-
BMC Medical Genomics Oct 2023Intellectual disability (ID) is characterized by an IQ < 70, which implies below-average intellectual function and a lack of skills necessary for daily living. ID...
BACKGROUND
Intellectual disability (ID) is characterized by an IQ < 70, which implies below-average intellectual function and a lack of skills necessary for daily living. ID may occur due to multiple causes, such as metabolic, infectious, and chromosomal causes. ID affects approximately 1-3% of the population; however, the cause can be identified in only 25% of clinical patients.
METHODS
To find the cause of genetic ID in a family, we performed whole-exome sequencing and Sanger sequencing to confirm the presence of a SETBP1 variant and real-time quantitative polymerase chain reaction to detect SETBP1 expression in the proband and normal controls.
RESULTS
A novel variant, c.942_943insGT (p. Asp316TrpfsTer28), was found in SETBP1. Furthermore, we observed that SETBP1 expression in patients was only 20% that of normal controls (P < 0.05).
CONCLUSION
A heterozygous variant in SETBP1 associated with ID was found. This report provides further evidence for its genetic basis and support for clinical genetic diagnosis.
Topics: Humans; Intellectual Disability; East Asian People; Family; Asian People; Pedigree; Mutation; Carrier Proteins; Nuclear Proteins
PubMed: 37798664
DOI: 10.1186/s12920-023-01649-x -
Life Science Alliance Mar 2024Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no...
Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.
Topics: Humans; Cell Proliferation; Computational Biology; Intellectual Disability; Neurogenesis; Mental Retardation, X-Linked
PubMed: 38182161
DOI: 10.26508/lsa.202302258 -
Journal of Intellectual Disability... Sep 2023Working memory training (WMT) can offer therapeutic benefits to patients with neurodevelopmental disorders (NDD) and mild to borderline intellectual disability (MBID).... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Working memory training (WMT) can offer therapeutic benefits to patients with neurodevelopmental disorders (NDD) and mild to borderline intellectual disability (MBID). However, consistent evidence for treatment benefits of WMT over placebo training is missing. So far, participants in double-blind research designs did receive non-specific coaching, whereas active coaching based on individual training results might increase the efficacy of WMT. Furthermore, the intensity and duration of WMT is often too stressful for these children. This study therefore investigated whether a less intensive but more prolonged WMT, with active personalised coaching and feedback, would reduce behavioural symptoms and improve neurocognitive functioning and academic achievements in children with NDD and MBID.
METHOD
A double-blind randomised controlled trial in children (aged 10;0-13;11) with MBID (60 < IQ < 85) and ADHD and/or ASD evaluated the effects of a less intensive but prolonged version of the original Cogmed WMT (30 min a day, 4 days a week, 8 weeks in total). Eighteen participants received active, personalised coaching and feedback, based on their actual individual performance during training. Twenty-two received general non-personalised coaching for the same amount of time. Executive functioning, academic achievements and several behavioural measurements were administered, before and after training, with a 6-months follow-up.
RESULTS
We observed a significant effect of time on both primary and secondary outcome measures, indicating that all children improved in working memory performance and other neurocognitive and academic outcomes. The interaction between time and group was not significant.
DISCUSSION
This study was unable to document superior effects of active personalised coaching and feedback compared with general non-personalised coaching and no feedback in an adaptive WMT in children with MBID and NDD. The objectively documented changes over time suggest that for these vulnerable children, a regular, structured and structural contact with a coach and adapted exercises is enough to develop therapy fidelity, boost motivation and improve neurodevelopmental task performance. Further research is needed to examine which possible subgroups within this heterogenic group of children profit more from WMT compared with other subgroups.
Topics: Humans; Child; Memory, Short-Term; Intellectual Disability; Mentoring; Cognitive Training; Attention Deficit Disorder with Hyperactivity; Learning Disabilities
PubMed: 37313626
DOI: 10.1111/jir.13047 -
American Journal of Medical Genetics.... Mar 2024Pathogenic variants in pleckstrin homology domain interacting protein (PHIP) are associated with Chung-Jansen syndrome characterized by developmental delay, intellectual...
