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International Journal of Molecular... Jun 2024Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene,...
Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene, Freud-1/CC2D1A, a transcriptional repressor of human serotonin-1A (5-HT1A) and dopamine-D2 receptor genes. The altered expression of these Freud-1-regulated genes is implicated in mental illnesses such as major depression and schizophrenia. We hypothesized that Freud-1 is blocked by CaMK-induced phosphorylation. The incubation of purified Freud-1 with either CaMKIIα or CaMKIV increased Freud-1 phosphorylation that was partly prevented in Freud-1-Ser644Ala and Freud-1-Thr780Ala CaMK site mutants. In human SK-N-SH neuroblastoma cells, active CaMKIV induced the serine and threonine phosphorylation of Freud-1, and specifically increased Freud-1-Thr780 phosphorylation in transfected HEK-293 cells. The activation of purified CaMKIIα or CaMKIV reduced Freud-1 binding to its DNA element on the 5-HT1A and dopamine-D2 receptor genes. In SK-N-SH cells, active CaMKIV but not CaMKIIα blocked the Freud-1 repressor activity, while Freud-1 Ser644Ala, Thr780Ala or dual mutants were resistant to inhibition by activated CaMKIV or calcium mobilization. These results indicate that the Freud-1 repressor activity is blocked by CaMKIV-induced phosphorylation at Thr780, resulting in the up-regulation of the target genes, such as the 5-HT1A receptor gene. The CaMKIV-mediated inhibition of Freud-1 provides a novel de-repression mechanism to induce 5-HT1A receptor expression for the regulation of cognitive development, behavior and antidepressant response.
Topics: Humans; Phosphorylation; Receptor, Serotonin, 5-HT1A; HEK293 Cells; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Cell Line, Tumor; Repressor Proteins; Gene Expression Regulation; DNA-Binding Proteins
PubMed: 38892382
DOI: 10.3390/ijms25116194 -
International Journal of Molecular... May 2024Heterozygous mutations in the gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as "intellectual developmental disorder with...
Heterozygous mutations in the gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as "intellectual developmental disorder with language impairment with or without autistic features" (OMIM#613670) or FOXP1 syndrome for short. The main features of the condition are global developmental delay/intellectual disability; speech impairment in all individuals, regardless of their level of cognitive abilities; behavioral abnormalities; congenital anomalies, including subtle dysmorphic features; and strabismus, brain, cardiac, and urogenital abnormalities. Here, we present two siblings with a de novo heterozygous variant, namely, a four-year-old boy and 14-month-old girl. Both children have significantly delayed early psychomotor development, hypotonia, and very similar, slightly dysmorphic facial features. A lack of expressive speech was the leading symptom in the case of the four-year-old boy. We performed whole-exome sequencing on the male patient, which identified a pathogenic heterozygous c.1541G>A (p.Arg514His) mutation. His sister's targeted mutation analysis also showed the same heterozygous variant. Segregation analysis revealed the de novo origin of the mutation, suggesting the presence of parental gonadal mosaicism. To the best of our knowledge, this is the first report of gonadal mosaicism in -related neurodevelopmental disorders in the medical literature.
Topics: Humans; Forkhead Transcription Factors; Male; Mosaicism; Female; Child, Preschool; Neurodevelopmental Disorders; Infant; Repressor Proteins; Mutation; Exome Sequencing; Heterozygote
PubMed: 38891897
DOI: 10.3390/ijms25115709 -
Healthcare (Basel, Switzerland) May 2024People with intellectual disability want friendships and meaningful relationships, and some want intimacy. However, the expression of sexuality is an area where...
The Experiences of Young People with Intellectual Disability, Parents and Professionals in Relationships and Sexuality Education Programmes: Findings from a Qualitative Study.
People with intellectual disability want friendships and meaningful relationships, and some want intimacy. However, the expression of sexuality is an area where potential freedoms are often limited and restricted compared to their peers. While some relationships and sexuality education programmes do exist for this population, most focus on knowledge acquisition regarding sexuality and sex but lack in their focus on relationships, informed choices and decision-making. The aim of this study was to identify good practices and methods of delivery in relationships and sexuality education for children and young people with intellectual disability. A qualitative design was undertaken. Information about our study was distributed to eight special schools in the UK. Semi-structured interviews and focus groups were employed for data collection. Data from 37 pupils with intellectual disability, 11 parents and 16 healthcare and other professionals were thematically analysed. Following data analysis, three themes emerged: (i) seeking and sharing information; (ii) protecting and keeping safe; and (iii) learning for the future. The findings highlight that pupils are keen to learn about life changes and societal influences and want reliable information. Parents and professionals recognise that children and young people with intellectual disability will develop into adults and may be vulnerable when they leave the security of the school setting. They recognise that children and young people need to know about socialising, puberty, consent and contraception. Evidence-based programmes should be designed with these stakeholders to ensure children and young people with intellectual disability receive developmentally appropriate information to make happy and safe decisions about their relationships.
PubMed: 38891180
DOI: 10.3390/healthcare12111105 -
JCI Insight Jun 2024Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause autosomal recessive intellectual disability and...
Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause autosomal recessive intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). Trappc9-deficient mice have been shown to appear overweight shortly after weaning. Here, we analyzed serum biochemistry and histology of adipose and liver tissues to determine the incidence of obesity and NAFLD in trappc9-deficient mice and combined transcriptomic and proteomic analyses, pharmacological studies, and biochemical and histological examinations of postmortem mouse brains to unveil mechanisms involved. We found that trappc9-deficient mice presented with systemic glucose homeostatic disturbance, obesity and NAFLD, which were relieved upon chronic treatment combining dopamine receptor D2 (DRD2) agonist quinpirole and DRD1 antagonist SCH23390. Blood glucose homeostasis in trappc9-deficient mice was restored upon administrating quinpirole alone. RNA-sequencing analysis of DRD2-containing neurons and proteomic study of brain synaptosomes revealed signs of impaired neurotransmitter secretion in trappc9-deficient mice. Biochemical and histological studies of mouse brains showed that trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine synapse formation.
PubMed: 38889014
DOI: 10.1172/jci.insight.181339 -
Journal of Medical Internet Research Jun 2024Families of individuals with neurodevelopmental disabilities or differences (NDDs) often struggle to find reliable health information on the web. NDDs encompass various...
Families of individuals with neurodevelopmental disabilities or differences (NDDs) often struggle to find reliable health information on the web. NDDs encompass various conditions affecting up to 14% of children in high-income countries, and most individuals present with complex phenotypes and related conditions. It is challenging for their families to develop literacy solely by searching information on the internet. While in-person coaching can enhance care, it is only available to a minority of those with NDDs. Chatbots, or computer programs that simulate conversation, have emerged in the commercial sector as useful tools for answering questions, but their use in health care remains limited. To address this challenge, the researchers developed a chatbot named CAMI (Coaching Assistant for Medical/Health Information) that can provide information about trusted resources covering core knowledge and services relevant to families of individuals with NDDs. The chatbot was developed, in collaboration with individuals with lived experience, to provide information about trusted resources covering core knowledge and services that may be of interest. The developers used the Django framework (Django Software Foundation) for the development and used a knowledge graph to depict the key entities in NDDs and their relationships to allow the chatbot to suggest web resources that may be related to the user queries. To identify NDD domain-specific entities from user input, a combination of standard sources (the Unified Medical Language System) and other entities were used which were identified by health professionals as well as collaborators. Although most entities were identified in the text, some were not captured in the system and therefore went undetected. Nonetheless, the chatbot was able to provide resources addressing most user queries related to NDDs. The researchers found that enriching the vocabulary with synonyms and lay language terms for specific subdomains enhanced entity detection. By using a data set of numerous individuals with NDDs, the researchers developed a knowledge graph that established meaningful connections between entities, allowing the chatbot to present related symptoms, diagnoses, and resources. To the researchers' knowledge, CAMI is the first chatbot to provide resources related to NDDs. Our work highlighted the importance of engaging end users to supplement standard generic ontologies to named entities for language recognition. It also demonstrates that complex medical and health-related information can be integrated using knowledge graphs and leveraging existing large datasets. This has multiple implications: generalizability to other health domains as well as reducing the need for experts and optimizing their input while keeping health care professionals in the loop. The researchers' work also shows how health and computer science domains need to collaborate to achieve the granularity needed to make chatbots truly useful and impactful.
Topics: Humans; Neurodevelopmental Disorders; Internet; Software
PubMed: 38888947
DOI: 10.2196/50182 -
Medical Science Educator Jun 2024Persons with disabilities (PWD) often require special accommodations and more comprehensive healthcare yet frequently have encounters with physicians who are unprepared...
UNLABELLED
Persons with disabilities (PWD) often require special accommodations and more comprehensive healthcare yet frequently have encounters with physicians who are unprepared to provide tailored and complete care. A multipronged disability awareness curriculum for second-year medical students was implemented, including content on disability etiquette, patient-centered and interprofessional learning sessions for individuals with physical disabilities and intellectual and developmental disabilities, and a debriefing session with physiatrists. The objective of this study was to utilize a mixed methods approach to evaluate the disability awareness curriculum in undergraduate medical education (UME). Assessment was conducted using course evaluations, pre- and post-surveys including the Attitudes and Perspectives Towards Persons with Disabilities (APPD) scale and Multidimensional Attitudes Scale Toward Persons with Disabilities (MAS), and student focus groups. The mean scores from both the APPD (2.11 ± 0.43 pre-score vs. 1.7 ± 0.39 post-score) and MAS (2.45 ± 0.43 pre-score vs. 2.25 ± 0.55 post-score) indicate the curriculum improved medical students' attitudes toward PWD ( < 0.05), with lower numbers representing more favorable attitudes. After completing the curriculum, medical students' attitudes were comparable to those of doctor of physical therapy (DPT) students. Qualitative analysis from focus groups highlighted four major themes: education, comfort level, impact on future practice, and disability differences. This curriculum has potential as a valuable framework for delivering effective disability education to medical students to prepare future physicians to serve PWD and their unique needs. It meets core competencies, provides an opportunity to learn in interprofessional environments, and integrates PWD into the educational process.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40670-024-02004-0.
