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Journal of Neurodevelopmental Disorders Nov 2023The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman...
OBJECTIVE
The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]).
METHODS
Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences.
RESULTS
The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications.
CONCLUSION
Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.
Topics: Humans; Child; Infant; Prader-Willi Syndrome; Chromosome Disorders; Chromosomes; Angelman Syndrome; Trisomy
PubMed: 37936142
DOI: 10.1186/s11689-023-09504-x -
Journal of Visualized Experiments : JoVE Oct 2023This manuscript describes a battery of behavioral tests available to characterize Angelman syndrome (AS)-like phenotypes in an established murine model of AS. We use the...
This manuscript describes a battery of behavioral tests available to characterize Angelman syndrome (AS)-like phenotypes in an established murine model of AS. We use the rotarod learning paradigm, detailed gait analysis, and nest building test to detect and characterize animal motor impairments. We test animal emotionality in the open field and elevated plus maze tests, as well as the affect in the tail suspension test. When AS mice are tested in the open field test, the results should be interpreted with care, since motor dysfunctions influence mouse behavior in the maze and alter activity scores. The reproducibility and effectiveness of the presented behavioral tests has already been validated in several independent Uba3a mouse lines with different knockout variants, establishing this set of tests as an excellent validation tool in AS research. Models with the relevant construct and face validity will warrant further investigations to elucidate the pathophysiology of the disease and grant the development of causal treatments.
Topics: Mice; Animals; Angelman Syndrome; Disease Models, Animal; Reproducibility of Results; Learning; Motor Activity; Behavior, Animal; Maze Learning
PubMed: 37929955
DOI: 10.3791/65182 -
Frontiers in Cell and Developmental... 2023Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia,... (Review)
Review
Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia, and paroxysmal laughter. The condition arises due to the loss of the maternally inherited copy of the gene in neurons. The paternally inherited allele is unable to compensate because it is silenced by the expression of an antisense transcript () on the paternal chromosome. , encoding enigmatic E3 ubiquitin ligase variants, regulates target proteins by either modifying their properties/functions or leading them to degradation through the proteasome. Over time, animal models, particularly the Knock-Out (KO) mice, have significantly contributed to our understanding of the molecular mechanisms underlying AS. However, a shift toward human pluripotent stem cell models (PSCs), such as human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), has gained momentum. These stem cell models accurately capture human genetic and cellular characteristics, offering an alternative or a complement to animal experimentation. Human stem cells possess the remarkable ability to recapitulate neurogenesis and generate "brain-in-a-dish" models, making them valuable tools for studying neurodevelopmental disorders like AS. In this review, we provide an overview of the current state-of-the-art human stem cell models of AS and explore their potential to become the preclinical models of choice for drug screening and development, thus propelling AS therapeutic advancements and improving the lives of affected individuals.
PubMed: 37928900
DOI: 10.3389/fcell.2023.1274040 -
Cureus Oct 2023Autosomal dominant intellectual development disorder-6 (MRD6) arises from a gene mutation, inducing neurodevelopmental issues. The effects of MRD6 encompass cognitive...
Autosomal Dominant Intellectual Development Disorder-6 (MRD6) Without Seizures Linked to a De Novo Mutation in the grin2b Gene Revealed by Exome Sequencing: A Case Report of a Moroccan Child.
Autosomal dominant intellectual development disorder-6 (MRD6) arises from a gene mutation, inducing neurodevelopmental issues. The effects of MRD6 encompass cognitive disabilities, seizures, muscle tone decline, and autism-like traits. Its severity ranges from mild impairment to severe epilepsy. The disorder's rarity is emphasized by roughly 100 reported GRIN2B-related cases, spotlighting the gene's significance in brain development. We present the case of a three-year-old Moroccan boy who was referred to a neuropediatric department for a molecular diagnosis. Initial genetic testing yielded inconclusive results, and subsequent tests for Angelman syndrome and metabolic diseases showed no abnormalities. Given the complexity of the disorder, exome sequencing was employed to identify the underlying genetic cause. Exome sequencing identified a nonsense (STOP) mutation c.3912C>G (p.Tyr1304Ter) in the gene in the heterozygous state known to be present in MRD6 (Online Mendelian Inheritance in Man (OMIM) 613970). The family segregation study shows that this is a de novo variant, which is confirmed by Sanger sequencing. This variant has not been previously reported in the GnomAD database. Based on current scientific knowledge, the variant is considered pathogenic (PVS1, PS2, PM2, PP3, PP5) according to the criteria of the American College of Medical Genetics and Genomics (ACMG). The mutation in the gene (p.Tyr1304Ter) was predicted to be deleterious through bioinformatics analysis tools. This study highlights the crucial role of the gene in normal brain development and communication within the nervous system. It also sheds light on the impact of a novel genetic mutation, identified through exome sequencing, on causing an intellectual developmental disorder in a child patient from Morocco.
PubMed: 37927744
DOI: 10.7759/cureus.46456 -
FEBS Letters Jan 2024Aberrant brain-derived neurotrophic factor (BDNF) signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as...
Aberrant brain-derived neurotrophic factor (BDNF) signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have previously shown that targeting the tropomyosin receptor kinase B/postsynaptic density protein-95 (PSD-95) nexus in the BDNF signaling pathway by peptidomimetic inhibitors is a promising approach for therapeutic intervention. Here, we used structure-based knowledge to develop a new Syn3 peptidomimetic compound series that fuses peptides derived from the PSD-95-binding protein SynGAP to our prototype compound CN2097. The new compounds target the PSD-95 PDZ3 domain and adjoining αC helix to achieve bivalent binding that results in up to 7-fold stronger affinity compared to CN2097. These compounds were designed to improve CN2097 specificity for the PSD-95 PDZ3 domain, and structure-activity relationship studies were performed to improve their resistance to proteolysis.
