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Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications.Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications.Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency).Fisher Exact test, Spearman correlations.These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation.During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.

Preclinical and early phase clinical studies suggest that an appropriately dosed umbilical cord blood (CB) infusion has the potential to help improve motor function in young children with cerebral palsy (CP). As many children with CP do not have their own CB available, use of allogeneic cells would extend access to this potentially beneficial therapy to more children. In this phase I, open-label study, 15 children, aged 1 to 6 years, with moderate to severe spastic CP were treated with a single intravenous infusion of allogeneic human leukocyte antigen (HLA) matched or partially matched sibling CB with a cell dose of ≥2.5 × 107 cells/kg based on the pre-cryopreservation count (median infused cell dose, 3.3 × 107; range, 1.8-5.2 × 107). There were a total of 49 adverse events (AEs) over a 2-year time period, but there were no AEs related to the CB infusions. Specifically, there were no acute infusion reactions and no antibody formation against platelets, red blood cells, or donor-specific HLA antigens. Donor cells were not detected in peripheral blood 6 months later. Six months after infusion, participants were assessed for response and experienced a mean ± SD increase of 4.7 ± 2.5 points on the Gross Motor Function Measure-66 and 1 ± 2.9 points on the Peabody Gross Motor Quotient. Appropriately dosed, allogeneic partially or fully HLA-matched sibling CB infusion is well tolerated and potentially beneficial in young children with CP.

Background: Though much research has been done on the cognitive profiles of children, the abilities of patients with SBM as they age into adulthood are not well understood.Objective: Determine if adults with SBM have impairments in overall cognition, attention, executive function, and memory compared to typically developing adults or a standardized population mean.Methods: A medical librarian composed a search of spina bifida, adults, and cognitive function. 549 results were screened using title and abstract. Data were extracted using Covidence review software, including risk of bias assessments. 24 studies were included.Results: Memory impairments, notably working and prospective, have been reported. Results in other domains varied. Average VIQ or PIQ did not imply lack of impairment in other specific domains.Conclusion: Memory impairments should be accounted for and neuropsychological testing should be considered when providing care to adults with SBM. Future longitudinal cognitive aging and interventional studies are needed.

Pneumonia and respiratory infections impact infants and children with Down syndrome; pneumonia is a leading cause of mortality in adults with Down syndrome. We aimed to review the literature to evaluate gaps and address key questions. A series of key questions were formulated a priori to inform the search strategy and review process; addressed prevalence, severity, etiology, risk factors, preventive methods, screening, and financial costs, potential benefits or harms of screening. Using the National Library of Medicine database, PubMed, detailed literature searches on pneumonia and respiratory infections in Down syndrome were performed. Previously identified review articles were also assessed. The quality of available evidence was then evaluated and knowledge gaps were identified. Forty-two relevant original articles were identified which addressed at least one key question. Study details including research design, internal validity, external validity, and relevant results are presented. Pneumonia and respiratory infections are more prevalent and more severe in individuals with Down syndrome compared to healthy controls through literature review, yet there are gaps in the literature regarding the etiology of pneumonia, the infectious organism, risk factors for infection, and to guide options for prevention and screening. There is urgent need for additional research studies in Down syndrome, especially in the time of the current COVID-19 pandemic.

AIM To evaluate presence and severity of social impairments in alternating hemiplegia of childhood (AHC) and determine factors that are associated with social impairments. METHOD This was a retrospective analysis of 34 consecutive patients with AHC (19 females, 15 males; mean age: 9y 7mo, SD 8y 2mo, range 2y 7mo-40y), evaluated with the Social Responsiveness Scale, Second Edition (SRS-2). RESULTS SRS-2 scores, indicating level of social impairment, were higher than population means (75, SD 14 vs 50, SD 10, p 76), four moderate (66-76). All subscale domains, including social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior, had abnormal scores compared to population means (p

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.

Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M-motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M-motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M-motif to myosin, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early-onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort (n = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool- mice at prepubescent and adult ages (n = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: P, Uchitel et al. found, in Alternating Hemiplegia of Childhood patients, that over time there is: (i) Mild worsening of non-paroxysmal neurological disability, correlating with the degree of initial (, Graphical Abstract Graphical Abstract

PURPOSE: Neurogenic bowel dysfunction (NBD) is a common comorbidity of myelomeningocele (MMC), the most common and severe form of spina bifida. The National Spina Bifida Patient Registry (NSBPR) is a research collaboration between the CDC and Spina Bifida Clinics. Fecal continence (continence) outcomes for common treatment modalities for NBD have not been described in a large sample of individuals with MMC. NSBPR patients with MMC and NBD were studied to determine variation in continence status and their ability to perform their treatment independently according to treatment modality and individual characteristics. METHODS: Continence was defined as < 1 episode of incontinence per month. Eleven common treatments were evaluated. Inclusion criteria were established diagnoses of both MMC and NBD, as well as age ≥ 5 years (n = 3670). Chi-square or exact statistical tests were used for bivariate analyses. Logistic regression models were used to estimate the odds of continence outcomes by age, sex, race/ethnicity, level of motor function, and insurance status. RESULTS: At total of 3670 members of the NSBPR met inclusion criteria between November 2013 and December 2017. Overall prevalence of continence was 45%. Prevalence ranged from 40–69% across different treatments. Among continent individuals, 60% achieved continence without surgery. Antegrade enemas were the most commonly used treatment and had the highest associated continence rate. Ability to carry out a treatment independently increased with age. Multivariable logistic regression showed significantly higher odds of continence among individuals aged ≥ 12 years, female, non-Hispanic white, and with private insurance. CONCLUSIONS: The prevalence of continence was generally low and varied between treatment modalities. Better treatment algorithms considering patient factors may result in improved outcomes.

PURPOSE: Determine the feasibility and utility of using a battery of tests utilized, so far, to assess neurological-cognitive functions in the typical adult population and identify the spectrum of these functions in adult SBM patients. METHODS: Prospective study in which 15 participants (mean age = 28.7 ± 8.7 years, range = 19–45 years) completed the targeted battery of tests (n = 5–15/test) previously standardized to the general population. Results were compared with normative data. RESULTS: Statistically significant differences with normative means were noted in the following tests: Montreal Cognitive Assessment (MoCA), Functional Activities Questionnaire (FAQ), and NIH Toolbox Fine Motor (Dexterity and Grip Strength) tests. Cohort means for NIH Toolbox Fluid, Crystallized, and Cognitive Composite Scores and Timed Up and GO (TUG) were not different from normative means. CONCLUSION: All tests were successfully completed by cohort. Whereas many aspects of cognition were normal, tests assessing visual-constructural, calculation, motor, and fluency functions did show differences from population means. Numerous tests assessing multiple domains are needed and can be used in future aging studies to appreciate the spectrum of cognitive and motor abilities in adults with SBM.

Background ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. Aim We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. Methods A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. Results Patients (age 2.5–20 years) had symptom onset at an early age (6 days–1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks–4.8 years) with some improvements reported in all five. Conclusions Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure–function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.

Background Alternating hemiplegia of childhood often manifests severe or extreme behavioral problems, the nature of which remains to be fully characterized. Methods We analyzed 39 consecutive patients with alternating hemiplegia of childhood for occurrence of behavioral problems and categorized those by severity: mild (not requiring intervention), moderate (requiring intervention but no risk), severe (minor risk to self, others, or both), and extreme (major risk). We then analyzed behavioral manifestations, concurrent morbidity, and medication responses in patients with severe or extreme symptoms. Results Two patients had mild behavioral problems, five moderate, 10 severe, six extreme, and 16 none. Extreme cases exhibited disruptive behaviors escalating to assaults. Triggers, when present, included peer-provocation, low frustration tolerance, limits set by others, and sleep disruption. Reversible psychotic symptoms occurred in two patients: in one triggered by infection and trihexyphenidyl, and in another triggered by sertraline. Of the 16 patients with severe or extreme symptoms, 13 had concurrent neuropsychiatric diagnoses. Occurrence of severe or extreme symptoms did not correlate with age, puberty, severity of intellectual disability, or mutation status (P > 0.05). A multidisciplinary team including mental health professionals comanaged all patients with severe or extreme symptoms with either behavioral therapy, medications, or both. When considering medications prescribed to more than four patients, medicines that demonstrated efficacy or partial efficacy in more than 50% of patients were alpha-adrenergic agonists and selective-serotonin-reuptake-inhibitors. Conclusions Patients with alternating hemiplegia of childhood (41%) often experience severe or extreme behavioral problems and, rarely, medication-triggered psychotic symptoms. These observations are consistent with current understanding of underlying alternating hemiplegia of childhood brain pathophysiology. Increasing awareness of these behavioral problems facilitates alternating hemiplegia of childhood management and anticipatory guidance.