PubMed: 38887426
DOI: 10.1007/s40670-024-02004-0 -
Cureus May 2024Alström syndrome is a genetic disease that impacts numerous systems in the human body. The symptoms can vary and appear gradually. Childhood obesity, heart disease...
Alström syndrome is a genetic disease that impacts numerous systems in the human body. The symptoms can vary and appear gradually. Childhood obesity, heart disease (cardiomyopathy), abnormalities in vision, and hearing issues are the main symptoms of this disorder in children. Diabetes mellitus, hepatic issues, and renal dysfunction can all occur over time. Genetic alterations in the ALMS1 gene are the cause of Alström syndrome. It has an autosomal recessive inheritance pattern. We address the case of a Saudi woman in her 20s. She had been initially referred for type 2 diabetes, intellectual disability since early childhood, metabolic acidosis, and micrognathia; however, she also exhibited blindness, chronic kidney disease (CKD), and hearing loss, all of which are indicative of Alström syndrome. DNA testing showed that she has a homozygous pathogenic variant in the ALMS gene. Autosomal recessive Alström syndrome has been confirmed as a genetic diagnosis. No other clinically significant variations were found that are associated with the mentioned phenotype. By reporting this mutation, we hope to learn more about the genotypic range of the disease, particularly in the Saudi population. As each member of the family underwent genetic testing, we established a stringent follow-up schedule for our patient and her family.
PubMed: 38883102
DOI: 10.7759/cureus.60396 -
Cureus May 2024A relatively rare neurocutaneous condition known as linear nevus sebaceous syndrome (LNSS) is marked by a variety of symptoms as well as the unusual characteristics of...
A relatively rare neurocutaneous condition known as linear nevus sebaceous syndrome (LNSS) is marked by a variety of symptoms as well as the unusual characteristics of developing mosaic RASopathies of phacomatoses. Mental retardation, seizures, and midline facial linear nevus sebaceous were the usual diagnostic triad. A hallmark of LNSS is the papillomatous growth of the epidermis, also known as nevus sebaceous. In this case report, we presented a case of a 13-year-old male with LNSS with a vascular conjunctival lesion and a coloboma of the optic disc.
PubMed: 38883086
DOI: 10.7759/cureus.60487 -
Cureus May 2024Down syndrome (DS) is the most common chromosomal disorder in live-born infants, often associated with intellectual disability and various medical conditions, including...
Down syndrome (DS) is the most common chromosomal disorder in live-born infants, often associated with intellectual disability and various medical conditions, including thyroid dysfunction. Hashimoto's thyroiditis (HT), an autoimmune subtype, is a leading cause of acquired hypothyroidism in DS children. Severe hypothyroidism can precipitate myxedema, a critical condition linked to complications like pericardial effusion and cardiac tamponade. This case study presents a nine-year-old male with DS who was admitted for acute respiratory distress exhibiting classic signs of myxedema. Initial investigations revealed severe hypothyroidism and significant pericardial effusion. Surgical pericardiotomy drained 800 mL of fluid, confirming myxedema secondary to HT. Levothyroxine therapy led to progressive improvement, resolving myxedematous infiltrate and associated symptoms within a month. Follow-up at 12 months demonstrated sustained improvement with normalized thyroid function and no clinical disease activity. This case highlights an atypical presentation of HT in a DS child with cardiac pre-tamponade.
PubMed: 38883046
DOI: 10.7759/cureus.60367 -
Frontiers in Neurology 2024This study aimed to investigate the impact of cognitive load, particularly its escalation during the execution of the same test, under varying vision conditions, on...
INTRODUCTION
This study aimed to investigate the impact of cognitive load, particularly its escalation during the execution of the same test, under varying vision conditions, on postural balance among adolescents with intellectual disability (ID).
METHODS
Twenty adolescents underwent balance assessments under different visual conditions (Open Eyes (OE), Closed Eyes (CE), Flash, Goggles, Visual Stimulation (VS)) and task settings (Single Task (ST), Dual Task (DT) without challenges, and DT with challenges). The cognitive test was assessed using Verbal Fluency (VF).
RESULTS AND DISCUSSION
Significant effects were found for Task ( < 0.001, ηp = 0.85), indicating that CoP values significantly increased ( < 0.05) with the introduction of the DT. Dual Task Cost (DTC) demonstrated significant effects for Vision ( = 0.008, ηp = 0.62), with values varying significantly ( < 0.05) among different vision conditions, especially in CE and Flash conditions. Visual Dependency Quotient (VDQ) analyses revealed significant effects of condition ( < 0.001, ηp = 0.84), with significant changes observed in CE/OE and Flash/OE conditions ( < 0.05). Significant effects were observed for Cognitive performance in the Challenge condition ( < 0.001, ηp = 0.86), with decreased performance with cognitive task challenges, particularly in Flash and Goggles conditions ( < 0.05). In conclusion, cognitive tasks, especially challenging ones, and visual variations significantly impact postural balance in adolescents with ID.
PubMed: 38882695
DOI: 10.3389/fneur.2024.1385286