RESUMO
BACKGROUND AND OBJECTIVES: Breastfeeding has important health benefits for both mother and child. We characterize breastfeeding initiation and duration in mothers with epilepsy relative to control mothers in a large prospective cohort. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a prospective, multicenter observational, US cohort study. Pregnant individuals with and without epilepsy, aged 14-45 years, were enrolled between December 19, 2012, and February 11, 2016. Exclusion criteria included intelligence quotient (IQ) <70, and gestational age >20 weeks at enrollment. Breastfeeding was assessed through electronic diary and at study visits until 2 years postpartum. Odds of initiating breastfeeding was compared between cohorts using unadjusted and adjusted logistic regression models. Duration of breastfeeding was compared between cohorts using the log-rank test. RESULTS: Three hundred fifty-one pregnant individuals with epilepsy and 105 pregnant controls were enrolled. Breastfeeding data were available for 325 mothers with epilepsy and 98 controls. Study cohorts were similar demographically except race (p = 0.008); 84.9% of mothers with epilepsy and 71.4% of controls were White. The mean IQ was lower in mothers with epilepsy compared with that in controls (97.7 vs 104.2, p < 0.001). Breastfeeding was initiated by 74.8% mothers with epilepsy and 88.8% controls; this difference was significant in unadjusted logistic regression (odds ratio [OR] 0.4 [95% CI 0.2, 0.7], p = 0.004), but not in adjusted model (OR 0.5 [95% CI 0.2, 1.0], p = 0.051). Factors associated with breastfeeding were higher maternal education and IQ. There was no difference in duration of breastfeeding between mothers with and without epilepsy (median duration 8.5 months vs 9.9 months, p = 0.793). Among mothers with epilepsy, both convulsive seizures and all seizures that impair awareness during pregnancy were associated with lower breastfeeding initiation (OR 0.4 [95% CI 0.2, 0.8], p = 0.013) and (OR 0.4 [95% CI 0.2, 0.8], p = 0.003, respectively). Any peripartum seizures were associated with shorter breastfeeding duration (median 6 months vs 9.7 months, [p = 0.040]). DISCUSSION: Mothers with epilepsy were less likely to initiate breastfeeding compared with controls; however, this difference was not significant when controlling for maternal IQ and education level. Continuation of breastfeeding once initiated was not different between mothers with and without epilepsy. Seizure control was associated with breastfeeding initiation and duration in mothers with epilepsy. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier NCT01730170.
Assuntos
Anticonvulsivantes , Epilepsia , Feminino , Humanos , Gravidez , Anticonvulsivantes/efeitos adversos , Aleitamento Materno , Estudos de Coortes , Epilepsia/tratamento farmacológico , Mães , Estudos Prospectivos , Convulsões/tratamento farmacológico , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-IdadeRESUMO
Assessing cognitive development is critical in clinical research of autism spectrum disorder (ASD). However, collecting cognitive data from clinically administered assessments can add a significant burden to clinical research in ASD due to the substantial cost and time required, and it is often prohibitive in large-scale studies. There is a need for more efficient, but reliable, methods to estimate cognitive functioning for researchers, clinicians, and families. To examine the degree to which caregiver estimates of cognitive level agree with actual measured intelligence/developmental scores and understand factors that may impact that agreement, 1,555 autistic individuals (81.74% male; age 18 months-18 years) were selected from a large cohort (Simons Foundation Powering Autism Research for Knowledge, SPARK). Results suggest that querying parents about recent testing results and developmental diagnoses can provide valid and useful information on cognitive ability. The agreement of parental estimates varied with age, measured cognitive ability, autistic traits, and adaptive skills. In the context of large-scale research efforts, parent-reported cognitive impairment may be a good proxy for categorical IQ range for survey-based studies when specific IQ scores are not available, circumventing the logistical and financial obstacles of obtaining neuropsychological or neurodevelopmental testing.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Masculino , Criança , Lactente , Feminino , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/psicologia , Pais , Inteligência , CogniçãoRESUMO
PURPOSE: Recurrent 16p11.2 duplications produce a wide range of clinical outcomes with varying effects on cognition and social functioning. Family-based studies of copy number variants (CNVs) have revealed significant contributions of genomic background on variable expressivity. In this study, we measured the phenotypic effect of 16p11.2 duplications and quantified the modulating effect of familial background on cognitive and social outcomes. METHODS: Genomic and clinical data were ascertained from 41 probands with a 16p11.2 duplication and their first-degree relatives. Paired comparisons were completed to determine the duplication's effect on expected vs actual performance on standardized tests of intelligence (IQ) and social functioning (Social Responsiveness Scale-2). Intraclass correlations between relatives and probands were also calculated. RESULTS: Cognitive and social functioning were significantly lower among individuals with 16p11.2 duplications than their CNV-negative relatives, whereas intraclass correlations between the groups remained high for full-scale IQ and Social Responsiveness Scale-2 scores. CONCLUSION: The 16p11.2 duplication confers deleterious effects on cognition and social functioning, whereas familial background significantly influences phenotypic expression of these traits. Understanding variable expressivity in CNV disorders has implications for anticipatory clinical care, particularly for individuals who receive a genetic diagnosis at an early age, long before the full scope of manifestations becomes evident.
