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.

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.

Sleep and the Social Profiles of Individuals With Rett Syndrome.

BACKGROUND: This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness. METHODS: Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness. RESULTS: The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: "interactive motricity," "mood change," "anxiety/agitation," and "gazing." Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness. CONCLUSIONS: The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.

Euthanasia and physician-assisted suicide in people with intellectual disabilities and/or autism spectrum disorders: investigation of 39 Dutch case reports (2012-2021).

BACKGROUND: Euthanasia review committees (Regionale Toetsingscommissies Euthanasie, RTE) scrutinise all Dutch cases of euthanasia and physician-assisted suicide (EAS) to review whether six legal 'due care' criteria are met, including 'unbearable suffering without prospect of improvement'. There are significant complexities and ethical dilemmas if EAS requests are made by people with intellectual disabilities or autism spectrum disorders (ASD). AIMS: To describe the characteristics and circumstances of people with intellectual disabilities and/or ASD who were granted their EAS request; investigate the main causes of suffering that led to the EAS request; and examine physicians' response to the request. METHOD: The online RTE database of 927 EAS case reports (2012-2021) was searched for patients with intellectual disabilities and/or ASD (n = 39). Inductive thematic content analysis was performed on these case reports, using the framework method. RESULTS: Factors directly associated with intellectual disability and/or ASD were the sole cause of suffering described in 21% of cases and a major contributing factor in a further 42% of cases. Reasons for the EAS request included social isolation and loneliness (77%), lack of resilience or coping strategies (56%), lack of flexibility (rigid thinking or difficulty adapting to change) (44%) and oversensitivity to stimuli (26%). In one-third of cases, physicians noted there was 'no prospect of improvement' as ASD and intellectual disability are not treatable. CONCLUSIONS: Examination of societal support for suffering associated with lifelong disability, and debates around the acceptability of these factors as reasons for granting EAS, are of international importance.

An investigation of the sleep macrostructure of girls with Rett syndrome.

OBJECTIVE/BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2) is of utmost importance in neuronal function. We aim to characterize phenotypic traits in the sleep of individuals with Rett Syndrome (RTT, OMIM # 312750), a rare disorder predominantly caused by mutations of the MECP2 gene. PATIENTS/METHODS: An overnight polysomnographic recording was performed. Outcomes investigated were parameters of nocturnal sleep macrostructure, and sample stratification per genetic and clinical characteristics, and six key features of clinical severity was applied. RESULTS: The sleep of our 21 RTT female subjects with a mutant MECP2 gene, aged 8.8 ± 5.4 years, showed no significant differences within strata. However, compared to a normative dataset, we found longer duration of wake time after sleep onset and total sleep time (TST) but shorter sleep onset latency, in RTT. Regarding the proportion of sleep stages per TST, higher stage N3 (%) with lower stage N2 (%) and REM (%) were generally seen. Such abnormalities became more uniformly expressed at the severe level of clinical features, particularly for hand functioning and walking. CONCLUSIONS: RTT girls with MECP2 mutations in our study demonstrated an increased deep sleep and reduced rapid eye movement sleep proportion, which is mostly allied with their hand dysfunction severity. Poor sleep-on/off switching in RTT since embryogenesis is possibly linked to (psycho)motor impairment in the cases with MECP2 mutations.

Sleep Respiratory Disturbances in Girls with Rett Syndrome.

