication (AAC) as it pertains to Rett syndrome. To address this need, international consensus-based guidelines for managing the communication of individuals with Rett syndrome were developed by combining available evidence and lived experience with expert opinion. A two-phase Delphi survey was built on statements and recommendations extracted from a review of over 300 pieces of literature combined with survey responses from communication professionals and caregivers. All statements that reached a pre-determined threshold of ≥70% agreement were incorporated into guidelines that consist of 268 statements and recommendations relating to (a) rights of the individual; (b) beliefs and attitudes of communication partners; (c) professional knowledge and team work; (d) strategies to optimize engagement; (e) assessment; and (f) intervention (targets and goals, techniques), including the use of AAC. To date, this project is the largest of its kind, with 650 participants from 43 countries contributing to development of consensus-based guidelines for Rett syndrome.

MECP2 variation in Rett syndrome-An overview of current coverage of genetic and phenotype data within existing databases.

Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases, it results from a loss-of-function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counseling for parents. In this study, 13 genotype-phenotype databases were surveyed for their general functionality and availability of RTT-specific MECP2 variation data. For each database, we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis, or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data.

Non-pharmacological management of problematic sleeping in children with developmental disabilities.

AIM: Sleep is important for underlying neural plasticity, and children with developmental disabilities suffer behavioural, emotional, cognitive, and sensory-motor issues that affect their wake and sleep states. Problematic sleeping can be hypothesized to have adverse effects on both of these areas in children with developmental disabilities. With this review, we aim to provide a benchmark in managing problematic sleeping in children with developmental disabilities. METHOD: A literature search was conducted and data on the study descriptives, patient characteristics, study design, study-related factors, criteria applied to operationalize sleep and developmental disability, and sleep 'management' were collected. Each management strategy was tabulated and analysed. RESULTS: We identified 90 studies involving 1460 children with developmental disabilities, of whom 61.6% were male. The highest proportion of studies, almost half, were in children with syndromes (44.4%), followed by studies in children with intellectual disabilities (18.9%). Non-pharmacological sleep management was primarily aimed at improving sleep quality (86.7%), followed by sleep-wake schedules and, to a certain extent, sleep regularity (42.2%). About 56.7% of the studies reported more than one approach. Studies mostly focused on disorders of initiating and maintaining sleep through a diversity of strategies and relied heavily on subjective measures to identify and monitor problematic sleeping. Sleep management approaches were primarily delivered at the level of the individual in the home setting. The number of management approaches per study was unrelated to the number of sleep problems discussed. INTERPRETATION: Modifying sleep management strategies to meet the specific needs of children with developmental disabilities is encouraged, and studies that look beyond sleep quality or sleep quantity are required. It is also advocated that modifications to sleep hygiene, sleep regularity, and sleep ecology in a population with developmental disabilities are rigorously investigated. Finally, daytime somnolence should not be overlooked when aiming to optimize sleep in children with developmental disabilities across the ages and stages of their lives. There were several limitations in the research findings of problematic sleep in children with developmental disabilities. In general, the sleep problems and the developmental disabilities investigated were multicomponent in nature. It is likely that management approaches impacted those problems on multiple levels or through diverse 'therapeutic' pathways. There is a need for randomized controlled trials and more objective measures that quantify improved sleep or wake states.

Reflecting on the efficacy of cognitive mapping for decision-making in intellectual disability care: a case study.

The central aspect of this study is a set of reflections on the efficacy of soft operational research techniques in understanding the dynamics of a complex system such as intellectual disability (ID) care providers. Organizations providing services to ID patients are complex and have many interacting stakeholders with often different and competing interests. Understanding the causes for failures in complex systems is crucial for appreciating the multiple perspectives of the key stakeholders of the system. Knowing the factors that adversely affect delivery of a patient-centred care by ID provider organizations offers the potential for identifying more effective resource-allocation solutions. The authors suggest cognitive mapping as a starting point for system dynamics modelling of optimal resource-allocation projects in ID care. The application of the method is illustrated via a case study in one of the ID care providers in the Netherlands. The paper discusses some of the practical implications of applying problem-structuring methods that support gathering feedback from vulnerable service users and front-line workers. The authors concluded that cognitive mapping technique can assist the management of healthcare organizations in strategic decision-making.

Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome.

Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and noradrenergic markers in 67 adults with 22q11DS. Levels of serotonin and the catecholamine metabolite homovanillic acid were significantly lower in the 22q11DS subjects compared to healthy controls. Within the 22q11DS group, levels of dopamine, homovanillic acid, norepinephrine, vanillyl mandelic acid and serotonin positively correlated with Full Scale Intelligence Quotient scores. Our results suggest that cognitive deficits in 22q11DS are associated with abnormal function of several neurotransmitters.

A novel insight into neurological disorders through HDAC6 protein-protein interactions.