Assuntos
Deleção Cromossômica , Variações do Número de Cópias de DNA , Humanos , Variações do Número de Cópias de DNA/genética , Cognição , Fenótipo , Duplicação Cromossômica/genéticaRESUMO
BACKGROUND: SLC6A1 encodes GAT-1, a major gamma-aminobutyric acid (GABA) transporter in the brain. GAT-1 maintains neurotransmitter homeostasis by removing excess GABA from the synaptic cleft. Pathogenic variants in SLC6A1 disrupt the reuptake of GABA and are associated with a neurobehavioural phenotype. METHODS: Medical history interviews, seizure surveys, Vineland Adaptive Behavior Scales Second Edition and other behavioural surveys were completed by primary care givers of 28 participants in Simons Searchlight. All participants underwent clinical whole exome sequencing or gene panel sequencing. Additional cases from the medical literature with comparable data were included. RESULTS: We identified 28 individuals with largely de novo pathogenic/likely pathogenic variants including missense (15/21 or 71%) and truncating variants (6/21 or 29%). Missense variants were largely clustered around the sixth and seventh transmembrane domains, which functions as a GABA binding pocket. The phenotype of individuals with pathogenic variants in SLC6A1 includes hypotonia, intellectual disability/developmental delay, language disorder/speech delay, autism spectrum disorder, sleep issues and seizures. CONCLUSION: Pathogenic variants in SLC6A1 are associated with a clinical phenotype of developmental delay, behaviour problems and seizures. Understanding of the genotype-phenotype correlation within SLC6A1 may provide opportunities to develop new treatments for GABA-related conditions.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Transtornos do Neurodesenvolvimento , Proteínas da Membrana Plasmática de Transporte de GABA/química , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Humanos , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Convulsões/genética , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismoRESUMO
Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.
Assuntos
Subunidade Apc7 do Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Encéfalo/enzimologia , Heterocromatina/metabolismo , Deficiência Intelectual/enzimologia , Células-Tronco Neurais/enzimologia , Neurogênese , Adolescente , Animais , Antígenos CD , Subunidade Apc7 do Ciclossomo-Complexo Promotor de Anáfase/genética , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Heterocromatina/genética , Humanos , Lactente , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Inteligência , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitose , Mutação , Células-Tronco Neurais/patologia , Proteólise , Transdução de Sinais , Síndrome , Ubiquitinação , Adulto JovemRESUMO
Because of the COVID-19 pandemic, in-person services for individuals with neurodevelopmental disabilities were disrupted globally, resulting in a transition to remote delivery of services and therapies. For individuals with neurogenetic conditions, reliance on nonclinical caregivers to facilitate all therapies and care was unprecedented. The study aimed to (1) describe caregivers' reported impact on their dependent's services, therapies, medical needs, and impact on themselves as a result of the COVID-19 pandemic and (2) assess the relationship between the extent of disruption of services and the degree of self-reported caregiver burden. Two online questionnaires were completed by caregivers participating in Simons Searchlight in April and May 2020. Surveys were completed by caregivers of children or dependent adults with neurodevelopmental genetic conditions in Simons Searchlight. Caregivers reported that the impact of the COVID-19 pandemic moderately or severely disrupted services, therapies, or medical supports. The majority of caregivers were responsible for providing some aspect of therapy. Caregivers reported "feeling stressed but able to deal with problems as they arise," and reported lower anxiety at follow-up. Caregivers reported that telehealth services were not meeting the needs of those with complex medical needs. Future surveys will assess if and how medical systems, educational programs, therapists, and caregivers adapt to the challenges arising during the COVID-19 pandemic.