Pathogenic variants in pleckstrin homology domain interacting protein (PHIP) are associated with Chung-Jansen syndrome characterized by developmental delay, intellectual disability, behavioral challenges, hypotonia, obesity, and dysmorphic features. We report phenotypes and genotypes of 47 individuals with likely pathogenic/pathogenic PHIP variants. Variants were de novo in 61.7%, unknown inheritance in 29.8%, and inherited in 8.5%. The median age of the individuals was 10.9 years, approximately equally divided by sex. Individuals in this cohort frequently had a history of developmental delay (85.1%), attention-deficit/hyperactivity disorder (51.1%), anxiety (46.8%), depression (27.7%), and sleep difficulties (42.6%). Depression was significantly higher in the older age group (>12 years old). Most individuals had moderately low adaptive functioning based on the Vineland-3 (mean = 76.8, standard deviation = 12.0). Overall, 55.8% of individuals were obese/overweight. The percentage of obese individuals was greater in the older age group (>12 years old) and evolves over time. Other common symptoms were hypotonia (78.7%), constipation (48.9%), visual problems (66%), and cryptorchidism (39.1% of males). Our findings provide additional natural history data for Chung-Jansen syndrome and provide opportunities for early intervention of healthy eating habits and awareness of developing mood and behavioral challenges over the life course.
Topics: Male; Humans; Aged; Child; Muscle Hypotonia; Intellectual Disability; Phenotype; Genotype; Obesity
PubMed: 37961033
DOI: 10.1002/ajmg.a.63471 -
Neuropediatrics Dec 2023Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial...
BACKGROUND
Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene (, *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS.
METHODS
This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data.
RESULTS
We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving , and two with pathogenic variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance.
CONCLUSION
Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive.
Topics: Humans; Child, Preschool; Intellectual Disability; Autism Spectrum Disorder; Muscle Hypotonia; Mutation; Epilepsy; Seizures; Language Development Disorders
PubMed: 37802085
DOI: 10.1055/s-0043-1775977 -
Pediatric Transplantation Dec 2023Historically, intellectual and developmental disability (IDD) has been considered an important factor in choosing potential recipients of organ transplants among many... (Review)
Review
BACKGROUND
Historically, intellectual and developmental disability (IDD) has been considered an important factor in choosing potential recipients of organ transplants among many transplant centers. This study evaluated the temporal changes at the national and regional levels in the proportion of heart transplantation in children with IDD.
METHODS
Children younger than 19 years in the United Network for Organ Sharing (UNOS) database who received heart transplants from 2010 to 2021 were included in this study. The patients were grouped into only definitive intellectual disability, both definitive intellectual and motor disability, only definitive motor disability, and no developmental disability. Multinomial logistic regressions were used to examine the proportion of heart transplants in each category for the whole cohort and each geographic transplant region.
RESULTS
There were 4273 pediatric heart transplant recipients included in the study. From 2010 to 2021, the percentages of pediatric heart transplants increased from 3.8% (95% CI, 0.01-0.05) to 5.8% (95% CI, 0.03-0.08) in children with only definitive intellectual disability (OR 0.07; 95% CI, 0.02-0.1, p < .002), from 3.4% (95% CI, 0.01-0.05) to 6.6% (95% CI, 0.04-0.09) in children with both definitive intellectual disability and motor disability (OR 0.09; 95% CI, 0.05-0.13, p < .001), and from 5.2% (95% CI, 0.02-0.07) to 8.3% (95% CI, 0.05-0.1) in children with only definitive motor disability (OR 0.06; 95% CI, 0.02-0.09, p < .002). There were several regional differences in the proportion of children with intellectual and developmental disabilities who received heart transplants.
CONCLUSION
There is increasing inclusion of children diagnosed with intellectual and developmental disabilities in heart transplantation. A review of the current allocation policies may address the marked geographic variations found in this study.
Topics: Child; Humans; Developmental Disabilities; Intellectual Disability; Disabled Persons; Motor Disorders; Heart Transplantation
PubMed: 37842949
DOI: 10.1111/petr.14620 -
American Journal of Medical Genetics.... Dec 2023Individuals with Down syndrome (DS) or Autism Spectrum Disorder (ASD), and especially those with both DS and co-occurring ASD (DS + ASD) commonly display behavioral... (Review)
Review
Individuals with Down syndrome (DS) or Autism Spectrum Disorder (ASD), and especially those with both DS and co-occurring ASD (DS + ASD) commonly display behavioral and psychiatric symptoms that can impact quality of life and places increased burden on caregivers. While the mainstay of treatment in DS and ASD is focused on educational and behavioral therapies, pharmacological treatments can be used to reduce symptom burden. There is a paucity of evidence and limited clinical trials in DS and DS + ASD. Some scientific evidence is available, primarily in open label studies and case series that can guide treatment choices. Additionally, clinical decisions are often extrapolated from evidence and experience from those with ASD, or intellectual disability in those without DS. This article reviews current research in pharmacological treatment in DS, ASD, and DS + ASD, reviews co-occurring neurodevelopmental and mental health diagnoses in individuals with DS + ASD across the lifespan, and describes practical approaches to psychopharmacological management.