Due to its involvement in physiological and pathological processes, histone deacetylase 6 (HDAC6) is considered a promising pharmaceutical target for several neurological manifestations. However, the exact regulatory role of HDAC6 in the central nervous system (CNS) is still not fully understood. Hence, using a semi-automated literature screening technique, we systematically collected HDAC6-protein interactions that are experimentally validated and reported in the CNS. The resulting HDAC6 network encompassed 115 HDAC6-protein interactions divided over five subnetworks: (de)acetylation, phosphorylation, protein complexes, regulatory, and aggresome-autophagy subnetworks. In addition, 132 indirect interactions identified through HDAC6 inhibition were collected and categorized. Finally, to display the application of our HDAC6 network, we mapped transcriptomics data of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis on the network and highlighted that in the case of Alzheimer's disease, alterations predominantly affect the HDAC6 phosphorylation subnetwork, whereas differential expression within the deacetylation subnetwork is observed across all three neurological disorders. In conclusion, the HDAC6 network created in the present study is a novel and valuable resource for the understanding of the HDAC6 regulatory mechanisms, thereby providing a framework for the integration and interpretation of omics data from neurological disorders and pharmacodynamic assessments.

End-of-life decisions for people with intellectual disabilities, an interview study with patient representatives.

BACKGROUND: Not much is known about the process of end-of-life decision-making for people with intellectual disabilities. AIM: To clarify the process of end-of-life decision-making for people with intellectual disabilities from the perspective of patient representatives. DESIGN: A qualitative study based on semi-structured interviews, recorded digitally and transcribed verbatim. Data were analysed using Grounded Theory procedures. PARTICIPANTS: We interviewed 16 patient representatives after the deaths of 10 people with intellectual disabilities in the Netherlands. RESULTS: The core category 'Deciding for someone else' describes the context in which patient representatives took end-of-life decisions. The patient representatives felt highly responsible for the outcomes. They had not involved the patients in the end-of-life decision-making process, nor any professionals other than the doctor. The categories of 'Motives' and 'Support' were connected to the core category of 'Deciding for someone else'. 'Motives' refers to the patient representatives' ideas about quality of life, prevention from suffering, patients who cannot understand the burden of interventions and emotional reasons reported by patient representatives. 'Support' refers to the support that patient representatives wanted the doctors to give to them in the decision-making process. CONCLUSIONS: From the perspective of the patient representatives, the process of end-of-life decision-making can be improved by ensuring clear roles and an explicit description of the tasks and responsibilities of all participants. Regular discussion between everyone involved including people with intellectual disabilities themselves can improve knowledge about each other's motives for end-of-decisions and can clarify expectations towards each other.

Exploring the development of existing sex education programmes for people with intellectual disabilities: an intervention mapping approach.

BACKGROUND: People with intellectual disabilities face barriers that affect their sexual health. Sex education programmes have been developed by professionals working in the field of intellectual disabilities with the aim to overcome these barriers. The aim of this study was to explore the development of these programmes. METHODS: Sex education programmes geared to people with intellectual disabilities were examined in the context of the Intervention Mapping protocol. Data were obtained via interviews with the programme developers. RESULTS: All programmes lack specific programme outcomes, do not have a theoretical basis, did not involve members of relevant groups in the development process and lack systematic evaluation. CONCLUSIONS: Based on our findings and the literature, we conclude that these programmes are unlikely to be effective. Future programmes should be developed using a more systematic and theory- and evidence-based approach.

Aging in Prader-Willi syndrome: twelve persons over the age of 50 years.

The life expectancy of persons with Prader-Willi syndrome (PWS) has increased in recent years. Because of the paucity of reports on older persons with PWS, the natural history, the onset, and type of age-related problems are poorly understood. Twelve persons with a genetically confirmed diagnosis of PWS aged over 50 years are described (4 deletion; 8 mUPD). Data on physical, behavioral, psychiatric, and aging characteristics were collected through semi-structured interviews with the individuals with PWS and their main carers. Cardiovascular diseases, diabetes, dermatological, and orthopedic problems were common physical complaints in older people with PWS. Functioning in activities of daily living, psychological functioning, physical functions, and care dependence were substantially worse in the older age group (50+) compared to the control group (18-49 years). Seven out of eight persons with mUPD had a history of psychiatric illness. Behavioral problems were observed in the older age group. Given the combination of age-related physical morbidity, physical appearance, behavioral and psychiatric problems, and functional decline in our cohort, we hypothesize that premature aging occurs in PWS. The care for older people with PWS requires a lifespan approach that recognizes the presence, progression, and consequences of specific morbidity. Special medical surveillance of people with PWS from 40 years onwards would ensure that intervention and support is offered with respect to specific areas of decline at the earliest possible time.

Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice.

