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BioRxiv : the Preprint Server For... Jun 2024Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity...
Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in topdown modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.
PubMed: 38915683
DOI: 10.1101/2024.06.13.598957 -
Open Access Emergency Medicine : OAEM 2024The objective of this review was to explore parents' experiences and information needs regarding management of their child with an intellectual and/or developmental... (Review)
Review
Seeking Care for Children with Intellectual and/or Developmental Disabilities in the Emergency Department: A Mixed Methods Systematic Review of Parents' Experiences and Information Needs.
The objective of this review was to explore parents' experiences and information needs regarding management of their child with an intellectual and/or developmental disability (IDD) in the emergency department (ED). We searched six electronic databases and grey literature to identify primary studies in English published since 2000. We synthesized quantitative and qualitative outcome data simultaneously using a convergent integrated approach and used a Mixed Methods Appraisal Tool (MMAT) to assess methodological quality of the included studies. Nine articles derived from seven studies were included (3 qualitative, 3 quantitative, 1 mixed method). Four main themes related to parents' self-reported experiences were identified: 1) appropriateness of the ED to manage and support their child; 2) acknowledgement/recognition of their child's IDD and incorporation of those considerations into overall care and management; 3) managing and navigating the ED environment; and 4) decision to disclose their child's condition when visiting the ED. Two articles provided data relevant to information needs, highlighting parents' desire to have resources supporting ED orientation and access to services within and outside of the ED setting. From the limited number of studies, it was evident that parents wanted better communication with healthcare providers and a greater understanding by ED staff around physical space settings needed to support their child. Resources supporting ED staff and parents to communicate effectively and work together can ensure that children with IDDs care needs are met. Further research into understanding parents' experiences and information needs related to managing a child with an IDD in the ED is needed to guide the development of effective resources.
PubMed: 38912093
DOI: 10.2147/OAEM.S450191 -
Cureus Jun 2024Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in...
Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a "variant of unknown significance." Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.
PubMed: 38912084
DOI: 10.7759/cureus.62749 -
Therapeutic Advances in Rare Disease 2024Existing clinical tools that measure non-seizure outcomes lack the range and granularity needed to capture skills in developmental and epileptic encephalopathy... (Review)
Review
Existing clinical tools that measure non-seizure outcomes lack the range and granularity needed to capture skills in developmental and epileptic encephalopathy (DEE)-affected individuals who also fall in the severe to profound range of intellectual disability. This effectively excludes those with severe impairments from clinical trials, impeding the ability of sponsors to evaluate disease-modifying therapies (DMTs). The Inchstone Project, an international, patient advocate-led collaboration, brings together leading researchers, clinicians, pharmaceutical companies, and advocates to develop an adapted, validated assessment battery within 5 years. The goal is to support trials of DMTs for the DEEs by providing sufficiently sensitive measurement tools to demonstrate therapeutic efficacy. An initial pilot study administered 7 established assessments to 10 individuals affected by SCN2A-DEE, identifying specific limitations of existing measures and areas for improvement. It was clear that most tools do not account for challenges throughout the DEE population, including vision impairments, significant motor impairments and profound intellectual disability, which need to be accounted for in creating a 'fit-for-purpose' battery for the DEE population. Several novel assessments, including two measures of responsivity developed for use in monitoring recovery after acquired brain injury as well as individualized Goal Attainment Scaling, showed promise in this group. The team also completed a DEE-wide survey with over 270 caregivers documenting their children's abilities and priorities for their improvement from new treatments. The Inchstone team is using this information to evaluate how existing tools might be updated to better capture what is most important to families and measure their child's small but important improvements over time. These efforts are building a coherent picture across multiple DEEs of what domains, or concepts of interest, have the greatest impact on most patients and families. The Inchstone team is on course to adapt non-seizure outcome measures that are (1) sufficiently sensitive to measure small increments of meaningful change ('Inchstones') and (2) applicable to multiple DEE conditions.
PubMed: 38911512
DOI: 10.1177/26330040241249762 -
Reproductive Biology and Endocrinology... Jun 2024Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian...
BACKGROUND
Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian insufficiency (FXPOI). Only 20% of female premutation carriers develop early ovulatory dysfunction, the reason for this incomplete penetrance is unknown. This study validated the mathematical model in premutation alleles, after assigning each allele a score representing allelic complexity. Subsequently, allelic scores were used to investigate the impact of allele complexity on age at amenorrhea for 58 premutation cases (116 alleles) previously published.
METHODS
The allelic score was determined using a formula previously described by our group. The impact of each allelic score on age at amenorrhea was analyzed using Pearson's test and a contour plot generated to visualize the effect.
RESULTS
Correlation of allelic score revealed two distinct complexity behaviors in premutation alleles. No significant correlation was observed between the allelic score of premutation alleles and age at amenorrhea. The same lack of significant correlation was observed regarding normal-sized alleles, despite a nearly significant trend.
CONCLUSIONS
Our results suggest that the use of allelic scores combination have the potential to explain female infertility, namely the development of FXPOI, or ovarian dysfunction, despite the lack of correlation with age at amenorrhea. Such a finding is of great clinical significance for early identification of females at risk of ovulatory dysfunction, enhancement of fertility preservation techniques, and increasing the probability for a successful pregnancy in females with premutations. Additional investigation is necessary to validate this hypothesis.
Topics: Humans; Female; Fragile X Mental Retardation Protein; Amenorrhea; Alleles; Primary Ovarian Insufficiency; Adult; Heterozygote; Mutation; Fragile X Syndrome; Age Factors; Young Adult; Adolescent
PubMed: 38907244
DOI: 10.1186/s12958-024-01227-5 -
JMIR Formative Research Jun 2024Timely detection of stress in people with dementia and people with an intellectual disability (ID) may reduce the occurrence of challenging behavior. However, detecting...
