There is a critical need to identify biomarkers and objective outcome measures that can be used to understand underlying neural mechanisms in autism spectrum disorder (ASD). Visual evoked potentials ...(VEPs) offer a noninvasive technique to evaluate the functional integrity of neural mechanisms, specifically visual pathways, while probing for disease pathophysiology.
Transient VEPs (tVEPs) were obtained from 96 unmedicated children, including 37 children with ASD, 36 typically developing (TD) children, and 23 unaffected siblings (SIBS). A conventional contrast-reversing checkerboard condition was compared to a novel short-duration condition, which was developed to enable objective data collection from severely affected populations who are often excluded from electroencephalographic (EEG) studies.
Children with ASD showed significantly smaller amplitudes compared to TD children at two of the earliest critical VEP components, P60-N75 and N75-P100. SIBS showed intermediate responses relative to ASD and TD groups. There were no group differences in response latency. Frequency band analyses indicated significantly weaker responses for the ASD group in bands encompassing gamma-wave activity. Ninety-two percent of children with ASD were able to complete the short-duration condition compared to 68% for the standard condition.
The current study establishes the utility of a short-duration tVEP test for use in children at varying levels of functioning and describes neural abnormalities in children with idiopathic ASD. Implications for excitatory/inhibitory balance as well as the potential application of VEP for use in clinical trials are discussed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose of Review
Neuropsychological assessment involves the comprehensive evaluation of intellectual, attentional, executive, social-cognitive, language, and motor functioning. Such assessments are ...used to characterize areas of strength and weakness, inform differential diagnosis, guide treatment planning, and evaluate change over time. Individuals with autism spectrum disorder (ASD) present with varied clinical presentations, which can make the design of testing batteries and subsequent interpretation of results challenging. Here we provide an overview of neuropsychological domains as they relate to the evaluation of individuals with ASD.
Recent Findings
Individuals with ASD demonstrate unique patterns of neuropsychological functioning across various domains. Recent findings related to intellectual, adaptive, executive, attentional, social, language, motor, and autism-specific functioning are reviewed.
Summary
Clarifying the relationship between ASD symptoms and neuropsychological functioning is critical for differential diagnosis and for optimal treatment planning. Tools and methods for developing appropriate neuropsychological testing protocols for individuals with ASD are discussed.
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to
...haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in
has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking.
We provide detailed clinical and genetic data on 17 individuals carrying mutations in
. We also review 60 previously reported patients with pathogenic or likely pathogenic
variants, often lacking detailed phenotypic information.
mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems.
Haploinsufficiency of
resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by
point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of
.
Abstract
CHAMP1-related neurodevelopmental disorder, or CHAMP1 disorder, is a recently described genetic syndrome associated with developmental delay, intellectual disability, behavioral symptoms, ...medical comorbidities, and dysmorphic features. To date, literature has focused on medical review and dysmorphology but has yet to prospectively assess neurobehavioral core domains such as autism, or behavioral, language, cognitive, and sensory features. Here, we present deep phenotyping results for 11 individuals with CHAMP1 disorder, based on approximately 12 hours of remote clinician-administered assessments and standardized caregiver questionnaires. Diagnoses of autism spectrum disorder were given to 33% of participants; repetitive behaviors and sensory-seeking symptoms were prominent in this cohort. In addition, 60% of participants met the criteria for attention-deficit/hyperactivity disorder (ADHD). High rates of ADHD and relatively low rates of treatment suggest potential areas for intervention. This study represents the first prospective phenotyping analysis of individuals with CHAMP1 disorder. The utility of specific measures as clinical endpoints, as well as benefits and limitations of remote phenotyping, are described.
CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the
CHAMP1
gene that result in premature termination codons. The disorder is associated with intellectual disability, ...medical comorbidities, and dysmorphic features. Deletions of the
CHAMP1
gene, as part of 13q34 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in
CHAMP1
to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in
CHAMP1
. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through
CHAMP1
haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.
Abstract
Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate ...genotype–phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype–phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype–phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.
