Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.

Background and Objectives: Deletions and duplications at 16p11.2 (BP4 to BP5; 29.5-30.1 Mb) have been associated with several neurodevelopmental and neuropsychiatric disorders including autism spectrum disorder, intellectual disability (ID), and schizophrenia. Seizures have also been reported in individuals with these particular copy number variants, but the epilepsy phenotypes have not been well-delineated. We aimed to systematically characterize the seizure types, epilepsy syndromes, and epilepsy severity in a large cohort of individuals with these 16p11.2 deletions and duplications. Methods: The cohort of ascertained participants with the recurrent 16p11.2 copy number variant was assembled through the multicenter Simons Variation in Individuals Project. Detailed data on individuals identified as having a history of seizures were obtained using a semistructured phone interview and review of medical records, EEG, and MRI studies obtained clinically or as part of the Simons Variation in Individuals Project. Results: Among 129 individuals with the 16p11.2 deletion, 31 (24%) had at least one seizure, including 23 (18%) who met criteria for epilepsy; 42% of them fit the phenotype of classic or atypical Self-limited (Familial) Infantile Epilepsy (Se(F)IE). Among 106 individuals with 16p11.2 duplications, 16 (15%) had at least one seizure, including 11 (10%) who met criteria for epilepsy. The seizure types and epilepsy syndromes were heterogeneous in this group. Most of the individuals in both the deletion and duplication groups had well-controlled seizures with subsequent remission. Pharmacoresistant epilepsy was uncommon. Seizures responded favorably to phenobarbital, carbamazepine, and oxcarbazepine in the deletion group, specifically in the Se(F)IE, and to various antiseizure medications in the duplication group. Discussion: These findings delineate the spectrum of seizures and epilepsies in the recurrent 16p11.2 deletions and duplications and provide potential diagnostic, therapeutic, and prognostic information.

Reducing Barriers to Autism Screening in Community Primary Care: A Pragmatic Trial Using Web-Based Screening.

OBJECTIVE: To determine whether an intervention addressing both logistical and knowledge barriers to early screening for autism spectrum disorder (ASD) increases evidence-based screening during 18-month well-child visits and primary care providers' (PCPs') perceived self-efficacy in caring for children with ASD. METHODS: Forty-six PCPs from 10 diverse practices across four counties in Washington State participated. PCPs attended a 2-hour training workshop on early recognition and care for toddlers with ASD and use of a REDCap-based version of the Modified Checklist for Autism in Toddlers-Revised with Follow-up (webM-CHAT-R/F) that provided automated presentation and scoring of follow-up questions. Data were collected at baseline and 6 months following each county's training window. PCPs' screening methods and rates and perceived self-efficacy regarding ASD care were measured by self-report and webM-CHAT-R/F use was measured via REDCap records. RESULTS: At follow-up, 8 of the 10 practices were using the webM-CHAT-R/F routinely at 18-month visits. The proportion of PCPs reporting routine M-CHAT screening increased from 82% at baseline to 98% at follow-up (16% increase, 95% confidence interval [CI] 3%-28%; McNemar exact P = .02). The proportion using the M-CHAT-R/F follow-up interview questions increased from 33% to 82% (49% increase, 95% CI 30%-68%, exact McNemar test, P < .001). Significant increases in self-efficacy were found for all seven areas assessed (Ps ≤ .008). CONCLUSIONS: This brief intervention increased PCPs' self-reported valid use of the M-CHAT-R/F at 18 months and their self-efficacy regarding ASD care. Combining educational information with a web-based ASD screen incorporating the M-CHAT-R/F follow-up questions may increase universal ASD screening with improved fidelity.

Functional Neurological Symptom Disorder in Children and Adolescents within Medical Settings.

Pediatric functional neurological symptom disorder (FNSD or conversion disorder) is an often misunderstood but treatable condition that frequently presents in medical settings with unexplained symptoms. Although research regarding treatment of pediatric FNSD is increasing, it is still in its infancy and studies in pediatrics do not provide clear guidelines about which patients are most likely to benefit from various treatments. The role of pediatric psychologists may include consultation, assessment, treatment, program development, and providing education to patients, families, and healthcare colleagues in various disciplines. The purpose of this article is to provide a review of FNSD, discuss the importance of timely and accurate diagnosis, suggest how to present information to patients and families, and present options for treatment that are either supported by preliminary research or clinical experiences of the authors.

Language characterization in 16p11.2 deletion and duplication syndromes.