Topics: Brain-Derived Neurotrophic Factor; Peptidomimetics; Disks Large Homolog 4 Protein; Signal Transduction; PDZ Domains
PubMed: 37904289
DOI: 10.1002/1873-3468.14767 -
Scientific Reports Oct 2023Angelman syndrome (AS) is a rare neurogenetic disorder caused by UBE3A deficiency and characterized by severe developmental delay, cognitive impairment, and motor...
Angelman syndrome (AS) is a rare neurogenetic disorder caused by UBE3A deficiency and characterized by severe developmental delay, cognitive impairment, and motor dysfunction. In the present study, we performed RNA-seq on hippocampal samples from both wildtype (WT) and AS male mice, with or without contextual fear memory recall. There were 281 recall-associated differentially expressed genes (DEGs) in WT mice and 268 DEGs in AS mice, with 129 shared by the two genotypes. Gene ontology analysis showed that extracellular matrix and stimulation-induced response genes were prominently enriched in recall-associated DEGs in WT mice, while nuclear acid metabolism and tissue development genes were highly enriched in those from AS mice. Further analyses showed that the 129 shared DEGs belonged to nuclear acid metabolism and tissue development genes. Unique recall DEGs in WT mice were enriched in biological processes critical for synaptic plasticity and learning and memory, including the extracellular matrix network clustered around fibronectin 1 and collagens. In contrast, AS-specific DEGs were not enriched in any known pathways. These results suggest that memory recall in AS mice, while altering the transcriptome, fails to recruit memory-associated transcriptional programs, which could be responsible for the memory impairment in AS mice.
Topics: Mice; Male; Animals; Angelman Syndrome; Memory Disorders; Hippocampus; Fear; Memory
PubMed: 37903805
DOI: 10.1038/s41598-023-45769-x -
Molecular Syndromology Oct 2023is an instrumental protein in neuronal synaptic transmission in the brain, facilitating neurotransmitter release. It is encoded by the gene, and pathogenic variants in...
INTRODUCTION
is an instrumental protein in neuronal synaptic transmission in the brain, facilitating neurotransmitter release. It is encoded by the gene, and pathogenic variants in this gene cause neurodevelopmental features including early onset axial hypotonia, intellectual disability, and features of autism spectrum disorder. To date, only three types of allelic variants (loss of function, in-frame deletions, and missense variants) in the gene have been previously reported in 11 patients with learning difficulties. Here, we describe a patient in whom a novel de novo pathogenic variant in the gene was identified.
CASE PRESENTATION
A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies. Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis. Gene agnostic analysis of whole genome sequencing data identified a novel de novo heterozygous missense variant c.197G>C (p.Arg66Pro) in the gene SNARE motif region.
DISCUSSION
This is the fourth report describing gene-related neurodevelopmental disorder. This report adds to the genotype-phenotype correlation and highlights this condition as an important differential diagnosis of Rett/Angelman-type spectrum of disorders. Patients presenting with features of either Rett syndrome or Angelman syndrome, in whom genetic testing is not suggestive, should be evaluated for variants in the gene, given the significant overlap in clinical presentation of these disorders.
PubMed: 37901860
DOI: 10.1159/000530150 -
Epilepsy Currents 2023
PubMed: 37901779
DOI: 10.1177/15357597231191885 -
MedRxiv : the Preprint Server For... Sep 2023Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We...
Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We provide population-based estimates of rCNV-associated risk of neuropsychiatric disorders for 34 rCNVs in the iPSYCH2015 case-cohort sample (n=120,247). Most observed significant increases in rCNV-associated risk for ADHD, autism or schizophrenia were moderate (HR:1.42-5.00), and risk estimates were highly correlated across these disorders, the most notable exception being high autism-associated risk with Prader-Willi/Angelman Syndrome duplications (HR=20.8). No rCNV was associated with significant increase in depression risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint. Comparison with published rCNV studies suggests that prevalence of some rCNVs is higher, and risk of psychiatric disorders lower, than previously estimated. In an era where genetics is increasingly being clinically applied, our results highlight the importance of population-based risk estimates for genetics-based predictions.
PubMed: 37886536
DOI: 10.1101/2023.09.04.23294975 -
American Journal on Intellectual and... Nov 2023Automated methods for processing of daylong audio recordings are efficient and may be an effective way of assessing developmental stage for typically developing...
Automated methods for processing of daylong audio recordings are efficient and may be an effective way of assessing developmental stage for typically developing children; however, their utility for children with developmental disabilities may be limited by constraints of algorithms and the scope of variables produced. Here, we present a novel utterance-level processing (ULP) system that 1) extracts utterances from daylong recordings, 2) verifies automated speaker tags using human annotation, and 3) provides vocal maturity metrics unavailable through automated systems. Study 1 examines the reliability and validity of this system in low-risk controls (LRC); Study 2 extends the ULP to children with Angelman syndrome (AS). Results showed that ULP annotations demonstrated high coder agreement across groups. Further, ULP metrics aligned with language assessments for LRC but not AS, perhaps reflecting limitations of language assessments in AS. We argue that ULP increases accuracy, efficiency, and accessibility of detailed vocal analysis for syndromic populations.
Topics: Humans; Child; Speech; Angelman Syndrome; Reproducibility of Results
PubMed: 37875276
DOI: 10.1352/1944-7558-128.6.425