Assuntos
COVID-19/psicologia , Sobrecarga do Cuidador/psicologia , Cuidadores/psicologia , Pesquisas sobre Atenção à Saúde/métodos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Transtornos do Neurodesenvolvimento/terapia , Adolescente , Adulto , Cuidadores/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Pesquisas sobre Atenção à Saúde/estatística & dados numéricos , Humanos , Masculino , Avaliação das Necessidades , Pandemias , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006-2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kgâ¢day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989-2018) were identified by NBS and treated with natural protein restriction (1.0-1.3 g/kgâ¢day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973-2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Encéfalo/patologia , Encefalopatias Metabólicas/dietoterapia , Encefalopatias Metabólicas/epidemiologia , Encefalopatias Metabólicas/metabolismo , Carnitina/metabolismo , Criança , Pré-Escolar , Corpo Estriado/patologia , Dieta , Feminino , Glutaril-CoA Desidrogenase/metabolismo , Humanos , Lactente , Recém-Nascido , Lisina/metabolismo , MasculinoRESUMO
Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.
Assuntos
3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Aminoácidos de Cadeia Ramificada/metabolismo , Biomarcadores/sangue , Leucina/sangue , Transplante de Fígado , Doença da Urina de Xarope de Bordo/dietoterapia , Doença da Urina de Xarope de Bordo/terapia , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Dieta , Feminino , Homozigoto , Humanos , Lactente , Leucina/metabolismo , Masculino , Doença da Urina de Xarope de Bordo/genética , Doença da Urina de Xarope de Bordo/metabolismo , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , FenótipoRESUMO
We developed an iOS-based app with a transmitter/disposable sensor and corresponding manualized intervention for children with autism spectrum disorder. The app signaled the onset of urination, time-stamped accidents for analysis, reminded parents to reinforce intervals of continence, provided a visual outlet for parents to communicate reinforcement, and afforded opportunity for timely feedback from clinicians. We compared this intervention with an intervention that uses standard behavioral treatment in a pilot randomized controlled trial of 33 children with autism spectrum disorder aged 3-6 years with urinary incontinence. Parents in both groups received initial training and four booster consultations over 3 months. Results support the feasibility of parent-mediated toilet training studies (e.g., 84% retention rate, 92% fidelity of parent-implemented intervention). Parents used the app and related technology with few difficulties or malfunctions. There were no statistically significant group differences for rate of urine accidents, toilet usage, or satisfaction at close of intervention or 3-month follow-up; however, the alarm group trended toward greater rate of skill acquisition with significantly less day-to-day intervention. Further development of alarm and related technology and future comparative studies with a greater number of participants are warranted.
Assuntos
Transtorno do Espectro Autista/reabilitação , Enurese/reabilitação , Aplicativos Móveis , Pais , Treinamento no Uso de Banheiro , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Masculino , Projetos Piloto , Reforço Psicológico , Tecnologia sem FioRESUMO
Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Animais , Humanos , Transtornos do Neurodesenvolvimento/tratamento farmacológicoRESUMO
The goal of the current study was to develop and pilot the utility of two simple internal response bias metrics, over-reporting and under-reporting, in terms of additive clinical value within common screening practices for early detection of autism spectrum disorder risk. Participants were caregivers and children under 36 months of age (n = 145) participating in first-time diagnostic appointments across our clinical research center due to developmental concerns. Caregivers were asked to complete the Modified Checklist for Autism in Toddlers (MCHAT) as well as a questionnaire embedding six response bias indicator questions. These questions were items that in previous clinical studies had been endorsed by an overwhelming majority of parents within clinically identified populations. Results indicated that removal of self-reports indicative of potential response bias dramatically reduced both false positives and false negatives on the MCHAT within this sample. This suggests that future work developing internal metrics of response bias may be promising in addressing limits of current screening measures and practices.