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Biochemical Society Transactions Feb 2023Mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene are associated with Renpenning syndrome, which is characterized by microcephaly, intellectual... (Review)
Review
Mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene are associated with Renpenning syndrome, which is characterized by microcephaly, intellectual deficiency, short stature, small testes, and distinct facial dysmorphism. Studies using different models have revealed that PQBP1 plays essential roles in neural development and function. In this mini-review, we summarize recent findings relating to the roles of PQBP1 in these processes, including in the regulation of neural progenitor proliferation, neural projection, synaptic growth, neuronal survival, and cognitive function via mRNA transcription and splicing-dependent or -independent processes. The novel findings provide insights into the mechanisms underlying the pathogenesis of Renpenning syndrome and may advance drug discovery and treatment for this condition.
Topics: Humans; Carrier Proteins; Mental Retardation, X-Linked; Mutation; Cerebral Palsy; Intellectual Disability; DNA-Binding Proteins
PubMed: 36815699
DOI: 10.1042/BST20220920 -
Biological Psychiatry Jan 202415q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional...
BACKGROUND
15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited.
METHODS
Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype.
RESULTS
Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination.
CONCLUSIONS
Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.
Topics: Humans; Intellectual Disability; Actins; Autism Spectrum Disorder; Polymerization; Adaptor Proteins, Signal Transducing; Fragile X Mental Retardation Protein
PubMed: 37704042
DOI: 10.1016/j.biopsych.2023.08.027 -
Behavioral and Brain Functions : BBF May 2022Genetic variants of DCX, COMT and FMR1 have been linked to neurodevelopmental disorders related to intellectual disability and social behavior. In this systematic review... (Review)
Review
Genetic variants of DCX, COMT and FMR1 have been linked to neurodevelopmental disorders related to intellectual disability and social behavior. In this systematic review we examine the roles of the DCX, COMT and FMR1 genes in the context of hippocampal neurogenesis with respect to these disorders with the aim of identifying important hubs and signaling pathways that may bridge these conditions. Taken together our findings indicate that factors connecting DCX, COMT, and FMR1 in intellectual disability and social behavior may converge at Wnt signaling, neuron migration, and axon and dendrite morphogenesis. Data derived from genomic research has identified a multitude of genes that are linked to brain disorders and developmental differences. Information about where and how these genes function and cooperate is lagging behind. The approach used here may help to shed light on the biological underpinnings in which key genes interface and may prove useful for the testing of specific hypotheses.
Topics: Catechol O-Methyltransferase; Cognitive Dysfunction; Fragile X Mental Retardation Protein; Hippocampus; Humans; Intellectual Disability; Neurogenesis; Social Behavior
PubMed: 35590332
DOI: 10.1186/s12993-022-00191-7 -
Molecular Genetics and Metabolism Nov 2023Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include... (Review)
Review
Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.
Topics: Male; Humans; Female; Intellectual Disability; Creatine; Brain Diseases, Metabolic, Inborn; Mental Retardation, X-Linked; Plasma Membrane Neurotransmitter Transport Proteins; Nerve Tissue Proteins
PubMed: 37708665
DOI: 10.1016/j.ymgme.2023.107694 -
Computers in Biology and Medicine Dec 2022Mental retardation (MR) is a group of mental disorders characterized by low intelligence and social adjustment difficulties. Early diagnosis is beneficial for the timely...
Mental retardation (MR) is a group of mental disorders characterized by low intelligence and social adjustment difficulties. Early diagnosis is beneficial for the timely intervention of children with MR to ease the degree of disability. Children with MR always have impaired speech functions compared to normal children, which is significant for clinical diagnosis. On the basis of this, our study proposes a spontaneous speech-based framework (MT-Net) for screening MR, which merges mobile inverted bottleneck convolutional blocks (MBConv) and visual Transformer blocks. MT-Net takes log-mel spectrograms converted from raw interview speech as data source, and utilizes MBConv and visual Transformer to learn low-level and high-level features well. In addition, SpecAugment, a data augmentation strategy, has been used to expand our audio dataset to further enhance the performance of MT-Net. The experimental results show that our proposed MT-Net outperforms Transformer networks (ViT) and convolutional neural networks (ResNet18, MobileNetV2, EfficientNetV2), achieving accuracy of 91.60% after using SpecAugment. Our proposed MT-Net has fewer parameters, low computing consumption and high prediction accuracy, which is expected to be an auxiliary screening tool for MR.
