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Background: Caring for persons with profound intellectual and multiple disabilities (PIMD) demands specific expertise. Tacit knowledge seems to play an important role, but little is known about its nature, including what is necessary for its development and transfer. Aim: To gain understanding of the nature and development of tacit knowledge between persons with PIMD and their caregivers. Method: We conducted an interpretative synthesis of literature on tacit knowledge in caregiving dyads with persons with PIMD, persons with dementia or infants. Twelve studies were included. Results: Tacit knowledge is about caregivers and care-recipients becoming sensitive and responsive to each other's cues and together crafting care routines. Learning takes place in a constant process of action and response that transforms those involved. Conclusion: Building tacit knowledge together is necessary for persons with PIMD to learn to recognise and express their needs. Suggestions are made for ways to facilitate its development and transfer.

Background: Since the life expectancy of people with profound intellectual and multiple disabilities (PIMD) is increasing, siblings may take over care/support roles from their parents. Method: To explore how parents and siblings of persons with PIMD view siblings' role regarding future care/support for their family member, we interviewed eight parents and 13 siblings of seven persons with PIMD and analysed the data thematically. Results: While some parents expected that a future care/support role would burden the sibling unfairly, most siblings anticipated such a role and reported no concerns about this future responsibility. Despite a lack of explicit communication, expectations of parents and siblings regarding future responsibilities corresponded. However, some siblings mentioned the lack of explicit communication made them feel unprepared for the future. Conclusions: Explicit family communication may make siblings feel more prepared for the future and decrease the discrepancy between parents' and siblings' views regarding an expected future burden.

SMC1A epilepsy syndrome or developmental and epileptic encephalopathy‐85 with or without midline brain defects (DEE85, OMIM #301044) is an X‐linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the onset of severe refractory epileptic seizures in the first year of life, global developmental delay, a variable degree of intellectual disability, and dysmorphic facial features not typical of CdLS. This was a descriptive observational study for the largest international cohort with this specific disorder. The main goal of this study was to improve the knowledge of the natural history of this phenotype with particular attention to the psychomotor development and the epilepsy data. The analyzed cohort shows normal prenatal growth with the subsequent development of postnatal microcephaly. The incidence of neonatal problems (seizures and respiratory compromise) is considerable (51.4%). There is a significant prevalence of central nervous system (20%) and cardiovascular malformations (20%). Motor skills are generally delayed. The presence of drug‐resistant epilepsy is confirmed; the therapeutic role of a ketogenic diet is still uncertain. The significant regression of previously acquired skills following the onset of seizures has been observed. Facial dysmorphisms are variable and no patient shows a classic CdLS phenotype. To sum up, SMC1A variants caused drug‐resistant epilepsy in these patients, more than two‐thirds of whom were shown to progress to developmental and epileptic encephalopathy. The SMC1A gene variants are all different from each other (apart from a couple of monozygotic twins), demonstrating the absence of a mutational hotspot in the SMC1A gene. Owing to the absence of phenotypic specificity, whole‐exome sequencing is currently the diagnostic gold standard. [ABSTRACT FROM AUTHOR]

In this article, we describe the healthcare system for people with intellectual disabilities (ID) in the Netherlands. The general background about healthcare for people with ID is the same worldwide: their health needs are often unrecognized and unmet. We delineate, from a historical perspective, the steps the Netherlands has taken to change the situation for them. The Netherlands crossed a milestone in 2016 when it ratified the UN Convention on the Rights of Persons with Disabilities. Despite challenges in establishing numbers, an estimated ID prevalence of 1.45% was determined. The Dutch healthcare system has different levels, is funded through six distinct laws, and is complicated. The Netherlands has a spectrum of disability care services that increasingly collaborate in shaping the care of people with ID. People with ID and their representatives are increasingly involved in the process of shaping this care. The general practitioner plays a central role in the Dutch healthcare system, serving as the gatekeeper to medical specialists. Furthermore, the Netherlands recognizes the role of a physician for people with ID as a medical specialization. The core competencies of the ID physician include knowledge of the etiology and consequences of ID and associated health problems. The ID physician also knows how to deal with diagnostic and therapeutic barriers. Key challenges facing ID healthcare in the Netherlands include difficulties supporting people with ID due to the increasing complexity of society, concerns about continuity of care at the transition age (18−/18+), inadequate reach of population screening programs for people with ID, and limited availability of (routine) data for research on the ID population. The Dutch government encourages research in the ID field to overcome these challenges by financially supporting academic collaboratives. Substantial progress has been made, but key challenges remain, showing that there is still great room for improvement. [ABSTRACT FROM AUTHOR]

