A Prospective, Longitudinal Study of Caregiver-Reported Adaptive Skills and Function of Individuals with HNRNPH2-related Neurodevelopmental Disorder.

Objectives: This study presents a cohort of individuals in a natural history study with de novo pathogenic missense variants in HNRNPH2 causative of HNRNPH2-related neurodevelopmental disorder (NDD) to describe individuals' adaptive functional abilities. Methods: We measured adaptive function using the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) and the Vineland Adaptive Behavior Scale (VABS-III). Results were compared using inferential statistics and regression analysis. Results: Sixty-seven individuals carried known pathogenic or likely pathogenic variants in HNRNPH2. Thirty-five participants (2.89-42.04 years, 83% female) and caregivers completed PEDI-CAT assessments with 25 of these participants completing the VABS-III. Sixteen, three and two participants completed a follow-up PEDI-CAT assessment at one, two and three years respectively. Individuals had mean normative scores less than age-matched peers across all domains on both PEDI-CAT and VABS-III measures, with 91% participants < 5th percentile on both the PEDI- CAT and VABS-III. Verbal and ambulatory participants had significantly higher PEDI-CAT scores across all domains, using both raw and normative data. There was no significant change in PEDI-CAT scores over 3 years. Conclusions: Overall scores, both raw and normative, are low across all individuals with HNRNPH2-related NDD using both the PEDI-CAT and VABS-III. PEDI-CAT normative scores do not likely represent the clinical variability, but raw scores may be able to capture functional variability. In a small sample, longitudinal data from the PEDI-CAT domain scores demonstrate stability in performance at 3 years.Trial Registration: ClinicalTrials.gov NCT03492060.

Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders.

Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lympoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.

Clinical characteristics, longitudinal adaptive functioning, and association with electroencephalogram activity in PPP2R5D-related neurodevelopmental disorder.

Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D-related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in-person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D-related NDD. Forty-two individuals (median age 6 years, range = 0.8-25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure-66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland-3 adaptive behavior composite score (VABS-3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS-3 growth scale value scores increased from baseline in all subdomains (range = 0.6-5.9) after a mean follow-up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS-3 score; p < 0.05. Individuals had a mean Quality-of-life inventory-disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D-related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials.

Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.

KIF1A-associated neurological disorder (KAND) is a neurodegenerative and often lethal ultrarare disease with a wide phenotypic spectrum associated with largely heterozygous de novo missense variants in KIF1A. Antisense oligonucleotide treatments represent a promising approach for personalized treatments in ultrarare diseases. Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele. The first intrathecal administration was complicated by an epidural cerebrospinal fluid collection, which resolved spontaneously. Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved. There was little change in the 6-min Walk Test distance, but qualitative changes in gait resulting in meaningful reductions in falls and increasing independence were observed. Cognitive performance was stable and did not degenerate over time. Our findings provide preliminary insights on the safety and efficacy of an allele-specific antisense oligonucleotide as a possible treatment for KAND.

Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder.

PURPOSE: Pathogenic variants in kinesin family member 1A (KIF1A) are associated with KIF1A-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with KIF1A-associated neurological disorder. METHODS: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments. RESULTS: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland adaptive behavior composite score (VABS-ABC) was low (M = 62.9, SD = 19.1). The mean change in VABS-ABC over time was -3.1 (SD = 7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between evolutionary scale model (ESM) score for the variants and final VABS-ABC (P = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (P < .001). CONCLUSION: In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.

Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

3' UTR Deletion of FBXO28 in a Patient with Brain Abnormalities and Developmental Delay.

Constitutional deletions of chromosome 1q42 region are rare. The phenotype spectrum associated with this copy number change is variable, including developmental delay, intellectual disability, seizures, and dysmorphology. This study describes a patient with developmental delays and brain abnormalities. G-banded karyotype, FISH, SNP oligonucleotide microarray analysis (SOMA), and whole exome sequencing analysis were performed. Postnatal reanalysis of prenatal SOMA and follow-up parental testing revealed a paternally inherited 63 kb deletion at 1q42.11 in the patient. We characterized the clinical features of this patient, providing insight into the clinical phenotype associated with deletions of the 1q42.11 sub-band. Our study provides new evidence supporting the potential functional importance of the FBXO28 3' UTR region and the hypothesis that FBXO28 is a critical gene in the pathogenesis of chromosome 1q41q42 microdeletion syndrome. It also highlights the different goals and reporting criteria between prenatal and postnatal microarray tests.

Clinical actionability of genetic findings in cerebral palsy.

Background and objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety/practicality of the intervention, and anticipated intervention efficacy . Results: We found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as actionable , defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting the primary disease mechanism , 16 had specific prevention strategies , and 26 had specific symptom management recommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class "D" or below. The potential interventions have clinical utility with 97% of outcomes being moderate-high severity if left untreated and 62% of interventions predicted to be of moderate-high efficacy . Most interventions (71%) were considered moderate-high safety/practicality . Discussion: Our findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy , outcome severity , and intervention safety / practicality indicates moderate-high clinical utility of these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder.