Individuals with Rett Syndrome (RTT), a rare neurodevelopmental disorder, present disordered breathing during wakefulness. Whilst findings on breathing during sleep are contradictory, the relation between sleep breathing and their clinical features, genetic characteristics, age, and sleep phase is rarely investigated, which is the objective of this study. Overnight polysomnography (PSG) was performed. Sleep macrostructure parameters were compared between the RTT subjects with and without sleep-disordered breathing (SDB). The association between the apnea-hypopnea index (AHI) with age at PSG was tested. Particularly for RTT subjects with SDB, the respiratory indexes in REM and NREM sleep were compared. Stratified analyses per clinical characteristics, genetic characteristics, and clinical features' severity were performed. Non-parametric statistics were applied. A sample of 11 female RTT subjects, aged 8.69 ± 5.29 years with ten confirmed with MECP2 mutations, were studied. The average AHI was 3.94 ± 1.19/h TST, of which eight (72.73%) had obstructive sleep apnea, i.e., six in 1/h TST ≤ AHI ≤ 5/h TST, and two in AHI > 5/h TST. The mean SpO2% was 81.00 ± 35.15%. The AHI was not significantly correlated with their age at PSG (rs = -0.15, p = 0.67). Sleep macrostructure in SDB-absent and SDB-present groups was not different. Respiratory indexes in those with obstructive sleep apnea showed no difference between REM and NREM sleep nor any of the strata. In our clinical sample, more than half of the RTT subjects with MECP2 mutations had obstructive sleep apnea in both NREM and REM sleep which was unrelated to their clinical features. Our results also indicated hypoxemia throughout nocturnal sleep in RTT. To conclude, our results suggest that disordered breathing during sleep is prevalently present in RTT as an independent clinical feature.

Incontinence and sleep disturbances in young children: A population-based study.

AIMS: Nocturnal enuresis (NE), daytime urinary incontinence (DUI), fecal incontinence (FI), as well as sleep and behavioral problems are common in young children. The aim of this study was to analyze the association of sleep and psychological parameters for all types of incontinence in a representative sample of young children. METHODS: Six hundred thirty eight (of 1161) children with a mean age of 5.9 years (50.9% boys) were assessed during their mandatory school entry examination. The participation rate was 55%. Instruments included the Strengths and Difficulties Questionnaire, the Children's Sleep Habits Questionnaire and other clinical questions. Incontinence was diagnosed according to ICCS standards. Constipation was assessed by two questions. RESULTS: 17.1% of children had at least one type of incontinence, 14.8% had NE, 5.0% DUI, 2.1% FI, and 4.8% were constipated. 6.7% of children had clinically relevant psychological problems. 22.7% of children had sleep problems regularly (5-7 times/week). A wide variety of sleep problems were reported. Children with incontinence were not affected by a higher rate of sleep problems. Children with NE had fewer night wakings and those with constipation fewer parasomnias. Sleep and psychological problems were significantly associated, especially in children with DUI and FI. CONCLUSIONS: Sleep and behavioral problems are common in young children. Psychological problems have a clear impact on sleep. Young children with incontinence do not have more sleep problems than continent children. Therefore, both sleep and psychological problems should be addressed in young children with incontinence.

The Rett Syndrome Gross Motor Scale - Dutch Version (RSGMS-NL) Can Reliably Assess Gross Motor Skills in Dutch Individuals with Rett Syndrome.

AIM: The Rett Syndrome Gross Motor Scale (RSGMS) is an observational measurement, assessing gross motor skills in individuals with Rett syndrome. A Dutch version is lacking. The current study aims to translate and cross-culturally adapt the original RSMGS to Dutch and assess its inter-rater and intra-rater reliability. DESIGN: Translation and cross-cultural adaptation were performed in concordance with internationally accepted guidelines. A pretest was performed, and expert validation was assured. Video data of three girls with Rett syndrome was independently assessed by 27 physiotherapists via an online webinar to measure inter-rater reliability. Additionally, videos of 17 individuals with Rett syndrome were scored twice by two raters to assess intra-rater reliability. The reliability of the total score, the three subscale scores and the new items were analyzed using Intraclass Correlation Coefficients (ICC). RESULTS: Good comprehensibility and expert validation of the RSMGS-NL was achieved, and four items were added to the original scale. Inter-rater reliability for the total score was excellent (ICC 0.97, 95% CI 0.89-0.99), and good to perfect inter-rater reliability for the three subscales; Sitting, Standing & walking and Challenge was found (ICC values 1.0 (95% CI 0), 0.98 (95% CI 0.91-0.99) and 0.82 (95% CI 0.93-0.99) respectively). The intra-rater reliability was excellent for the total test score (ICC 0.98, 95% CI 0.97-0.99) and good to excellent for the subscale scores (ICC values 0.87 (95% CI 0.75-0.94), 0.99 (95% CI 0.98-1.0) and 0.97 (95% CI 0.95-0.99) respectively). The four new items (Standing to sitting, walking down a slope, ascending the stairs, descending the stairs) showed good to excellent intra-rater reliability. CONCLUSION: The RSGMS-NL is a reliable measure of gross motor skills in Dutch individuals with Rett syndrome.

