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Molecular Autism Jun 2024Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in...
BACKGROUND
Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.
METHODS
To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).
RESULTS
We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D on the order of 1 × 10).
LIMITATIONS
We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.
CONCLUSIONS
This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.
Topics: Humans; Autistic Disorder; Phenotype; Male; Female; Linkage Disequilibrium; Multifactorial Inheritance; Child; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adult; Intellectual Disability
PubMed: 38877467
DOI: 10.1186/s13229-024-00605-5 -
Translational Psychiatry Jun 2024Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced...
Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1 rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1 rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.
Topics: Animals; Haploinsufficiency; Rats; Schizophrenia; Male; Adaptor Proteins, Signal Transducing; Prefrontal Cortex; Autistic Disorder; CA1 Region, Hippocampal; Disease Models, Animal; Nerve Net; Behavior, Animal; Corpus Striatum; Ventral Striatum
PubMed: 38876996
DOI: 10.1038/s41398-024-02969-x -
Frontiers in Neuroanatomy 2024Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited allele, leading to a loss of UBE3A protein expression in...
Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited allele is epigenetically silenced in neurons during development by a noncoding transcript (). The absence of neuronal UBE3A results in severe neurological symptoms, including speech and language impairments, intellectual disability, and seizures. While no cure exists, therapies aiming to restore UBE3A function-either by gene addition or by targeting -are under development. Progress in developing these treatments relies heavily on inferences drawn from mouse studies about the function of UBE3A in the human brain. To aid translational efforts and to gain an understanding of UBE3A and biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and expression in the developing brain of the rhesus macaque, a species that exhibits complex social behaviors, resembling aspects of human behavior to a greater degree than mice. Combining immunohistochemistry and hybridization, we mapped UBE3A and regional and cellular expression in normal prenatal, neonatal, and adolescent rhesus macaque brains. We show that key hallmarks of UBE3A biology, well-known in rodents, are also present in macaques, and suggest paternal silencing in neurons-but not glial cells-in the macaque brain, with onset between gestational day 48 and 100. These findings support proposals that early-life, perhaps even prenatal, intervention is optimal for overcoming the maternal allele loss of linked to AS.
PubMed: 38873093
DOI: 10.3389/fnana.2024.1410791 -
Cureus May 2024Pituitary stalk interruption syndrome is a triad of thin (<1 mm) or complete absence of the pituitary stalk with either an aplastic or ectopic posterior lobe of the...
Pituitary stalk interruption syndrome is a triad of thin (<1 mm) or complete absence of the pituitary stalk with either an aplastic or ectopic posterior lobe of the pituitary gland and a hypoplastic or absent anterior lobe of the pituitary. Patients present with growth retardation, short height, seizures, intellectual disability, and absence of sexual maturation at the expected time. Here, we presented a case of a 12-year-old male with stunted growth. Upon examination, there was reduced height, more than 3 standard deviations below the average for his chronological age. Laboratory results showed reduced levels of growth hormone and thyrotropin. Dual-energy X-ray absorptiometry revealed osteoporosis, while an X-ray of the wrist for bone age corresponded to seven years. MRI imaging confirmed the classical triad of findings for pituitary stalk interruption syndrome. Consequently, the patient was referred back to the endocrinology clinic for further management.
PubMed: 38872685
DOI: 10.7759/cureus.60232 -
Journal of Neurodevelopmental Disorders Jun 2024Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living,...
BACKGROUND
Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM-5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD.
METHODS
Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (m = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization).
RESULTS
Over a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model.
CONCLUSIONS
The present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.