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.

Rett-like Phenotypes in HNRNPH2-Related Neurodevelopmental Disorder.

Rett Syndrome (RTT) is a neurodevelopmental disorder with a prevalence of 1:10,000 to 15,000 females worldwide. Classic Rett Syndrome presents in early childhood with a period of developmental regression, loss of purposeful hand skills along with hand stereotypies, gait abnormalities, and loss of acquired speech. Atypical RTT is diagnosed when a child shows some but not all the phenotypes of classic RTT, along with additional supporting criteria. Over 95% of classic RTT cases are attributed to pathogenic variants in Methyl-CpG Binding Protein 2 (MECP2), though additional genes have been implicated in other RTT cases, particularly those with the atypical RTT clinical picture. Other genetic etiologies have emerged with similar clinical characteristics to RTT Syndrome. Our team has characterized HNRNPH2-related neurodevelopmental disorder (HNRNPH2-RNDD) in 33 individuals associated with de novo pathogenic missense variants in the X-linked HNRNPH2 gene, characterized by developmental delay, intellectual disability, seizures, autistic-like features, and motor abnormalities. We sought to further characterize RTT clinical features in this group of individuals by using caregiver report. Twenty-six caregivers completed electronic surveys, with only 3 individuals having previously received an atypical RTT diagnosis, and no individuals with a typical RTT diagnosis. Caregivers reported a high number of behaviors and/or phenotypes consistent with RTT, including the major criteria of the syndrome, such as regression of developmental skills and abnormal gait. Based on the survey results, 12 individuals could meet the diagnostic clinical criteria for atypical RTT Syndrome. In summary, individuals with HNRNPH2-RNDD exhibit clinical characteristics that overlap with those of RTT, and therefore, HNRNPH2-RNDD, should be considered on the differential diagnosis list with this clinical picture.

Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function.

Advances in sequencing technology have generated a large amount of genetic data from patients with neurological conditions. These data have provided diagnosis of many rare diseases, including a number of pathogenic de novo missense variants in GRIN genes encoding N-methyl-d-aspartate receptors (NMDARs). To understand the ramifications for neurons and brain circuits affected by rare patient variants, functional analysis of the variant receptor is necessary in model systems. For NMDARs, this functional analysis needs to assess multiple properties in order to understand how variants could impact receptor function in neurons. One can then use these data to determine whether the overall actions will increase or decrease NMDAR-mediated charge transfer. Here, we describe an analytical and comprehensive framework by which to categorize GRIN variants as either gain-of-function (GoF) or loss-of-function (LoF) and apply this approach to GRIN2B variants identified in patients and the general population. This framework draws on results from six different assays that assess the impact of the variant on NMDAR sensitivity to agonists and endogenous modulators, trafficking to the plasma membrane, response time course and channel open probability. We propose to integrate data from multiple in vitro assays to arrive at a variant classification, and suggest threshold levels that guide confidence. The data supporting GoF and LoF determination are essential to assessing pathogenicity and patient stratification for clinical trials as personalized pharmacological and genetic agents that can enhance or reduce receptor function are advanced. This approach to functional variant classification can generalize to other disorders associated with missense variants.

Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy.

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (ß = 0.31; 95% CI, -2.97 to 3.58), gross motor (ß = 0.82; 95% CI, -1.34 to 2.99), fine motor (ß = 0.36; 95% CI, -0.74 to 1.47), expressive language (ß = -1.00; 95% CI, -4.02 to 2.02), or receptive language (ß = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

Assessing the feasibility of using the ketogenic diet in autism spectrum disorder.

BACKGROUND: Evidence demonstrating efficacy of dietary interventions for autism spectrum disorder (ASD) remains inconsistent. Recent research on the ketogenic diet (KD) for the treatment of ASD has suggested a benefit. Children with ASD often demonstrate ritualised food-specific behaviours, taste and texture aversions, and an increased prevalence of food restrictions and allergies. There is a need to investigate how these features contribute to initiation and adherence of the KD. Two surveys were administered to assess the feasibility of utilising the KD for ASD. METHODS: First, paper surveys were given to caregivers of children presenting to outpatient neurology clinics. Next, experienced clinicians were recruited and surveyed online using Qualtrics. Chi-squared analysis was used to compare ASD and non-ASD caregiver responses. Descriptive metrics were used to present clinician responses. Responses to each question were evaluated individually. RESULTS: One hundred and fourteen surveys were collected from caregivers. There were no significant differences in (1) stated feasibility of adopting a new diet, (2) a carbohydrate restricted diet, (3) diet restrictions, (4) documented allergies or (5) personal/cultural restrictions between groups with and without ASD. Seventy clinician responses were collected. The majority (67.4%) indicated that feasibility for a child with ASD to adopt a KD for any reason depends on ASD severity. Some respondents 73% rated adherence to the KD as more difficult compared to age-matched controls, whereas 26% considered it similar. Multiple familial and child characteristics were rated as increasing the difficulty of successful KD. CONCLUSIONS: The results of the present study suggest that it is feasible for children with ASD to adopt a KD, and success is highly individualised to child and family.