Topics: Humans; Autism Spectrum Disorder; Down Syndrome; Quality of Life; Intellectual Disability
PubMed: 37870763
DOI: 10.1002/ajmg.c.32069 -
Journal of Applied Research in... Sep 2023Peer-provided services are a common model for addressing mental health concerns. Peer providers report a range of benefits and challenges associated with their role....
'Being a part of something': Experiences and perceived benefits of young adult peer mentors with intellectual/developmental disabilities and co-occurring mental health conditions.
BACKGROUND
Peer-provided services are a common model for addressing mental health concerns. Peer providers report a range of benefits and challenges associated with their role. However, there is little information about the experiences of peer providers with intellectual/developmental disabilities.
AIM
To explore the experiences of young adult peer-providers with intellectual/developmental disabilities in the context of a mental health intervention.
METHODS
We conducted interviews with four young adults with intellectual/developmental disabilities and their parents and teachers to understand their experiences providing a peer mentoring mental health intervention.
RESULTS
Young adult peer mentors perceived themselves as responsible for maintaining the mentoring relationship, delivering the intervention and acting as helpers and independent professionals. The experiences of young adult peer mentors were driven by the temporal, institutional and social contexts of their work. Peer mentoring was an enjoyable, social activity. Mentors, parents and teachers emphasised how taking on the peer mentoring role during the transition to adulthood and within the capital-rich university context led to a sense of pride and professional development. Further, these contexts may have led mentors to emphasise their intervention-delivery, helper and professional roles over relationship maintenance.
DISCUSSION & CONCLUSION
Context may shape the perceived roles and benefits for young adult peer mentors with intellectual/developmental disabilities.
Topics: Humans; Young Adult; Child; Mentors; Mental Health; Developmental Disabilities; Intellectual Disability; Peer Group
PubMed: 37194908
DOI: 10.1111/jar.13117 -
Neurology Apr 2024Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and...
BACKGROUND AND OBJECTIVES
Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials.
METHODS
As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software.
RESULTS
Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence.
DISCUSSION
In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials.
TRIAL REGISTRATION INFORMATION
ANSM Registration Number 2010-A00327-32.
Topics: Humans; Male; Female; Child; Fragile X Syndrome; Autism Spectrum Disorder; Caregiver Burden; Intellectual Disability; Creatine; Epilepsy; Nerve Tissue Proteins; Plasma Membrane Neurotransmitter Transport Proteins; Brain Diseases, Metabolic, Inborn; Mental Retardation, X-Linked
PubMed: 38531017
DOI: 10.1212/WNL.0000000000209243 -
American Journal of Medical Genetics.... Oct 2023Floating-Harbor syndrome (FLHS) is a neurodevelopmental disorder (NDD) caused by truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein gene...
Floating-Harbor syndrome (FLHS) is a neurodevelopmental disorder (NDD) caused by truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein gene (SRCAP). Truncating variants proximal to this location in SRCAP result in a non-FLHS SRCAP-associated NDD; an overlapping but distinct NDD characterized by developmental delay with or without intellectual disability (ID), hypotonia, normal stature, and behavioral and psychiatric issues. Here, we report a young woman who initially presented in childhood with significant delays in speech and mild ID. In young adulthood, she developed schizophrenia. On physical examination, she had facial features suggestive of 22q11 deletion syndrome. After non-diagnostic chromosomal microarray and trio exome sequencing (ES), a re-analysis of trio ES data identified a de novo missense variant in SRCAP that was proximal to the FLHS critical region. Subsequent DNA methylation studies showed the unique methylation signature associated with pathogenic sequence variants in non-FLHS SRCAP-related NDD. This clinical report describes an individual with non-FLHS SRCAP-related NDD caused by an SRCAP missense variant, and it also demonstrates the clinical utility of ES re-analysis and DNA methylation analysis for undiagnosed patients, in particular, those with variants of uncertain significance.
Topics: Female; Humans; Young Adult; Abnormalities, Multiple; Adenosine Triphosphatases; DNA Methylation; Intellectual Disability; Neurodevelopmental Disorders
PubMed: 37340855
DOI: 10.1002/ajmg.a.63329