Topics: Humans; Male; Child; Adolescent; Female; Adaptation, Psychological; Young Adult; Adult; Intellectual Disability; Developmental Disabilities; Cognition; Longitudinal Studies; Activities of Daily Living; Socialization; Down Syndrome; Fragile X Syndrome
PubMed: 38872099
DOI: 10.1186/s11689-024-09542-z -
Journal of Neurodevelopmental Disorders Jun 2024Fragile X syndrome (FXS) is caused by epigenetic silencing of the X-linked fragile X messenger ribonucleoprotein 1 (FMR1) gene located on chromosome Xq27.3, which leads... (Review)
Review
Fragile X syndrome (FXS) is caused by epigenetic silencing of the X-linked fragile X messenger ribonucleoprotein 1 (FMR1) gene located on chromosome Xq27.3, which leads to the loss of its protein product, fragile X messenger ribonucleoprotein (FMRP). It is the most prevalent inherited form of intellectual disability and the highest single genetic cause of autism. Since the discovery of the genetic basis of FXS, extensive studies using animal models and human pluripotent stem cells have unveiled the functions of FMRP and mechanisms underlying FXS. However, clinical trials have not yielded successful treatment. Here we review what we have learned from commonly used models for FXS, potential limitations of these models, and recommendations for future steps.
Topics: Fragile X Syndrome; Humans; Animals; Fragile X Mental Retardation Protein; Disease Models, Animal; Pluripotent Stem Cells
PubMed: 38872088
DOI: 10.1186/s11689-024-09545-w -
The International Journal of... Jun 2024Mutations in the gene encoding Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) protein are associated with a variety of neurological disorders, ranging from...
Mutations in the gene encoding Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) protein are associated with a variety of neurological disorders, ranging from non-syndromic hearing loss to drug-resistant lethal epileptic encephalopathy and DOORS syndrome [Deafness, Onychodystrophy, Osteodystrophy, intellectual disability (formerly referred to as mental Retardation), and Seizures]. TBC1D24 is a vesicle-associated protein involved in neural crest cell and neuronal migration, maturation, and neurotransmission. In the cochlea, TBC1D24 has been detected in auditory neurons, but few reliable and convergent data exist about the sensory epithelium. Here, the expression of TBC1D24 has been characterized via immunolabelling throughout the postnatal maturation of the mouse cochlear sensory epithelium. TBC1D24 was detected in glia-like non-sensory epithelial cells during early developmental stages. In contrast, TBC1D24 was virtually absent in adjacent sensory hair cells. This expression distinguishing non-sensory from sensory epithelial cells almost disappears around the onset of hearing. Until now, TBC1D24 was mainly described as a neuronal protein either in the brain or in the cochlea. The present observations suggest that TBC1D24 could also regulate vesicle trafficking in cochlear glia-like non-sensory epithelial cells. For a long time, research about epilepsy has been mainly neurocentric. However, there is now evidence proving that glial cell dysregulation contribute to pathogenesis of epilepsy and neurodevelopmental disorders. As a consequence, exploring the possibility that TBC1D24 could also have a role in glial cells of the central nervous system could help to gain insight into TBC1D24-related neurological pathogenesis.
PubMed: 38869222
DOI: 10.1387/ijdb.240060jd -
IScience Jun 2024The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD)...
The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD) 'Intellectual Disability, Autosomal Dominant 57' (MRD57), characterized by intellectual disability and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a heterozygous TLK1 variant (c.1435C>G, p.Q479E), as well as a mutation in MDM1 (c.1197dupT, p.K400∗). Cells expressing TLK1 p.Q479E exhibited reduced cytokine responses and elevated DNA damage, but not increased radiation sensitivity or DNA repair defects. The TLK1 p.Q479E variant impaired kinase activity but not proximal protein interactions. Our study provides the first functional characterization of NDD-associated TLK1 variants and suggests that, such as TLK2, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.
PubMed: 38868186
DOI: 10.1016/j.isci.2024.109984 -
Acta Neuropathologica Communications Jun 2024Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and...
Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.
Topics: Humans; Down Syndrome; tau Proteins; Cryoelectron Microscopy; Middle Aged; Alzheimer Disease; Female; Adult; Male; Neurofibrillary Tangles; Brain
PubMed: 38867338
DOI: 10.1186/s40478-024-01806-y