Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).

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. The association between the primary outcome of death and clinical variables was analyzed by using Kaplan-Meier estimates and multivariable Cox proportional hazard models. Outcomes assessed after discharge were technology dependence, neurologic deficits, and Functional Status Score. Improved functional status was defined as a change in total Functional Status Score [Formula: see text] 2. RESULTS: Of 106 patients (58% boys, median age 3.9 years) with CBI, 86 (81%) died. Withdrawal of life-sustaining therapies was the most common cause of death (60 of 86, 70%). In our multivariable analysis, each unit increase in admission pediatric sequential organ failure assessment score was associated with 10% greater hazard of death (hazard ratio 1.10, 95% confidence interval 1.04-1.17, p < .01). After controlling for admission pediatric sequential organ failure assessment scores, compared with those of patients with traumatic brain injury, all other etiologies of CBI were associated with a greater hazard of death (p = .02; hazard ratio 3.76-10). The median survival time for the cohort was 22 days (95% confidence interval 14-37 days). Of 23 survivors to hospital discharge, 20 were still alive after a median of 2 years (interquartile range 1-3 years), 6 of 20 (30%) did not have any technology dependence, 12 of 20 (60%) regained normal levels of alertness and responsiveness, and 15 of 20 (75%) had improved functional status. CONCLUSIONS: Most children with acute CBI died within 1 month of hospitalization. Having traumatic brain injury as the etiology of CBI was associated with greater survival, whereas increased organ dysfunction score on admission was associated with a higher hazard of mortality. Of the survivors, some recovered consciousness and functional status and did not require permanent technology dependence. Larger prospective studies are needed to improve prediction of CBI among critically ill children, understand factors guiding clinician and family decisions on the continuation or withdrawal of life-sustaining treatments, and characterize the natural history and long-term outcomes among CBI survivors.

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. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.

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. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.

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. In the years that followed, the ACGME received and reviewed feedback about the milestones and set out to revise them. METHODS: A committee was assembled to review the original milestones and develop a new set of milestones. The group was also encouraged to not only consider the child neurology residency graduate of today but also the graduate of tomorrow, taking into account growing fields such as genetics and technology. RESULTS: A diverse group of 12 individuals, including 10 child neurologists (all of whom were current or previous program directors or associate program directors), one child neurology resident, and one non-physician program coordinator, were recruited from programs of varying size across the country. CONCLUSIONS: The committee developed a revision to the child neurology milestones. All changes made were with a focus on how the milestones can be useful to trainees, program directors, and clinical competency committee members. Implementation and further feedback should help guide future revisions. These changes should help trainees, clinical competency committee members, and program directors find more meaning from their use.

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. Although the realities of a global pandemic have the potential to require a shift from our usual, highly individualistic standards of care to crisis standards of care, shifting priorities should nonetheless be informed by good facts. Resource allocation guidelines with the potential to affect children and young adults with neuromuscular disorders should take into account the known trajectory of acute respiratory illness in this population and rely primarily on contemporary long-term outcome data.

A case of congenital glycogen storage disease type IV with a novel GBE1 mutation.

Glycogen storage disease type IV (Andersen disease) is a rare metabolic disorder characterized by deficient glycogen branching enzyme activity resulting in abnormal, amylopectin-like glycogen deposition in multiple organs. This article reports on an infant with the congenital neuromuscular subtype of glycogen storage disease type IV who presented with polyhydramnios, hydrops fetalis, bilateral ankle contractures, biventricular cardiac dysfunction, and severe facial and extremity weakness. A muscle biopsy showed the presence of material with histochemical and ultrastructural characteristics consistent with amylopectin. Biochemical analysis demonstrated severely reduced branching enzyme activity in muscle tissue and fibroblasts. Genetic analysis demonstrated a novel deletion of exon 16 within GBE1, the gene associated with glycogen storage disease type IV. Continued genetic characterization of glycogen storage disease type IV patients may aid in predicting clinical outcomes in these patients and may also help in identifying treatment strategies for this potentially devastating metabolic disorder.

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. METHODS: We designed and implemented a two-year longitudinal teaching curriculum for child neurology and neurodevelopmental disabilities residents using adult learning theory principles: experiential learning and immediate applicability to specific roles. Core modules included teaching in clinical settings, adult learning, and giving feedback. Training-year-specific modules for second-year residents (n = 11) and final-year residents (n = 10) included teaching through consultation and promoting clinical reasoning in supervisory roles. Learners completed an 11-item self-assessment before and after intervention. RESULTS: The overall program significantly increased residents' self-assessed knowledge of how to assess the level of a learner (P = 0.02, Cohen d = 0.84) and comfort and skill in giving feedback (P = 0.04, d = 0.64; P = 0.04, d = 0.71). The final-year-specific curriculum additionally increased self-assessed skill in teaching same-specialty residents (P = 0.05, d = 1.07) and in promoting clinical reasoning (P = 0.03, d = 1.14). The program was rated highly by trainees and faculty, and has been adopted as an ongoing part of our training program. CONCLUSIONS: Our experience offers a reproducible model and theoretical framework for child neurology, neurodevelopmental disabilities, and other specialty programs to develop customized trainee-as-teacher curricula with specialty- and training-year-specific content.