Background: Caring for persons with profound intellectual and multiple disabilities (PIMD) demands specific expertise. Tacit knowledge seems to play an important role, but little is known about its nature, including what is necessary for its development and transfer. Aim: To gain understanding of the nature and development of tacit knowledge between persons with PIMD and their caregivers. Method: We conducted an interpretative synthesis of literature on tacit knowledge in caregiving dyads with persons with PIMD, persons with dementia or infants. Twelve studies were included. Results: Tacit knowledge is about caregivers and care‐recipients becoming sensitive and responsive to each other's cues and together crafting care routines. Learning takes place in a constant process of action and response that transforms those involved. Conclusion: Building tacit knowledge together is necessary for persons with PIMD to learn to recognise and express their needs. Suggestions are made for ways to facilitate its development and transfer. [ABSTRACT FROM AUTHOR]

Pitt‐Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by mutations of the transcription factor 4 (Tcf4) gene. Individuals with PTHS often suffer from severe abdominal bloating and constipation. In this short communication, we discuss two individuals with PTHS who died unexpectedly due to gastrointestinal complications. We aim to increase awareness among healthcare professionals who care for individuals with PTHS, to ensure adequate screening and management of gastrointestinal symptoms in this population. Moreover, we discuss how fatal gastrointestinal complications may be related to PTHS and provide an overview of the literature. [ABSTRACT FROM AUTHOR]

Cornelia de Lange syndrome (CdLS) is a spectrum disorder due to variants in genes of the cohesin protein complex. The following abstracts are from the Cornelia de Lange Syndrome Scientific and Educational Symposium held virtually in October 2020. Aspects of behavior, including autistic features, impulsivity, adaptive skills, executive function, and anxiety are described. Applied behavioral analysis is a promising approach for autism, and an N‐acetylcysteine trial is proposed. Children below 6 years with CdLS have an increased number of and further travel to medical providers, with insurance type comprising a significant barrier. Speech, language, and feeding abilities fall significantly below expectations for age in CdLS. Augmentative alternative communication can yield potential barriers as well as interesting benefits. Developmentally, studies in animal models further elucidate the mechanisms and roles of cohesin: link with mediator transcriptional complex; facilitation of enhancer‐promoter communication; regulation of gene expression; allocation of cells to germ layers; and repair of spontaneous DNA damage in placental cells. Genome and RNA sequencing can help identify the molecular cause in the 20% of individuals with suspected CdLS and negative testing. The phenotypes in individuals with variants in the SMC1A gene are distinct, and that with intractable seizures has been further evaluated. AMA CME credits provided by GBMC, Baltimore, MD. All studies approved by an ethics committee. [ABSTRACT FROM AUTHOR]

Since the life expectancy of people with profound intellectual and multiple disabilities (PIMD) is increasing, siblings may take over care/support roles from their parents. To explore how parents and siblings of persons with PIMD view siblings' role regarding future care/support for their family member, we interviewed eight parents and 13 siblings of seven persons with PIMD and analysed the data thematically. While some parents expected that a future care/support role would burden the sibling unfairly, most siblings anticipated such a role and reported no concerns about this future responsibility. Despite a lack of explicit communication, expectations of parents and siblings regarding future responsibilities corresponded. However, some siblings mentioned the lack of explicit communication made them feel unprepared for the future. Explicit family communication may make siblings feel more prepared for the future and decrease the discrepancy between parents' and siblings' views regarding an expected future burden. [ABSTRACT FROM AUTHOR]

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents. [ABSTRACT FROM AUTHOR]

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype–phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype–phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation. [ABSTRACT FROM AUTHOR]

Pitt‐Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care. [ABSTRACT FROM AUTHOR]

Introduction: Development and behaviour in Cornelia de Lange Syndrome (CdLS), including autism characteristics, have been described infrequently stratified to genetic cause and only a few studies have considered behavioural characteristics in relation to developmental level. Here, we describe the behavioural phenotype in individuals with CdLS with SMC1A variants. Methods: We performed an international, interdisciplinary study on 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome and with Autism Spectrum Disorder. Results on cognition and self‐injurious behaviour (SIB) are compared to those in individuals with CdLS caused by NIPBL variants. For Dutch participants with SMC1A variants we performed direct in‐person assessments of cognition, autism, and added an interview and questionnaire on adaptive behaviour and sensory processing. Results: Individuals with SMC1A variants show a higher cognitive level and less SIB than individuals with NIPBL variants. Individuals with SMC1A variants without classic CdLS phenotype but with a Rett‐like phenotype show more severe intellectual disability and more SIB compared to those with a CdLS phenotype. Autism is less present if outcomes in direct in‐person assessments are evaluated taking developmental level into account compared to results based on a questionnaire. Conclusions: Behaviour in individuals with CdLS should be evaluated taking genetic cause into account. Detailed interdisciplinary approaches are of clinical importance to inform tailored care and may eventually improve quality of life of patients and families. [ABSTRACT FROM AUTHOR]