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.

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.

Sleep problems among children with Fetal Alcohol Spectrum Disorders (FASD)- an explorative study.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) is a group of conditions resulting from prenatal alcohol exposure (PAE). Patients with FASD experience a variety of neuropsychological symptoms resulting from central nervous system impairment. Little is known about sleep disorders associated with PAE. The objective of this study was to investigate sleep problems related to FASD. METHODS: Forty patients (median age 8 years (6; 11)) diagnosed with FASD and forty typically developing children (median age 10 years (8; 13)) were recruited for the 1st phase of the study. In the 1st phase, the screening of sleep problems was performed with Child Sleep Habit Questionnaire (CSHQ) filled in by a caregiver. Those of the FASD group who scored above 41 points were qualified to the 2nd phase of the study and had an in-lab attended polysomnography (PSG) performed. The measurements consisted of electroencephalogram, electrooculograms, chin and tibial electromyogram, electrocardiogram, ventilatory monitoring, breathing effort, pulse oximetry, snoring and body position. Their results were compared to PSG laboratory reference data. RESULTS: The number of participants with sleep disturbances was markedly higher in the FASD group as compared to typically developing children (55% vs. 20%). The age-adjusted odds ratio for a positive result in CSHQ was 4.31 (95% CI: 1.54-12.11; p = 0.005) for FASD patients as compared to the control group. Significant differences between the FASD as compared to the typically developing children were observed in the following subscales: sleep onset delay, night wakings, parasomnias, sleep disordered breathing, and daytime sleepiness. Children from the FASD group who underwent PSG experienced more arousals during the sleep as compared with the PSG laboratory reference data. The respiratory indices in FASD group appear higher than previously published data from typically developing children. CONCLUSION: The results support the clinical observation that sleep disorders appear to be an important health problem in individuals with FASD. In particular distorted sleep architecture and apneic/hypopneic events need further attention.

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.

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.

Incontinence in persons with fetal alcohol spectrum disorders: a polish cohort.

INTRODUCTION: Fetal alcohol spectrum disorders (FASD) is an important preventable public health concern, associated to a number of common pediatric problems such as incontinence. Little is known about the prevalence and presentation of incontinence in FASD, which hinders effective management. OBJECTIVE: The aim of the present study was to investigate incontinence among people with FASD. STUDY DESIGN: Parental questionnaires were sent to all eligible FASD participants. To enable comparing the observed prevalence with typically developing, non-prenatally alcohol-exposed individuals, two clinical control groups of patients undergoing immunotherapy for pollen allergy (GKA) and patients diagnosed with celiac disease (GKG) were selected. RESULTS: A total of 119 participants were included in the study (FAS: n = 24, partial fetal alcohol syndrome [pFAS]: n = 19, alcohol-related neurodevelopmental disorder [ARND]: n = 28, GKA: n = 34, and GKG: n = 14). Overall incontinence for FASD was estimated to be 24% (confidence interval [CI] ranges from 15 to 36); nocturnal enuresis (NE) was present in 10% (CI ranges from 4 to 19), daytime urinary incontinence (DUI) in 11% (CI ranges from 5 to 21), and fecal incontinence (FI) in 13% (CI ranges from 6 to 23). Symptoms of urgency were present for 52%, voiding postponement for 10%, and straining for 2%. These data are both consistent with higher prevalence in individuals with FASD and with similar prevalence (the CIs overlap). CONCLUSION: Children and adolescents with FAS, pFAS, ARND, GKA, and GKG are affected by incontinence. Highest rates were observed in pFAS and ARND. Persons with FAS were mostly affected by DUI, those with pFAS by NE, and those with ARND by FI.

