Journal of Neurodevelopmental Disorders最新文献

Background: Restricted and repetitive behaviors (RRB) are core features of autism but are also observed in typical development. Our understanding of the neural underpinnings of RRBs is limited. Given that excitation-inhibition (E/I) balance may underlie RRBs, we aimed to evaluate the relationship between aperiodic exponent (as a proxy of E/I balance) and changes in RRBs over time in infants with and without elevated likelihood of autism.

Methods: Resting-state EEG data were collected from 12-to-14-month-old infants and aperiodic exponent was calculated. Parent-reported RRBs were obtained using the Repetitive Behavior Scale-Revised questionnaire to measure the severity and change in RRBs from 12-to-36 months. Multiple linear regressions were conducted to assess relationships between aperiodic and change in RRBs.

Results: Marginal effects analysis of linear regressions revealed significant associations such that lower aperiodic exponent was associated with elevated RRBs reported over time across the whole sample ([Formula: see text]=0.31, β= -0.21, p = 0.01), which was more prominently observed in the infants who later received an autism diagnosis (δy/δx = -15.57, p < .001).

Conclusions: Results suggest that early EEG aperiodic activity may serve as a potential correlate of increased manifestation of RRBs. Longitudinal studies are needed to elucidate whether the early trajectory of aperiodic activity in development influences the severity of RRBs in childhood.

Background: MED13L-related disorder is associated with intellectual disability, motor delay, and speech deficits. Previous studies have focused on broad clinical descriptions of individuals, but limited information regarding specific speech diagnoses and results of direct testing has been published to date. We conducted deep phenotyping to characterize the speech, language, motor, cognitive, and adaptive phenotypes of individuals with MED13L-related disorder.

Methods: In this cross-sectional study, we administered standardized articulation, language, motor, and cognitive testing to 17 children and adolescents (mean age 9y 9m; SD 4y 5m; range 4y 2m to 19y 7m). In-person testing was supplemented with broad developmental, medical, and behavioral information collected virtually from a cohort of 67 individuals.

Results: All individuals who completed in-person articulation testing met diagnostic criteria for speech apraxia, dysarthria, or both. Language impairment was present in all of the in-person cohort and reported for almost all (97%) of the virtual cohort. Those who were able to complete motor testing demonstrated significant deficits in visual motor integration (mean 57.08, SD 9.26). Full scale IQs fell in the borderline to intellectual disability range, consistent with reported cognitive impairment in 97% of the virtual cohort. Notable medical features included hypotonia (83%), vision problems (72%), recurrent otitis media (58%), gastrointestinal problems (57%), and seizures (31%).

Conclusions: MED13L-related disorder is characterized by a high rate of motor speech disorders that occur in the context of globally impaired motor, language, and cognitive skills. Children would benefit from early referrals to speech therapy to assess their speech, language, and support needs.

Background: There have been increasing numbers of clinical trials of medications for fragile X syndrome (FXS) in recent years, many targeted at proposed underlying cellular or circuit based mechanisms. As yet none of these have led to widespread changes in clinical practice. Genetic therapies represent a different therapeutic approach, which aim to address the genetic mechanisms by which FXS arises. Although not yet moving into human studies in FXS, this is an area of increasing research importance in neurodevelopmental conditions more broadly. It is important that families affected by FXS get the chance to give their views about future genetic therapies, given the potential controversies around genetic therapies.

Methods: We developed a questionnaire to capture caregiver views around gene therapy in FXS. The questionnaire was developed alongside a group of parents / caregivers of a child with FXS to ensure the language used was appropriate and that it would allow a variety of views to be captured. The questionnaire contained questions around current knowledge of gene therapy, what families think of gene therapy and their views on gene therapy trials taking place. Responses were analysed by thematic analysis carried out by two of the authors with data from the questionnaires being grouped into themes and subthemes.