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes. [ABSTRACT FROM AUTHOR]

Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are multiple clinical issues facing individuals with all forms of CdLS, particularly in the neurodevelopmental system, but also gastrointestinal, cardiac, and musculoskeletal. Aspects of developmental and cell biology have found common endpoints in the biology of the cohesin complex, with improved understanding of the mechanisms, easier diagnostic tests, and the possibility of potential therapeutics, all major clinical implications for the individual with CdLS. The following abstracts are the presentations from the 7th Cornelia de Lange Syndrome Scientific and Educational Symposium, June 22-23, 2016, in Orlando, FL, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting. In addition to the scientific and clinical discussions, there were talks related to practical aspects of behavior including autism, transitions, communication, access to medical care, and databases. At the end of the symposium, a panel was held, which included several parents, affected individuals and genetic counselors, and discussed the greatest challenges in life and how this information can assist in guiding future research. The Research Committee of the CdLS Foundation organizes this meeting, reviews, and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board and publications. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. [ABSTRACT FROM AUTHOR]

Aim: Careful study and accurate description of behaviour are important to understand developmental challenges for individuals with Cornelia de Lange syndrome (CdLS). Here we present a systematic review of current understanding of behaviour in CdLS.Method: A systematic search was performed for articles published between January 1946 and December 2015 evaluating autism, self-injury, and/or cognition in CdLS. After study-selection, 43 papers were included. The Cochrane quality criteria were adjusted to assign quality scores to the included studies.Results: Participants were mostly categorized in the severe/profound developmental level. Methodology and quality were very heterogeneous, as well as reporting occurrence of autism. Self-injurious behaviour was reported in 15 papers. Physical conditions were reported in 21 studies, mostly related to hearing and vision. Only nine studies mentioned details about medication.Interpretation: Comparison of presented results was hindered by heterogeneous assessment methods. Improving our understanding of behavioural characteristics in CdLS requires more uniform methodology. We propose a criterion standard of instruments that can ideally be used in assessment of behaviour and development. This will improve understanding of behaviour in the context of developmental level and daily functioning. [ABSTRACT FROM AUTHOR]

BackgroundMethodResultsConclusionsParents’ tacit knowledge plays an important role in the care of persons with profound intellectual and multiple disabilities (PIMD). As little is known about its nature and use, we aimed to explore this parental tacit knowledge.We conducted semi-structured interviews with parents (n = 11) about their tacit knowledge of their child, based upon video recordings they made of their child’s behaviour, and analysed the data thematically.Parents described their tacit knowledge as the capacity to read their child’s subtle signs, or to sense and “just know” their child’s situation. They had developed this knowledge because of their shared history of proximity and interaction and emphasised that it was crucial in ensuring their children’s needs are met.We describe how parents’ tacit knowledge contributes to “good care” for persons with PIMD, interpret the implications for (medical) care practice, and discuss ways to deal with its limitations. [ABSTRACT FROM AUTHOR]

Abstract: Background: The cardiac muscle is well regulated in response to changes in loading conditions. This cardiac plasticity has been studied intensively and is well known in trained athletes. Conversely, the mechanisms leading to the opposite response are less clear. The aim of this study was to investigate left ventricular (LV) dimensions in a physically inactive population of adults with an intellectual disability. Methods: Adults with an intellectual disability with and without Down syndrome (DS) and healthy controls were included (n =182). Echocardiography was performed in all included subjects and physical activity was measured by means of a questionnaire. Results: Physical activity was lower in adults with an intellectual disability compared to controls (p <0.001). In DS, iLVM was significantly lower compared to controls (64±17g/m2 vs. 94±17g/m2 p <0.001). Non-DS adults with an intellectual disability had higher iLVM (72±16g/m2) compared to subjects with DS, although not significantly different (p <0.08). LV volumes were significantly smaller in adults with DS compared to both controls and non-DS adults with an intellectual disability (p <0.001). Moderate diastolic dysfunction was found in 57% of the adults with an intellectual disability. In 48 children with DS and 79 controls, mean LV end diastolic diameter was not significantly different during childhood. Conclusions: LV dimensions are significantly smaller in adults with an intellectual disability compared to controls. These findings appear to be lifestyle related as differences become manifest at adulthood and adults with an intellectual disability generally experience a sedentary lifestyle. Presumably, physical inactivity leads to a condition of cardiac atrophy. [Copyright &y& Elsevier]