Expressive language impairment is one of the most frequently associated clinical features of 16p11.2 copy number variations (CNV). However, our understanding of the language profiles of individuals with 16p11.2 CNVs is still limited. This study builds upon previous work in the Simons Variation in Individuals Project (VIP, now known as Simons Searchlight), to characterize language abilities in 16p11.2 deletion and duplication carriers using comprehensive assessments. Participants included 110 clinically ascertained children and family members (i.e., siblings and cousins) with 16p11.2 BP4-BP5 deletion and 58 with 16p11.2 BP4-BP5 duplication between the ages of 2-23 years, most of whom were verbal. Regression analyses were performed to quantify variation in language abilities in the presence of the 16p11.2 deletion and duplication, both with and without autism spectrum disorder (ASD) and cognitive deficit. Difficulties in pragmatic skills were equally prevalent in verbal individuals in both deletion and duplication groups. NVIQ had moderate quantifiable effects on language scores in syntax and semantics/pragmatics (a decrease of less than 1 SD) for both groups. Overall, language impairments persisted even after controlling for ASD diagnosis and cognitive deficit. Language impairment is one of the core clinical features of individuals with 16p11.2 CNVs even in the absence of ASD and cognitive deficit. Results highlight the need for more comprehensive and rigorous assessment of language impairments to maximize outcomes in carriers of 16p11.2 CNVs.

Promoting early autism detection and intervention in underserved communities: study protocol for a pragmatic trial using a stepped-wedge design.

BACKGROUND: Despite the known benefits of early, specialized intervention for toddlers with Autism Spectrum Disorder (ASD), access to such intervention remains limited. This pragmatic trial examines a novel healthcare delivery model (Screen-Refer-Treat [SRT]), which capitalizes upon existing health care and early intervention (EI) infrastructure to increase community capacity for ASD detection and treatment before age 3, when it is likely to have the greatest impact. This model comprises three components: (1) universal use of Stage 1 ASD screening by primary care providers (PCPs) at 18-month well-child visits (i.e., Screen); (2) immediate referral of positive screens to a community-based EI program (i.e., Refer); and (3) provision of an inexpensive, evidence-based ASD-specialized treatment by EI providers, after verifying ASD risk with a Stage 2 screen (i.e., Treat). This paper describes our research design and the initial successes, challenges, and adaptations made during the early implementation phase. METHOD/DESIGN: A stepped-wedge cluster RCT was used to implement the SRT model sequentially in four diverse Washington State counties ("clusters"). Counties are randomly assigned to the time of receipt of the SRT intervention, which comprises training workshops and technical assistance focused on the use of evidence-based ASD screening and intervention tools. Separate cohorts of families with toddlers (16-35 months old) with and without ASD concerns are recruited before and after the SRT intervention from participating PCP practices and EI programs. PCPs and EI providers complete measures on their screening, referral, and intervention practices before and after the SRT intervention. Each family cohort completes surveys about their well-being, parenting efficacy, health care satisfaction, and toddler's social-communicative behaviors. CONCLUSION: This trial is the first of its kind to work simultaneously with two service delivery systems with the goal of improving early detection and treatment for ASD. Our approach was successful in attaining buy-in from PCPs and EI providers, building and maintaining partnerships with providers, and achieving high levels of retention and survey completion. Fostering provider engagement and problem-solving issues together as partners were integral to overcoming the main challenges. Numerous lessons have been learned thus far, which have applicability for implementation researchers in ASD and those in other fields. TRIAL REGISTRATION: The registration number for this trial is NCT02409303 and it was posted on ClinicalTrials.gov on April 6, 2015.

Longitudinal report of child with de novo 16p11.2 triplication.

16p11.2 deletions and duplications are commonly associated with autism spectrum disorder and linked to mirrored phenotypes of physical characteristics and higher penetrance for deletions. A male with a rare 16p11.2 triplication demonstrated a similar phenotypic presentation to deletion carriers with neurocognitive and adaptive skill deficits and above-average physical growth.

16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort.

Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication-the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs). The 16p11.2 deletion neurologic phenotype is characterized by highly prevalent speech articulation abnormalities, limb and trunk hypotonia with hyporeflexia, abnormalities of agility, sacral dimples, seizures/epilepsy, large head size/macrocephaly, and Chiari I/cerebellar tonsillar ectopia. Speech articulation abnormalities, hypotonia, abnormal agility, sacral dimples, and seizures/epilepsy are also seen in duplication carriers, along with more prominent hyperreflexia; less, though still prevalent, hyporeflexia; highly prevalent action tremor; small head size/microcephaly; and cerebral white matter/corpus callosum abnormalities and ventricular enlargement. The neurologic phenotypes of these reciprocal 16p11.2 CNVs include both shared and distinct features. Reciprocal phenotypic characteristics of predominant hypo- versus hyperreflexia and macro- versus microcephaly may reflect opposite neurobiological abnormalities with converging effects causing the functional impairments shared between 16p11.2 deletion and duplication carriers (i.e., abnormal motor agility and articulation). While the phenotypes exhibit overlap with other genetically-caused neurodevelopmental disorders, clinicians should be aware of the more striking features-such as the speech and motor impairments, growth abnormalities, tremor, and sacral dimples-when evaluating individuals with developmental delay, intellectual disability, ASD, and/or language disorders. © 2016 Wiley Periodicals, Inc.