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype-phenotype correlation studies have been performed. A number of general genotype-phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht-Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype-phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype-phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families.

The nominal group technique as an evaluation tool for solution-focused coaching.

BACKGROUND: Solution-focused coaching (SFC) helps individuals or groups to achieve their preferred outcomes by evoking and co-constructing solutions. SFC has been shown to be helpful for persons with ID as well as for teams coaching people with ID. Nominal Group Technique (NGT) helps to organize people's thoughts with regard to a single question. This study examines the perceived strengths of and recommendations for SFC for teams coaching people with ID via NGT, as well as the extent to which the NGT results reflect the results of an SFC questionnaire. METHODS: In total, 54 staff members participated in SFC. Of these, 18 participated in NGT, while 36 completed the SFC questionnaire. The strengths of and recommendations for SFC were obtained via NGT. Interrater agreement was calculated via Cohen's kappa. RESULTS: The strengths of SFC include 'exploring hidden successes' and 'focusing on solutions'. It was recommended that 'the results be consolidated in follow-up meetings'. The participants agreed on the content of the strengths and recommendations, but differed in terms of priorities (κ ≤ 0.1). CONCLUSIONS: NGT is a valuable tool in exploring people's opinions and priorities, but further research is needed to elucidate the perceived priorities of SFC for teams coaching persons with ID.

Physical health problems in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage.

The role of Extracellular Vesicles during CNS development.

With a diverse set of neuronal and glial cell populations, Central Nervous System (CNS) has one of the most complex structures in the body. Intercellular communication is therefore highly important to coordinate cell-to-cell interactions. Besides electrical and chemical messengers, CNS cells also benefit from another communication route, what is known as extracellular vesicles, to harmonize their interactions. Extracellular Vesicles (EVs) and their subtype exosomes are membranous particles secreted by cells and contain information packaged in the form of biomolecules such as small fragments of DNA, lipids, miRNAs, mRNAs, and proteins. They are able to efficiently drive changes upon their arrival to recipient cells. EVs actively participate in all stages of CNS development by stimulating neural cell proliferation, differentiation, synaptic formation, and mediating reciprocal interactions between neurons and oligodendrocyte for myelination process. The aim of the present review is to enlighten the presence and contribution of EVs at each CNS developmental milestone.

A resource to explore the discovery of rare diseases and their causative genes.

Here, we describe a dataset with information about monogenic, rare diseases with a known genetic background, supplemented with manually extracted provenance for the disease itself and the discovery of the underlying genetic cause. We assembled a collection of 4166 rare monogenic diseases and linked them to 3163 causative genes, annotated with OMIM and Ensembl identifiers and HGNC symbols. The PubMed identifiers of the scientific publications, which for the first time described the rare diseases, and the publications, which found the genes causing the diseases were added using information from OMIM, PubMed, Wikipedia, whonamedit.com, and Google Scholar. The data are available under CC0 license as spreadsheet and as RDF in a semantic model modified from DisGeNET, and was added to Wikidata. This dataset relies on publicly available data and publications with a PubMed identifier, but by our effort to make the data interoperable and linked, we can now analyse this data. Our analysis revealed the timeline of rare disease and causative gene discovery and links them to developments in methods.

A catalogue of 863 Rett-syndrome-causing MECP2 mutations and lessons learned from data integration.

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.

Food-Related Brain Activation Measured by fMRI in Adults with Prader-Willi Syndrome.

(1) Background: Prader-Willi syndrome (PWS) is characterized by hyperphagia, resulting in morbid obesity if not controlled. The primary aim of this study was to investigate whether PWS patients show altered activation of brain areas involved in hunger. As a secondary objective, we assessed whether there is an association between these brain areas and several endocrine and metabolic factors in the fasting state. (2) Methods: 12 PWS adults and 14 healthy controls (siblings) performed a food-related experimental task after an overnight fast while brain activation in regions of interest was measured by functional MRI. (3) Results: In controls, significantly more activation was found in the left insula (p = 0.004) and the bilateral fusiform gyrus (p = 0.003 and 0.013) when the individuals were watching food as compared to non-food pictures, which was absent in PWS patients. Moreover, in PWS adults watching food versus non-food pictures a significant negative correlation for glucose and right amygdala activation (p_fwe = 0.007) as well as a positive correlation for leptin and right anterior hippocampus/amygdala activation (p_fwe = 0.028) was demonstrated. No significant associations for the other hormonal and metabolic factors were found. (4) Conclusions: PWS individuals show aberrant food-related brain activation in the fasting state. Leptin is associated with activation within the neural motivation/reward circuitry, while the opposite is true for glucose.

Loss of response to melatonin treatment is associated with slow melatonin metabolism.

BACKGROUND: In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism. METHOD: In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose. RESULTS: In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%. CONCLUSION: We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.