Results: The questionnaire was completed by 195 individuals who are parents of, or who care for, someone with FXS. Respondents were primarily from the UK (60.5%) and the Americas (22.1%). The majority of dependants were male (86%). Responses showed a strong interest from the Fragile X community in gene therapy trials taking place, with themes emerging around quality of life, outcomes and feelings. Hope for positive change was balanced against caution about unintended consequences, the newness of the treatment and tolerability.

Conclusion: Overall, caregivers felt hopeful, excited and interested in the prospect of gene therapy potentially providing a new treatment option, but there was some trepidation about the potential effects. Taking caregiver views into account will help inform decisions around the development and testing of any future genetic interventions.

Background: Eukaryotic initiation factor 5 A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently described diseases caused by pathogenic heterozygous variants in the translation factor EIF5A or biallelic variants in the two enzymes involved in the post-translational synthesis of hypusine in the eIF5A precursor, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), necessary for its activation. We review the current knowledge regarding eIF5A-HRD, and report the case of the sixth and oldest known patient with DOHH-related disorder (DOHH-D), aiming to expand and discuss the molecular basis and the general and epilepsy phenotypes of this group of diseases.

Results: Literature review yielded one paper describing 7 individuals with eIF5A-related disorders (eIF5A-D), one reporting 5 subjects with DHPS-related disorders (DHPS-D) and one characterizing 5 individuals with DOHH-D. Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe neurodevelopmental disorders/intellectual disability and behavioral disorders. We report the case of a 24-years-old male with DOHH-D manifesting as Dravet-like syndrome. He displays microcephaly and neurodevelopmental delay with attention deficit with hyperactivity disorder, along with a happy demeanor. Basic language skills and ambulation capacity with crouch gait are preserved. Onset of epilepsy was at 8 months with refractory temperature-triggered hemiclonic seizures and status epilepticus, followed by nocturnal tonic-clonic seizures from adolescence. Fenfluramine was the most effective approach, reducing seizure intensity, duration and frequency, and contributing to cognitive and behavior improvements. No patient with eIF5A-D presented seizures. Taking our patient into account, 4/5 and 4/6 reported individuals with DHPS-D and DOHH-D, respectively, presented epilepsy. Seven out of 8 epilepsy patients debuted between 2 and 5 years, most of them presented developmental and epileptic encephalopathies or generalized epilepsies (5/8 with temperature or infection-triggered seizures), and 4/8 were refractory. We hypothesize that dysregulation of IQSEC2 and SHANK3, among other genes, might contribute to the eIF5A-HRD phenotype.

Conclusions: eIF5A-HRD are recently described entities displaying neurodevelopmental disorders and microcephaly, and reported patients are scarce. More than 70% of DHPS-D and DOHH-D patients present epilepsy, 63% of them with temperature-triggered seizures. Valproic acid or fenfluramine may be effective. Rare homozygous or compound heterozygous missense variants in these genes should be screened in patients with encephalopathy and temperature-triggered seizures.

Estimating time and making predictions is integral to our experience of the world. Given the importance of timing to most behaviors, disruptions in temporal processing and timed performance are reported in a number of neuropsychiatric disorders such as Schizophrenia, Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), and Attention-deficit Hyperactivity Disorder (ADHD). Symptoms that implicitly include disruption in timing are atypical turn-taking during social interactions, unusual verbal intonations, poor reading, speech and language skills, inattention, delays in learning, and difficulties making predictions. Currently, there are no viable treatments for these symptoms, the reason being the underlying neural dysfunction that contributes to timing deficits in neuropsychiatric disorders is unknown. To address this unknown, we have designed a novel Temporal Pattern Sensory Discrimination Task (TPSD) for awake-behaving mice. Stimuli consist of paired audiovisual stimuli that differ in duration. Compared to Wild-Type (WT) mice, Fmr1^-/- mice, a well-established mouse model of FXS, showed significant impairment in learning the TPSD task, as evidenced by reduced discriminability indices and atypical licking patterns. Often sensory information is multimodal and, indeed, studies show that learning in humans and rodents improves with multimodal stimuli than with unimodal stimuli. To test how the multimodal nature of stimuli impacted performance of Fmr1^-/- mice, following training on the audiovisual stimuli, we tested mice on audio-only or visual-only stimuli. While WT mice showed significant disruption in performance when tested on unimodal stimuli, Fmr1^-/- mice displayed equivalent performance on visual-only stimuli when compared to the multimodal task. Our novel task captures timing difficulties and multisensory integration issues in Fmr1^-/- mice and provides an assay to examine the associated neural dysfunction.