Mutations in ATP1A3 have been found to cause rapid-onset dystonia Parkinsonism, alternating hemiplegia of childhood, epileptic encephalopathy and other syndromes. We report a four-year, nine-month-old boy with episodes of frequent and recurrent status epilepticus, who first began having generalized tonic-clonic seizures at four months of age. Development was normal until the age of four months, and markedly slowed down after the onset of seizures. Between the age of seven months and two and a half years, the patient had recurrent attacks of unilateral and bilateral hemiplegia. At the age of 21 months, after a febrile illness with status epilepticus, he regressed and developed continuous severe dystonia and bradykinesia with superimposed intermittent painful dystonic spasms. Extensive neurological and genetic workup revealed a de novo p.V589F ATP1A3 mutation (NM_152296.5:c.1765GT, NC_000019.9:g.42482344CA). This is a novel mutation associated with a novel phenotype that shares features with epileptic encephalopathy, alternating hemiplegia of childhood, and rapid-onset dystonia Parkinsonism.

To determine the neuropsychological abnormalities that occur in alternating hemiplegia of childhood (AHC) and report on our experience in managing them.Patients underwent evaluations according to our standardized AHC pathway. Data were entered into our prospective AHC database and then analyzed.Of the cohort of 25 consecutive patients (ages 15mo-42y), eight had initial chief complaints about cognition, 14 language, five attention, and 11 behavior. As compared to population norms means, neuropsychological and behavioral assessment tools (including Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, and Wechsler Intelligence Quotient tests) showed significant impairments in multiple domains: cognition, expressive and receptive language, executive function/attention, and behavior (p0.05 in all comparisons). Evaluations generated management recommendations in all patients. Twenty had neuropsychiatric diagnoses: 10 attention-deficit/hyperactivity disorder (ADHD), seven disruptive behavior, and three anxiety disorder. Eight out of nine patients with ADHD who were prescribed medications responded to pharmacotherapy.Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. This supports the hypothesis that the underlying AHC pathophysiology involves diffuse neuronal dysfunction. Testing generated recommendations to help manage these difficulties. Patients with AHC also have a range of neuropsychiatric diagnoses, the most common being ADHD which responds to pharmacotherapy.Patients with alternating hemiplegia of childhood (AHC) have developmental difficulties with underlying neuropsychological impairments. The findings in this study are consistent with an underlying AHC pathophysiology which involves diffuse neuronal, probably largely GABAergic, dysfunction. Patients with AHC have a range of neuropsychiatric diagnoses, the most common being attention-deficit/hyperactivity disorder.PERFILES COGNITIVOS, ADAPTATIVOS Y DE COMPORTAMIENTO Y MANEJO DE LA HEMIPLEJIA ALTERNA EN LA INFANCIA: OBJETIVO: Determinar las anormalidades neuropsicológicas que ocurren en la hemiplejia alterna en la infancia (AHC) y reportar nuestra experiencia en su manejo.Los pacientes fueron evaluados de acuerdo a nuestra evaluación estandarizado de AHC. Los datos fueron introducidos en nuestra base de datos de AHC prospectiva y luego analizados.De la cohorte de 25 pacientes consecutivos (edades 15 meses - 42 años), ocho tenían desafíos iniciales sobre cognición, 14 de lenguaje, cinco de atención y 11 de comportamiento. Comparadas con la población tipica, las herramientas de evaluación neuropsicológica y de comportamiento (incluyendo Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, y Wechsler Intelligence Quotient Tests) mostraron discapacidades significativas en múltiples áreas: cognición, lenguaje expresivo y receptivo, atención y función ejecutiva, y comportamiento (p0.05 en todas las comparaciones). Las evaluaciones generaron recomendaciones de manejo para todos los pacientes. Veinte tenían diagnósticos neuropsiquiátricos: 10 desorden de hiperactividad y déficit de atención (TDAH), siete comportamientos disruptivos, y tres desorden de ansiedad. Ocho de cada nueve pacientes con TDAH a los cuales se les prescribió medicación respondieron a la terapia farmacológica.Los pacientes con AHC tienen dificultades en el desarrollo relacionadas a discapacidades en múltiples áreas neuropsicológicas. Esto apoyo la hipótesis que la fisiopatología AHC subyacente involucra disfunción neuronal difusa. Las evaluaciones generaron recomendaciones para ayudar a manejar esas dificultades. Los pacientes con AHC también tienen un rango de diagnósticos neuropsiquiátricos, siendo TDAH la más común que responde a terapia farmacológica.PERFIL COGNITIVO, ADAPTATIVO E COMPORTAMENTAL DA HEMIPLEGIA ALTERNANTE DA INFÂNCIA: OBJETIVO: Determinar anormalidades neuropsicológicas que ocorrem na hemiplegia alternante da infância (HAI) e relatar nossa experiência com o manejo dos mesmos. MÉTODO: Pacientes passaram por avaliações de acordo com nossa rotina para HAI. Os dados foram entrados em uma base de dados prospectiva e analisados. RESULTADOS: Da coorte de 25 pacientes consecutivos (idades 15m-42a), oito tiveram queixas iniciais importantes sobre cognição, 14 de linguagem, 5 de atenção e 8 de comportamento. Em comparação com valores normativos da população, os instrumentos de avaliação neuropsicológica e comportamental (incluindo Checklist de Comportamento da criança, Escalas Vineland de Comportamento Adaptativo, testes Peabody de Vocabulário pictórico e Quociente de inteligiencia Wechsler) mostraram alterações significativas em múltiplos domínios: cognição, linguagem expressiva e receptiva, função executiva/atenção, e comportamento (p0,05 em todas as comparações). As avaliações geraram recomendações de manejo em todos os pacientes. Vinte tiveram diagnósticos neuropsiquiátricos: 10 com transtorno de déficit de atenção e hiperatividade (TDAH), sete comportamento disruptivo, e três transtorno de ansiedade. Oito dos nove pacientes com TDAH que foram prescritos medicação responderam a farmacoterapia. INTERPRETAÇÃO: Pacientes com HAI têm dificuldades neurodesenvolvimentais relacionadas a deficiências em múltiplos domínios neuropsicológicos. Isso suporta a hipótese de que a fisiopatologia básica da HAI envolve disfunção neuronal difusa. As avaliações geraram recomendações que ajudaram a manejar estas dificuldades. Pacientes com HAI também têm uma variedade de diagnósticos neuropsiquiátricos, o mais comum sendo TDAH que responde a farmacoterapia.

