Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay.

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation.

Bipolar Disorder in a female with CDKL5 Deficiency Disorder: A Case Report.

Background: CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy. While a subset of individuals is believed to experience comorbid behavioral disorders, none have reported well-defined affective disorders. Though there is a documented association between epilepsy and mood disorders, they may go undetected in the CDD population due to difficulty assessing mood in the presence of severe/profound intellectual disability and disease-related sleep dysregulation.

Clinical Characteristics and Outcomes of Children with Acute Catastrophic Brain Injury: A 13-Year Retrospective Cohort Study.

Background: The purpose of this study was to describe and analyze clinical characteristics and outcomes in children with acute catastrophic brain injury (CBI).

Methods: This was a single-center, 13-year (2008-2020) retrospective cohort study of children in the pediatric and cardiac intensive care units with CBI, defined as (1) acute neurologic injury based on clinical and/or imaging findings, (2) the need for life-sustaining intensive care unit therapies, and (3) death or survival with a Glasgow Coma Scale score < 13 at discharge. Patients were excluded if they were discharged directly to home < 14 days from admission or had a chronic neurologic condition with a baseline Glasgow Coma Scale score < 13.

Developing a New Set of ACGME Milestones for Child Neurology Residency.

Background: The Educational Milestones developed by the Accreditation Council for Graduate Medical Education (ACGME) are a construct used to evaluate the development of core competencies during residency and fellowship training. The milestones were developed to create a framework for professional development during graduate medical education. The first iteration of milestones for the child neurology residency was implemented in 2015.

Ethical decision-making for children with neuromuscular disorders in the COVID-19 crisis.

The sudden appearance and proliferation of coronavirus disease 2019 has forced societies and governmental authorities across the world to confront the possibility of resource constraints when critical care facilities are overwhelmed by the sheer numbers of grievously ill patients. As governments and health care systems develop and update policies and guidelines regarding the allocation of resources, patients and families affected by chronic disabilities, including many neuromuscular disorders that affect children and young adults, have become alarmed at the possibility that they may be determined to have less favorable prognoses due to their underlying diagnoses and thus be assigned to lower priority groups. It is important for health care workers, policymakers, and government officials to be aware that the long-term prognoses for children and young adults with neuromuscular disorders are often more promising than previously believed due to a better understanding of the natural history of these diseases, benefits of multidisciplinary supportive care, and novel molecular therapies that can dramatically improve the disease course.

Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy.

The US Food and Drug Administration's December 2016 approval of nusinersen for the treatment of patients with all subtypes of spinal muscular atrophy ushered in a new era for patients with spinal muscular atrophy, their families, and all those involved in their care. The extreme cost of the medication and the complicated logistical requirements for administering nusinersen via lumbar puncture have created practical challenges that raise important ethical considerations. We discuss 6 challenges faced at the institutional level in the United States: cost, limited evidence, informed consent, treatment allocation, fair distribution of responsibilities, and transparency with stakeholders.

The Child Neurology Trainee-as-Teacher: A Clinical Teaching Curriculum Tailored to Learners' Needs and Developmental Roles.

Background: Clinical teaching skills programs for resident physicians are increasingly offered. Less attention has been devoted to the unique educational roles of specialty residents and subspecialty fellows, many of whom will become academic faculty physicians. These teaching roles, and therefore a trainee's learning needs and motivation, also change over the course of training.

Education on the Brain: A Partnership Between a Pediatric Primary Care Center and Neurology Residency.

The national shortage of pediatric neurologists is worsening, yet referral rates by pediatricians are high. Suboptimal training of pediatric residents in care of patients with neurologic disease may be a contributing factor. We formed a partnership between the Boston Children's Primary Care at Longwood clinic and Child Neurology Residency Training Program.

Defining Hand Stereotypies in Rett Syndrome: A Movement Disorders Perspective.

Introduction: Hand stereotypies (HS) are a primary diagnostic criterion for Rett syndrome (RTT) but are difficult to characterize and quantify systematically.

Methods: We collected video on 27 girls (2-12 years of age) with classic RTT who participated in a mecasermin trial. The present study focused exclusively on video analyses, by reviewing two five-minute windows per subject to identify the two most common HS.

Neurologic Evaluation in Children With Laryngeal Cleft.

Importance: Referral to a neurologist and imaging play important roles in the management of laryngeal cleft. Swallowing involves a complex series of neuromuscular interactions, and aspiration can result from anatomical causes (eg, laryngeal cleft), neuromuscular disorders, or some combination thereof. To date, no protocols or guidelines exist to identify which patients with laryngeal cleft should undergo neuroimaging studies and/or consultation with a neurologist.

Evaluation and Management of Chronic Aspiration in Children With Normal Upper Airway Anatomy.

Importance: Chronic airway aspiration is a challenging problem for physicians and caregivers and can cause significant pulmonary morbidity in pediatric patients. Our knowledge regarding the causes and optimal management of these patients is in its infancy.

Objective: To review our experience with the evaluation and management of pediatric patients with documented aspiration and normal upper airway anatomy.

Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations.

Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings.

MRI in assessing children with learning disability, focal findings, and reduced automaticity.

Objectives: In children with clinically diagnosed learning disabilities with focal findings on neurologic or neuropsychological evaluations, there is a hypothesized association between disorders in automaticity and focal structural abnormalities observed in brain MRIs.

Methods: We undertook a retrospective analysis of cases referred to a tertiary-hospital-based learning disabilities program. Individuals were coded as having a focal deficit if either neurologic or neuropsychological evaluation demonstrated focal dysfunction.

Increased pediatric functional neurological symptom disorders after the Boston marathon bombings: a case series.

Background: Functional neurological symptom disorders are frequently the basis for acute neurological consultation. In children, they are often precipitated by high-frequency everyday stressors. The extent to which a severe traumatic experience may also precipitate functional neurological abnormalities is unknown.

Functional neurological symptom disorders in a pediatric emergency room: diagnostic accuracy, features, and outcome.

Background: In children, functional neurological symptom disorders are frequently the basis for presentation for emergency care. Pediatric epidemiological and outcome data remain scarce.

Objective: Assess diagnostic accuracy of trainee's first impression in our pediatric emergency room; describe manner of presentation, demographic data, socioeconomic impact, and clinical outcomes, including parental satisfaction.

Copy number variation plays an important role in clinical epilepsy.

Objective: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.

Methods: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy.

Development and implementation of a quality improvement curriculum for child neurology residents: lessons learned.

Background: Quality improvement is a major component of the Accreditation Council for Graduate Medical Education core competencies required of all medical trainees. Currently, neither the Neurology Residency Review Committee nor the Accreditation Council for Graduate Medical Education defines the process by which this competency should be taught and assessed. We developed a quality improvement curriculum that provides mentorship for resident quality improvement projects and is clinically relevant to pediatric neurologists.

Experience with lacosamide in a series of children with drug-resistant focal epilepsy.

We report our pediatric experience with lacosamide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.

Clinical genetic testing for patients with autism spectrum disorders.

Background: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established.

Patients And Methods: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008.

Child neurology: autism as a model: considerations for advanced training in behavioral child neurology.

In this article, we advocate for advanced training for child neurologists in behavior and development in order to facilitate the investigation of childhood behavioral and neurodevelopmental disabilities, with autism serving as a model disorder. We explore the current training options and then propose alternative subspecialty training options that focus on behavior and development, with appreciation that most developmental disabilities are not static encephalopathies but, rather, dynamic processes representing the influence of genetics and environment on neural circuitry.