Topics: Child; Humans; Speech; Intellectual Disability; Learning; Neural Networks, Computer
PubMed: 36399858
DOI: 10.1016/j.compbiomed.2022.106281 -
Irish Journal of Psychological Medicine Sep 2022Ireland has an ageing population of persons with intellectual disability (ID), autism spectrum disorder (ASD) and both (ID/ASD). Despite this, little is known about the... (Review)
Review
INTRODUCTION
Ireland has an ageing population of persons with intellectual disability (ID), autism spectrum disorder (ASD) and both (ID/ASD). Despite this, little is known about the prevalence of ASD and its effect on functional outcomes, psychiatric comorbidity or diagnostic issues in an older population with ID. This article reviews the literature on older adults with ID/ASD and identifies opportunities for future research in this population.
METHOD
The authors searched the Medline, Pubmed, Embase, CINAHL and PsychInfo databases using the search terms using key words: (older adults) AND (ID OR mental retardation OR learning disability) AND (autism OR ASD). After excluding articles for relevance, a scoping review was carried out on the results retrieved.
RESULTS
Of the 1227 articles retrieved from the literature on ID and autism/ASD in older adults, 85 articles were relevant to an adult population with ID/ASD. The data were collated and are presented covering domains of diagnosis, prevalence, psychiatric comorbidities and functional outcomes.
CONCLUSIONS
Despite increased prevalence in childhood ASD in the last 20 years, there is a lack of research regarding adults, especially older adults, with ASD, up to half of whom will have some level of ID. The existing literature suggests that older adults with ID/ASD may have reduced functional independence, increased psychiatric comorbidity and psychotropic prescribing and more behavioural presentations than the older population generally or those with ID only. There is a need for longitudinal data to be collected on this ageing population so that care and management needs can be met in the future.
Topics: Aged; Autism Spectrum Disorder; Autistic Disorder; Humans; Intellectual Disability; Ireland; Prevalence
PubMed: 34612183
DOI: 10.1017/ipm.2021.65 -
Medicine Dec 2020The typical manifestations of patients with a trisomy 21 syndrome are mental retardation and anatomical deformities of face and neck. In the available literature, all...
Anesthesia and airway managements for emergency removal of esophageal foreign body in a trisomy 21 patient with mental retardation and predicted difficult airway: A case report.
INTRODUCTION
The typical manifestations of patients with a trisomy 21 syndrome are mental retardation and anatomical deformities of face and neck. In the available literature, all case reports regarding anesthetic management of mentally retarded patients have focused on elective surgeries. There is no report regarding anesthetic management of mentally retarded patients undergoing emergency surgery.
PATIENT CONCERNS
A 47-year-old woman with a mental retardation grade 2 by trisomy 21 syndrome suffered from an esophageal foreign body for 3 days and needed emergency removal of esophageal foreign body. The patient had a poor cooperation and obvious anatomical abnormalities of head and neck.
DIAGNOSES
Difficult anesthesia and airway managements for emergency removal of esophageal foreign bodies in a trisomy 21patients with mental retardation and predicted difficult airways.
INTERVENTIONS
Combined use of an intubating supraglottic airway and the flexible bronchoscope-guided intubation after intravenous anesthesia induction.
OUTCOMES
Effective airway was safely established and an esophageal foreign body was successfully removed by rigid esophagoscopy under anesthesia. The patient recovered smoothly without any complication.