Background: Phelan-McDermid Syndrome (PMS) is a rare genetic condition characterized by deletion or mutation of region 22q13.3, which includes the SHANK3 gene. Clinical descriptions of this population include severely impaired or absent expressive language, mildly dysmorphic features, neonatal hypotonia, developmental delays, intellectual impairments, and autistic-like traits including abnormal reactivity to sensory stimuli. Electroencephalography (EEG) has shown promise as a tool for identifying neurophysiological abnormalities in neurodevelopmental disorders. However, few EEG studies focused on sensory processing have been performed on this population. Thus, this study focuses on comparisons of event-related potential (ERP), event-related spectral perturbation (ERSP), and inter-trial coherence (ITC) between PMS and typically developing (TD) individuals in a standard auditory gating task measuring attenuation of neural activity to repetitive auditory stimuli.

Methods: A total of 37 participants, 21 PMS (12 females, age range 8-18.6 years) and 16 TD individuals (8 females, age range 8.2-15.3 years) were included. Analysis consisted of a series of general linear models using a regional (frontal) and global (whole-head) approach to characterize neural activity between PMS and TD participants by age, sex, and group.

Results: Most notably, individuals with PMS had delayed or low amplitude P50, N1, and P2 responses in frontal and whole-head analyses as well as poor frontal phase-locking to auditory stimuli for alpha, beta and gamma ITC, indicating impaired processing of stimulus properties. Additionally, individuals with PMS differed from TD by age in delta, theta, and alpha power, as well as frontal beta-gamma ITC, suggesting different developmental trajectories for individuals with PMS. Within PMS, larger deletion sizes were associated with increased auditory processing abnormalities for frontal P50 as well as whole-head P50 and N1.

Limitations: This is one of the largest EEG studies of PMS. However, PMS is a rare genetic condition, and our small sample has limited statistical power for subgroup comparisons. Findings should be considered exploratory.

Conclusions: Results suggest that participants with PMS exhibit auditory processing abnormalities with complex variation by deletion-size, age, and sex with congruency to impaired early recognition (P50), feature processing (N1), information integration (delta, theta), sensory processing and auditory inhibition (alpha), and inhibitory modulation of repeated auditory stimuli (beta, gamma). Findings may provide valuable insight into clinical characterization of sensory and speech behaviors in future studies.

Sturge-Weber Syndrome (SWS) is a congenital neurovascular disorder caused by a somatic mosaic mutation in the R183Q GNAQ gene and characterized by capillary-venous malformations of the brain, skin, and eyes. Clinical manifestations include facial port-wine birthmark, glaucoma, seizures, headache or migraine, hemiparesis, stroke or stroke-like episodes, developmental delay, behavioral problems, and hormonal deficiencies. SWS requires careful monitoring, management, and early identification to improve outcome and prevent neurological deterioration. Over the last 25 years, biomarkers have been developed to improve early diagnosis and prognosis and allow for the monitoring of clinical status and treatment response. Importantly, advancements in biomarker research may enable presymptomatic treatment for infants with SWS. This review summarizes current, ongoing, and potential future SWS biomarker studies. These biomarkers, in combination with clinical data, offer a rich source of data for rare disease research leveraging machine learning in future research.