Dental Homes for Children With Autism: A Longitudinal Analysis of Iowa Medicaid's I-Smile Program.

INTRODUCTION: Medicaid-enrolled children with autism spectrum disorder (ASD) encounter significant barriers to dental care. Iowa's I-Smile Program was implemented in 2006 to improve dental use for all children in Medicaid. This study compared dental home and preventive dental utilization rates for Medicaid-enrolled children by ASD status and within three time periods (pre-implementation, initial implementation, maturation) and determined I-Smile's longitudinal influence on ASD-related dental use disparities. METHODS: Data from 2002-2011 were analyzed for newly Medicaid-enrolled children aged 3-17 years (N=30,059); identified each child's ASD status; and assessed whether the child had a dental home or utilized preventive dental care. Log-linear regression models were used to generate rate ratios. Analyses were conducted in 2015. RESULTS: In 2003-2011, 9.8% of children with ASD had dental homes compared with 8% of children without ASD; 36.3% of children with ASD utilized preventive care compared to 45.7% of children without ASD. There were no significant differences in dental home rates by ASD status during pre-implementation, initial implementation, or maturation. There were no significant differences in preventive dental utilization by ASD status during pre-implementation or initial implementation, but children with ASD were significantly less likely to utilize preventive care during maturation (rate ratio=0.79, p<0.001). Longitudinal trends in dental home and preventive dental utilization rates were not significant (p=0.54 and p=0.71, respectively). CONCLUSIONS: Among newly Medicaid-enrolled children in Iowa's I-Smile Program, those with ASDs were not less likely than those without ASD to have dental homes but were significantly less likely to utilize preventive dental care.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Clinical phenotype of the recurrent 1q21.1 copy-number variant.

PURPOSE: To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. METHODS: Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging. RESULTS: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers. CONCLUSIONS: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Toward a narrower, more pragmatic view of developmental dyspraxia.

Apraxia traditionally refers to impaired ability to carry out skilled movements in the absence of fundamental sensorimotor, language, or general cognitive impairment sufficient to preclude them. The child neurology literature includes a much broader and varied usage of the term developmental dyspraxia. It has been used to describe a wide range of motor symptoms, including clumsiness and general coordination difficulties, in various developmental disorders (including autistic spectrum disorders, developmental language disorders, and perinatal stroke). We argue for the need to restrict use of the term developmental dyspraxia to describe impaired performance of skilled gestures, recognizing that, unlike acquired adult-onset apraxia, coexisting sensory and motor problems can also be present.

Neonatal watershed brain injury on magnetic resonance imaging correlates with verbal IQ at 4 years.

OBJECTIVE: We have previously described patterns of neonatal brain injury that correlate with global cognitive and motor outcomes. We now examine, in survivors of neonatal encephalopathy (presumed secondary to hypoxia-ischemia) without functional motor deficits, whether the severity and neuroanatomical involvement on neonatal MRI are associated with domain-specific cognitive outcomes, verbal and performance IQ, at 4 years of age. METHODS: In this prospective study, neonatal MRIs of 81 term infants with neonatal encephalopathy were scored for degree of injury in 2 common patterns: watershed distribution and basal ganglia distribution. Follow-up evaluation at 4 years of age by examiners blinded to clinical history and MRIs included a 5-point neuromotor score and the Wechsler Preschool and Primary Scale of Intelligence-Revised. In 64 subjects with no functional motor impairment, test of trend was used to examine the association of ordered watershed-distribution and basal ganglia-distribution MRI scores with mean verbal and performance IQ. RESULTS: Lower verbal and performance IQs were seen with increasing degree of injury on both watershed-distribution and basal ganglia-distribution scales in univariate analyses. When each MRI pattern score was adjusted for the other, only the association of decreasing verbal IQ with increasing watershed-distribution injury remained significant. A suggestion of decreasing verbal IQ with increasing basal ganglia-distribution injury was also seen in the multivariate model, whereas no association was seen between performance IQ and severity of injury in either MRI pattern. CONCLUSIONS: In survivors of neonatal encephalopathy without functional motor deficits at 4 years of age, an increasing severity of watershed-distribution injury is associated with more impaired language-related abilities.