BACKGROUND
Timely detection of stress in people with dementia and people with an intellectual disability (ID) may reduce the occurrence of challenging behavior. However, detecting stress is often challenging as many long-term care (LTC) residents with dementia and residents with ID have communication impairments, limiting their ability to express themselves. Wearables can help detect stress but are not always accepted by users and are uncomfortable to wear for longer periods. Integrating sensors into clothing may be a more acceptable approach for users in LTC. To develop a sensor system for early stress detection that is accepted by LTC residents with dementia and residents with ID, understanding their perceptions and requirements is essential.
OBJECTIVE
This study aimed to (1) identify user requirements for a garment-integrated sensor system (wearable) for early stress detection in people with dementia and people with ID, (2) explore the perceptions of the users toward the sensor system, and (3) investigate the implementation requirements in LTC settings.
METHODS
A qualitative design with 18 focus groups and 29 interviews was used. Focus groups and interviews were conducted per setting (dementia, ID) and target group (people with dementia, people with ID, family caregivers, health care professionals). The focus groups were conducted at 3 time points within a 6-month period, where each new focus group built on the findings of previous rounds. The data from each round were used to (further) develop the sensor system. A thematic analysis with an inductive approach was used to analyze the data.
RESULTS
The study included 44 participants who expressed a positive attitude toward the idea of a garment-integrated sensor system but also identified some potential concerns. In addition to early stress detection, participants recognized other potential purposes or benefits of the sensor system, such as identifying triggers for challenging behavior, evaluating intervention effects, and diagnostic purposes. Participants emphasized the importance of meeting specific system requirements, such as washability and safety, and user requirements, such as customizability and usability, to increase user acceptance. Moreover, some participants were concerned the sensor system could contribute to the replacement of human contact by technology. Important factors for implementation included the cost of the sensor system, added value to resident and health care professionals, and education for all users.
CONCLUSIONS
The idea of a garment-integrated sensor system for early stress detection in LTC for people with dementia and people with ID is perceived as positive and promising by stakeholders. To increase acceptability and implementation success, it is important to develop an easy-to-use, customizable wearable that has a clear and demonstrable added value for health care professionals and LTC residents. The next step involves pilot-testing the developed wearable with LTC residents with dementia and residents with ID in clinical practice.
PubMed: 38905626
DOI: 10.2196/52248 -
Orphanet Journal of Rare Diseases Jun 2024Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in...
BACKGROUND
Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis.
RESULTS
We employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles.
CONCLUSIONS
The diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study's findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Genotype; Phenotype; Brazil; Child, Preschool; Child; Adolescent; Adult; Uniparental Disomy; Chromosomes, Human, Pair 15; Infant; Young Adult
PubMed: 38902749
DOI: 10.1186/s13023-024-03157-2 -
Epidemiology and Health Jun 2024This cohort profile describes one of the largest linked datasets in the world concerning the health of people with intellectual disability. The cohort comprises a...
This cohort profile describes one of the largest linked datasets in the world concerning the health of people with intellectual disability. The cohort comprises a retrospective group of 100,089 individuals with intellectual disability who received disability and/or health services in New South Wales, Australia. Of these participants, 34% were female, with a median age at cohort entry of 3 years (interquartile range, 0 to 19 years). A separate comparator cohort included 455,677 individuals, matched by 5-year age group, sex, and residential postcode at a 5:1 ratio. Initial results indicate that between 2001 and 2018, people with intellectual disability experienced more than double the rate of hospitalisations (538 versus 235 per 1000 person-years), as well as markedly higher rates of emergency department presentations (707 versus 379 per 1000 person-years) and use of ambulatory mental health services (1012 versus 157 per 1000 person-years), relative to the comparator cohort. The largest disparities in hospital admissions were for mental disorders, dialysis, and diseases of the nervous system and sense organs. Furthermore, individuals with intellectual disability had more than double the rate of dispensed medications found in the comparator cohort. Of these medications, 46.6% were for the treatment of nervous system conditions, as opposed to 24.7% for the comparator cohort. The mean age at death was 52 years (standard deviation [SD], 19 years) for people with intellectual disability and 64 years (SD, 22 years) for the comparator participants.
PubMed: 38901827
DOI: 10.4178/epih.e2024054 -
Therapeutic Advances in Rare Disease 2024Syntaxin-binding protein 1 related disorder (STXBP1-RD) is a rare neurologic disorder associated with global neurodevelopmental delay, intellectual disability,... (Review)
Review
Syntaxin-binding protein 1 related disorder (STXBP1-RD) is a rare neurologic disorder associated with global neurodevelopmental delay, intellectual disability, early-onset epilepsy, motor abnormalities, and autism. The underlying pathophysiology stems from a mutation in the gene, which codes for the STXBP1 protein. The STXBP1 protein is involved in synaptic vesicle fusion and neurotransmitter release. Pathogenic variants in the gene generally result in haploinsufficiency, an impairment in neurotransmitter release, and subsequent dysfunction in neuronal communication. The STXBP1 Foundation was founded in 2017 to support families of children with STXBP1-RD and accelerate the development of effective therapies and, ultimately, a cure for the disorder. The Foundation initially supported research aimed at better understanding the complex phenotypic presentation of the disease as well as the development of animal and cellular models usable by the research community to more fully characterize STXBP1 function and disease pathogenicity. In 2023, the Foundation embarked on its STXBP1 Fast Forward Strategic Plan, which includes a prospective natural history study and substantive biomarker work to drive forward the development of new precision therapies for STXBP1-RD.
PubMed: 38898886
DOI: 10.1177/26330040241257221