As early identification of autism improves, there is a critical need for interventions to support the development of social communication skills in toddlers. Caregiver coaching and parental ...involvement is crucial for improving outcomes and providing children with adequate hours of planned active engagement. This pilot study assessed a 4-week intervention for individual caregiver–child dyads. Eight toddlers 21- to 45-months of age participated. Standardized assessments were collected at four study visits to assess autism symptomatology, language development, and both caregiver knowledge and engagement. Results demonstrated the feasibility of the intervention. Social communication, receptive and expressive language all improved as measured by direct assessment. Caregiver knowledge and caregivers’ subjective feelings of engagement with their toddlers also improved.
This study evaluated the efficacy of a targeted social skills training group in school-aged children with autism spectrum disorder (ASD). The intervention, Seaver-NETT (Nonverbal communication, ...Emotion recognition, and Theory of mind Training), is a 12-session cognitive-behavioral intervention (CBI) for verbal, school-aged children targeting ASD-specific social behavioral impairments.
Sixty-nine children with ASD, 8 to 11 years of age, with verbal IQs greater than 70, participated in a randomized comparative trial to examine the efficacy of NETT relative to a facilitated play group. Treatment outcomes included caregiver reports of social behavior and neuropsychological assessments of social cognition conducted by blinded raters. Outcomes were collected at baseline, endpoint, and 3 months posttreatment.
Significant improvements were found on social behavior outcomes such as nonverbal communication, empathic responding, and social relations in the NETT condition relative to the active control at endpoint. Verbal IQ moderated the interaction effect on social behavior, with higher verbal IQ associated with improvements in the CBI condition. No significant improvements were found on social cognitive outcomes. No significant group differences were found at 3-month follow-up conducted with approximately half the sample (n = 34).
These data indicate that targeted CBI social skills groups such as NETT improve social communication deficits in verbal, school-aged children with ASD. The moderating effects of high verbal IQ suggest a need to consider participant and treatment characteristics associated with outcomes in future studies. Clinical trial registration information-Neural and Behavioral Outcomes of Social Skills Groups in Children With Autism Spectrum Disorder; https://clinicaltrials.gov; NCT01190917.
Visual evoked potentials (VEPs) provide a means to examine neural mechanisms in autism with high temporal resolution. Conventional VEP analysis relies on subjective inspection of a few points (peaks ...and troughs) in the time‐domain waveform. The current study applied power spectral analysis and magnitude‐squared coherence (MSC) statistics (frequency‐domain measures) to VEPs recorded during 1‐minute runs and with a recently developed short‐duration technique that allow for objective examination of the responses (Zemon & Gordon, European Journal of Neuroscience, 2018, 48, 1765–1788) from nonautistic and autistic children. Results indicate that, for both groups, early time‐domain measures (P60, N75, P100) are highly correlated with middle‐ and high‐frequency (14–28 and 30–48 Hz, respectively) mechanisms, and late measures are highly correlated with a low‐frequency (6–12 Hz) mechanism. One frequency‐domain measure (power in the middle‐frequency band) is capable of predicting the key amplitude measure (N75‐P100) with high accuracy. MSC and power measures were combined to yield separate measures of signal and noise strength to evaluate alternate hypotheses in autism. Linear mixed‐effects modeling demonstrated selective differences in early time‐domain and middle‐to‐high frequency‐domain measures in autistic children as compared to nonautistic children given both recording techniques, implicating weaker excitatory input to the cortex. Receiver‐operating‐characteristic curve analysis showed predictive diagnostic accuracy for middle‐ and high‐frequency bands based on MSC. These findings support the value of frequency analysis measures (power spectral analysis and MSC) in the objective examination of neural differences in autism.
Lay Summary
Visual evoked potentials (VEPs) are used to assess neural mechanisms. Typically, VEPs are analyzed by subjective examination of time‐series waveforms; but here objective techniques were applied to quantify VEP frequency components to investigate neural differences between autistic and nonautistic children. The objective measures demonstrate group differences in brain function that point to weaker excitatory input to the cortex in autism.
FOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early ...development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.
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