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. The educational intervention included lectures, observed neurologic examinations, in-person and virtual triage, and an electronic medical record-based consult system. Residents in other primary care clinics served as the comparison group. Intervention-group residents reported significantly improved confidence in diagnosis of chronic/recurrent headache, attention deficit hyperactivity disorder (ADHD), and developmental delay; initial management of ADHD and developmental delay; and secondary management of ADHD, developmental delay, and concussion/traumatic brain injury. Comparison-group residents reported significantly improved confidence only in diagnosis of developmental delay. Our multipronged intervention is a promising approach to improving pediatric resident training in pediatric neurology and may be generalizable to subspecialty collaborations for other residency programs.

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. These challenges must be understood to ensure that patients with spinal muscular atrophy benefit from treatment, are protected from harm, and are treated fairly.

Neonatal subependymal giant cell astrocytoma: new case and review of literature.

Subependymal giant cell astrocytomas are one of the three major intracranial lesions found in tuberous sclerosis complex. Subependymal giant cell astrocytomas are typically slow-growing tumors of mixed glioneuronal lineage which can become aggressive and cause obstructive hydrocephalus usually in older children and adolescents. Neonatal subependymal giant cell astrocytomas are extremely rare, and their natural history and prognosis are poorly understood. This report investigates an extremely large neonatal subependymal giant cell astrocytoma which was initially identified in utero at 19 weeks of gestation in a high-risk pregnancy with no family history of tuberous sclerosis complex.

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. Objective: To establish guidelines for neurologic evaluation and imaging techniques to identify or rule out neuromuscular dysfunction in children with laryngeal cleft. Design: Retrospective review of the medical records of 242 patients who were diagnosed with laryngeal cleft at a tertiary children's hospital between March 1, 1998, and July 6, 2015. Based on this review, an algorithm to guide management of laryngeal cleft is proposed. Main Outcomes and Measures: Data extracted from patient medical records included the type of laryngeal cleft, details of neurologic referral, results of neuroimaging studies, and objective swallow study outcomes. Results: Of the 242 patients, 142 were male and 100 were female. Mean age at the time of data analysis was 8.7 years (range, 10 months to 25 years), and there were 164 type I clefts, 64 type II, 13 type III, and 1 type IV. In all, 86 patients (35.5%) were referred to a neurologist; among these, 33 (38.4%) had examination findings indicative of neuromuscular dysfunction or dyscoordination (eg, hypotonia, spasticity, or weakness). Abnormal findings were identified in 32 of 50 patients (64.0%) who underwent brain imaging. Neurosurgical intervention was necessary in 3 patients diagnosed with Chiari malformation and in 1 patient with an intraventricular tumor detected on neuroimaging. Conclusions and Relevance: A substantial proportion of patients with laryngeal cleft have coexistent neuromuscular dysfunction as a likely contributing factor to dysphagia and aspiration. Collaboration with a neurologist and appropriate neuroimaging may provide diagnostic and prognostic information in this subset of patients. At times, imaging will identify critical congenital malformations that require surgical treatment.

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. Three raters with expertise in movement disorders independently rated the five-minute windows using standardized terminology to determine the level of agreement. We iteratively refined the protocol in three stages to improve descriptive accuracy, categorizing HS as "central" or "peripheral," "simple" or "complex," scoring each hand separately. Inter-rater agreement was analyzed using Kappa statistics. RESULTS: In the initial protocol evaluating HS by video, inter-rater agreement was 20.7%. In the final protocol, inter-rater agreement for the two most frequent HS was higher than the initial protocol at 50%. CONCLUSION: Phenotypic variability makes standardized evaluation of HS in RTT a challenge; we achieved only 50% level of agreement and only for the most frequent HS. Therefore, objective measures are needed to evaluate HS.

Basilar meningitis associated with ethmoid and sphenoid cephaloceles.

Nontuberculous causes of basilar meningitis are rare. This study presents the case of a male who developed fever and meningitis caused by Streptococcus pneumoniae. He developed multiple cranial nerve palsies and imaging findings consistent with basilar meningitis and ventriculitis. Computed tomographic scans of the floor of the anterior fossa were performed after the detection of a cephalocele on magnetic resonance imaging. This imaging revealed a defect in the cribiform plate and fovea ethmoidalis with a large nasoethmoidal cephalocele. There was a second separate defect and cephalocele involving the middle cranial fossa. The association of basilar meningitis with an atypical organism should lead to a careful search for disruption in the floor of the anterior or middle cranial fossa.