LESSONS SUBSECTIONS AS PER STYLE
When general anesthesia and emergency airway management are required in the patients with mental retardation and predicted difficult airways, a combination of the supraglottic airway and the flexible bronchoscope maybe a safe and useful choice for airway control.
Topics: Airway Management; Down Syndrome; Esophagoscopy; Esophagus; Female; Foreign Bodies; Humans; Intellectual Disability; Middle Aged
PubMed: 33371118
DOI: 10.1097/MD.0000000000023710 -
Human Genetics Sep 2019Absence of part or all of the iris, aniridia, is a feature of several genetically distinct conditions. This review focuses on iris development and then the clinical... (Review)
Review
Absence of part or all of the iris, aniridia, is a feature of several genetically distinct conditions. This review focuses on iris development and then the clinical features and molecular genetics of these iris malformations. Classical aniridia, a panocular eye malformation including foveal hypoplasia, is the archetypal phenotype associated with heterozygous PAX6 loss-of-function mutations. Since this was identified in 1991, many genetic mechanisms of PAX6 inactivation have been elucidated, the commonest alleles being intragenic mutations causing premature stop codons, followed by those causing C-terminal extensions. Rarely, aniridia cases are associated with FOXC1, PITX2 and/or their regulatory regions. Aniridia can also occur as a component of many severe global eye malformations. Gillespie syndrome-a triad of partial aniridia, non-progressive cerebellar ataxia and intellectual disability-is phenotypically and genotypically distinct from classical aniridia. The causative gene has recently been identified as ITPR1. The same characteristic Gillespie syndrome-like iris, with aplasia of the pupillary sphincter and a scalloped margin, is seen in ACTA2-related multisystemic smooth muscle dysfunction syndrome. WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies and mental retardation/intellectual disability), is caused by contiguous deletion of PAX6 and WT1 on chromosome 11p. Deletions encompassing BDNF have been causally implicated in the obesity and intellectual disability associated with the condition. Lastly, we outline a genetic investigation strategy for aniridia in light of recent developments, suggesting an approach based principally on chromosomal array and gene panel testing. This strategy aims to test all known aniridia loci-including the rarer, life-limiting causes-whilst remaining simple and practical.
Topics: Animals; Aniridia; Cerebellar Ataxia; Eye Proteins; Humans; Intellectual Disability; Iris; Mutation
PubMed: 30242502
DOI: 10.1007/s00439-018-1934-8 -
Prilozi (Makedonska Akademija Na... Dec 2023Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a genetically and clinically heterogeneous disorder with four described subtypes. Autosomal...
Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a genetically and clinically heterogeneous disorder with four described subtypes. Autosomal recessive syndrome of cerebellar ataxia, mental retardation, and disequilibrium type 4 (CAMRQ4) is caused by mutations in the gene. We report an 8-year-old boy with choreoathetosis, hypotonia, without the ability to keep his head up and profound mental retardation. There was quadrupedal locomotion, as well. MRI of the brain revealed a hypotrophy of the corpus callosum, diffuse white matter reduction, widespread delayed myelination and ventriculomegaly. Trio whole-exome sequencing revealed compound heterozygosity in the gene consisting of a known variant c.1756C>T (p.Arg586*) inherited from the mother and a novel variant c.691_701delCTGATGAAGTT (p.Leu231fs) inherited from the father. CAMRQ type 4 has been found in about 50 patients. To the best of our knowledge, this is the first reported patient with CAMRQ4 with these gene variants. The clinical presentation is severe.
Topics: Male; Humans; Child; Cerebellar Ataxia; Intellectual Disability; Brain; Mutation
PubMed: 38109455
DOI: 10.2478/prilozi-2023-0051 -
European Journal of Human Genetics :... Dec 2023Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15...
Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.
Topics: Male; Humans; Female; Intellectual Disability; Mental Retardation, X-Linked; Hypogonadism; Obesity
PubMed: 37704779
DOI: 10.1038/s41431-023-01447-0