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders.

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.

Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications.

BACKGROUND: SLC6A1-related disorder is a recently identified, rare, genetic neurodevelopmental disorder that is associated with loss-of-function variants in SLC6A1. This gene encodes GABA transporter type I that is responsible for re-uptake of GABA from the synapse into the pre-synaptic terminal or circulating neuroglia. Based upon retrospective review of published cases and available research databases including Epi25 collective and SLC6A1 Connect patient database, the phenotypic spectrum is broad and includes developmental delay, epilepsy, and autism or autistic traits. SLC6A1 is one of the genes included in the Simons Searchlight registry, which includes standardized data collection across genetically identified neurodevelopmental conditions. METHODS: In this study, we compare parent-report measures of phenotypic features in the Simons Searchlight registry to previously published, provider-reported cases to assess if parent-report measures are consistent with what has been reported in the literature. RESULTS: There were 116 participants in the provider-reported dataset compared to 43 individuals in the caregiver-reported dataset. Carriers in Searchlight had 83 unique pathogenic or likely pathogenic variants in SLC6A1, which were predominantly missense or nonsense variants. There was no significant difference between groups for the prevalence of developmental delay, ASD, or ADHD. Caregivers more often reported hypotonia, while epilepsy was slightly more frequently reported by providers. CONCLUSIONS: We propose that standardized parent-report data collection methods are consistent with provider reports on many core features of SLC6A1-related disorder. The availability of patient registries and standardized natural history studies may fill an important need in clinical trial readiness programs, with larger sample sizes than smaller published case series.

Diagnostic preferences include discussion of etiology for adults with cerebral palsy and their caregivers.

AIM: To determine the views of individuals with cerebral palsy (CP) and their caregivers (CP community members) about carrying a CP diagnosis, an etiological diagnosis, or both diagnoses together. METHOD: We surveyed CP community members across two registries querying their views on carrying a CP diagnosis, one type of etiological diagnosis (specifically, a genetic diagnosis), or both. Open-ended responses were analyzed using a conventional content analysis approach. RESULTS: Of 197 respondents (108 adults with CP and 89 caregivers), most (75%) valued knowing the cause of their CP. Of those with a diagnostic preference, most preferred carrying both CP and etiological diagnoses together (68%). When compared with carrying an etiological diagnosis alone, significantly more respondents felt a CP diagnosis helped anticipate symptom evolution (84% vs 54%), explain symptoms to others (86% vs 48%), access services (86% vs 48%), and join support communities (78% vs 50%) (p <  0.01, χ2 test). INTERPRETATION: Most CP community members surveyed want to know the cause of their CP and would prefer carrying both CP and etiological diagnoses together. Clinical practice should evolve to meet these community needs.

Cerebral Palsy in Child Neurology and Neurodevelopmental Disabilities Training: An Unmet Need.

BACKGROUND: Cerebral palsy (CP) is the most common cause of childhood motor disability. However, there is limited guidance on training of child neurologists and neurodevelopmental disability specialists in the care of individuals with cerebral palsy. We sought to determine training program directors' impressions of the importance and adequacy of training in the diagnosis and management of cerebral palsy. METHODS: In this cross-sectional study, all 82 child neurology and neurodevelopmental disability program directors were asked to complete a survey querying program characteristics, aspects of training in cerebral palsy, importance of cerebral palsy training, and perceived competence at graduation in cerebral palsy care. RESULTS: There were 35 responses (43% response rate). Nearly all program directors (91%) reported "learning to diagnose cerebral palsy" as very important, and most (71%) felt that "learning to manage cerebral palsy" was very important. Although most program directors reported trainees to be very or extremely competent in cerebral palsy diagnosis (77%), only 43% of program directors felt that trainees were very or extremely competent in cerebral palsy management. Time spent with cerebral palsy faculty was associated with higher reported competence in cerebral palsy diagnosis (P = .03) and management (P < .01). The presence of a cerebral palsy clinic was associated with higher reported competence in cerebral palsy management (P = .03). CONCLUSIONS: Child neurology and neurodevelopmental disability program directors reported that training in cerebral palsy is important for residents; however, a significant proportion felt that residents were not very well prepared to manage cerebral palsy. The development of cerebral palsy curricula and exposure to cerebral palsy clinics may improve training, translating to better care of individuals with cerebral palsy.

Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.

Importance: Associations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown. Objective: To examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months. Design, Setting, and Participants: A cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses. Exposures: Maternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic. Main Outcomes and Measures: Outcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months. Results: Of 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267 = 12.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267 = 14.71; P < .005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267 = 6.37; P<.05) subdomains in fully adjusted models. Conclusions and Relevance: In this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.