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. Those with abnormal MRI findings were categorized based on findings. Children with abnormalities from each of these categories were compared in terms of deficits in automaticity, as measured by the tasks of Rapid Automatized Naming, Rapid Alternating Stimulus Naming, or the timed motor performance battery from the Physical and Neurological Examination for Soft Signs. Data were compared in children with and without disorders of automaticity regarding type of brain structure abnormality. RESULTS: Of the 1,587 children evaluated, 127 had a focal deficit. Eighty-seven had a brain MRI (52 on 1.5-tesla machines and 35 on 3.0-tesla machines). Forty of these images were found to be abnormal. These children were compared with a clinic sample of 150 patients with learning disabilities and no focal findings on examination, who also had undergone MRI. Only 5 of the latter group had abnormalities on MRI. Reduced verbal automaticity was associated with cerebellar abnormalities, whereas reduced automaticity on motor or motor and verbal tasks was associated with white matter abnormalities. CONCLUSION: Reduced automaticity of retrieval and slow timed motor performance appear to be highly associated with MRI findings.

Transient global amnesia in a young adult with cyanotic heart disease.

The etiology of transient global amnesia is poorly understood, particularly in children and young adults. Transient global amnesia may follow a wide range of precipitating events. Proposed causes have included vascular event, seizure, and migraine. A young man with cyanotic congenital heart disease experienced an episode of transient global amnesia in the setting of polycythemia. Differential diagnosis of acute confusional episodes in children should include transient global amnesia, as well as confusional migraine, and should include evaluation for underlying coagulation abnormalities and polycythemia.

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. METHODS: Before and after implementation of the quality improvement curriculum, a 14-item survey assessed resident comfort with quality improvement project skills and attitudes about implementation of quality improvement in clinical practice using a 5-point Likert scale. We used the Kruskal-Wallis and Fisher exact tests to evaluate pre to post changes. RESULTS: Residents' gained confidence in their abilities to identify measures (P = 0.02) and perform root cause analysis (P = 0.02). Overall, 73% of residents were satisfied or very satisfied with the quality improvement curriculum. CONCLUSIONS: Our child neurology quality improvement curriculum was well accepted by trainees. We report the details of this curriculum and its impact on residents and discuss its potential to meet the Accreditation Council for Graduate Medical Education's Next Accreditation System requirements.

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. METHODS: For the 2-week period after the Boston Marathon bombings, we prospectively collected data on patients whose presentation suggested a functional neurological symptom disorder. We assessed clinical and demographic variables, duration of symptoms, extent of educational impact, and degree of connection to the Marathon bombing. We contacted all patients at 6 months after presentation to determine the outcome and accuracy of the diagnosis. RESULTS: In a parallel study, we reported a baseline of 2.6 functional neurological presentations per week in our emergency room. In the week after the Marathon bombings, this frequency tripled. Ninety-one percent of presentations were delayed by 1 week, with onset around the first school day after a city-wide lockdown. Seventy-three percent had a history of a prior psychiatric diagnosis. At the 6 months follow-up, no functional neurological symptom disorder diagnoses were overturned and no new organic diagnosis was made. CONCLUSIONS: Pediatric functional neurological symptom disorder may be precipitated by both casual and high-intensity stressors. The 3.4-fold increase in incidence after the Boston Marathon bombings and city-wide lockdown demonstrates the marked effect that a community-wide tragedy can have on the mental health of children. Care providers must be aware of functional neurological symptom disorders after stressful community events in vulnerable patient populations, particularly those with prior psychiatric diagnoses.

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. METHODS: (1) More than 1 year, psychiatry consultations for neurology patients with a functional neurological symptom disorder were retrospectively reviewed. (2) For 3 months, all children whose emergency room presentation suggested the diagnosis were prospectively collected. (3) Three to six months after prospective collection, families completed a structured telephone interview on outcome measures. RESULTS: Twenty-seven patients were retrospectively assessed; 31 patients were prospectively collected. Trainees' accurately predicted the diagnosis in 93% (retrospective) and 94% (prospective) cohorts. Mixed presentations were most common (usually sensory-motor changes, e.g. weakness and/or paresthesias). Associated stressors were mundane and ubiquitous, rarely severe. Families were substantially affected, reporting mean symptom duration 7.4 (standard error of the mean ± 1.33) weeks, missing 22.4 (standard error of the mean ± 5.47) days of school, and 8.3 (standard error of the mean ± 2.88) of parental workdays (prospective cohort). At follow-up, 78% were symptom free. Parental dissatisfaction was rare, attributed to poor rapport and/or insufficient information conveyed. CONCLUSIONS: Trainees' clinical impression was accurate in predicting a later diagnosis of functional neurological symptom disorder. Extraordinary life stressors are not required to trigger the disorder in children. Although prognosis is favorable, families incur substantial economic burden and negative educational impact. Improving recognition and appropriately communicating the diagnosis may speed access to treatment and potentially reduce the disability and cost of this disorder.