[Formula: see text] Measuring visual matching and short-term recognition memory with the CANTAB® Delayed Matching to Sample task in schoolchildren: Effects of demographic influences, multiple outcome measures and regression-based normative data.

The study aims to establish demographically corrected, pediatric norms for the computerized Delayed Matching to Sample (DMS) test, a measure of "visual matching ability and short-term visual recognition memory, for non-verbalisable problems". The DMS was administered to n = 184 children aged 5.10 to 14.5 years old. The DMS is a 4-choice recognition task of non-verbal, abstract patterns. The child has "to select, among four different choice patterns, the one that matches a complex visual pattern presented," i.e., (the target stimulus). The DMS consists of two conditions: a) the overt condition in which the target stimulus and four choice patterns are shown simultaneously and b) the covert condition, in which the choice patterns are shown after the target pattern is covered. The DMS test provides three outcome measures: the accuracy score (i.e., the number of correct patterns selected), latency (i.e., the response speed) and the probability of making an error after an incorrect response. These outcome measures were calculated for both conditions and for both conditions combined. Results showed that demographic variables, such as age, sex, and/or level of parental education (LPE) affected scores on these outcome measures. Based on these data, demographically corrected norms were established for all outcome measures, per condition and for both conditions combined.

Integrated analysis of human transcriptome data for Rett syndrome finds a network of involved genes.

OBJECTIVES: Rett syndrome (RTT) is a rare disorder causing severe intellectual and physical disability. The cause is a mutation in the gene coding for the methyl-CpG binding protein 2 (MECP2), a multifunctional regulator protein. Purpose of the study was integration and investigation of multiple gene expression profiles in human cells with impaired MECP2 gene to obtain a robust, data-driven insight in molecular disease mechanisms. METHODS: Information about changed gene expression was extracted from five previously published studies, integrated and the resulting differentially expressed genes were analysed using overrepresentation analysis of biological pathways and gene ontology, and network analysis. RESULTS: We identified a set of genes, which are significantly changed not in all but several transcriptomics datasets and were not mentioned in the context of RTT before. We found that these genes are involved in several processes and molecular pathways known to be affected in RTT. Integrating transcription factors we identified a possible link how MECP2 regulates cytoskeleton organisation via MEF2C and CAPG. CONCLUSIONS: Integrative analysis of omics data and prior knowledge databases is a powerful approach to identify links between mutation and phenotype especially in rare disease research where little data is available.

Incontinence and psychological symptoms in Phelan-McDermid syndrome.

AIMS: Phelan-McDermid syndrome (PMD) is a congenital syndrome caused by a deletion on chromosome 22q13.3. About 600 cases have been identified worldwide. PMD is characterized by neonatal hypotonia, moderate/severe intellectual impairment, impaired expressive language, and typical dysmorphic features. Psychological symptoms as hyperactivity, attention problems, restlessness, and stereotyped-repetitive behavior were reported. The aim of the study was to assess incontinence and associated psychological problems in PMD. METHODS: Forty-one individuals with PMD were recruited through a German support group (48.8% male; mean age 13.4 years; range, 4-55 years). Parents or caregivers completed the developmental behavior checklist (DBC), as well as the parental questionnaire: enuresis/urinary incontinence, including six questions on adaptive toileting skills. RESULTS: Rates of nocturnal enuresis (NE), daytime urinary incontinence, and fecal incontinence were 86%, 73%, and 79%. Rates were similar in all age groups (children, teens, adults). Constipation was present in 19%. Forty-two percent of the sample had a clinically relevant DBC score, with adults more affected than teens. Persons with NE had significantly higher "anxiety/depression" subscale scores. Toileting skills were more developed in adults than in children. Sixty-eight percent had further physical disabilities. CONCLUSIONS: Incontinence rates in PMD are high in all age groups. However, persons with PMD can improve their toilet skills. Therefore, the assessment and treatment of incontinence in persons with PMD is recommended. Constipation does not seem to be a major problem in PMD. Due to the high prevalence rates of somatic conditions, an assessment for organic and functional incontinence is recommended.