Background & Aim: Umbilical cord blood (CB) and mesenchymal stromal cells (MSC) have shown safety in children with cerebral palsy (CP). While early phase clinical trials suggest potential functional benefit, small sample sizes, heterogeneous populations, and variable cell doses have impaired accurate assessment of motor gains following treatment. Aim: Describe change in gross motor function in young children with CP after treatment with high-dose allogeneic unrelated donor CB or allogeneic, third party human cord tissue-derived MSC (hCT-MSC) 12 months post treatment. Methods, Results & Conclusion: We conducted a phase 2 randomized trial of 90 children ages 2-4 years with hypertonic CP due to hypoxic ischemic encephalopathy, periventricular leukomalacia, or in utero stroke/bleed. Randomization, stratified by etiology and severity (Gross Motor Function Classification System (GMFCS) level), was to: (a) 10×107 total nucleated cells (TNC)/kg allogeneic CB at baseline, (b) three doses of 2×106 cells/kg hCT-MSC given at baseline, 3, and 6 months, or (c) Natural History in which 10×107 TNC/kg allogeneic CB was given at one year. Infusions were intravenous and premedicated with diphenhydramine and methylprednisolone without immunosuppression. Primary outcome was change in motor function one-year post enrollment, measured by the Gross Motor Function Measure-66 (GMFM-66). Ninety children (median 3.5 years) were randomized and completed baseline and 6-month evaluations. Due to the COVID pandemic, only 68 completed 12-month assessments. The only adverse events (AEs) related to the cell products were 8 transient infusion reactions (3 CB, 5 hCT-MSC). An additional 95 non-severe AEs and 33 severe AEs were unrelated to the products. At 6 months, there was no statistical difference in change in GMFM-66 scores between Natural History (n=31) and either treatment group (CB n=31, hCTMSC n=28). At 12 months, after adjustment for baseline GMFCS level, GMFM-66 score, and etiology of CP, the mean GMFM-66 score of the hCT- MSC group (n=23) was 1.4 points higher than Natural History (n=25;95% CI: -1.1, 4.0;p=0.27) and the CB group (n=20) was 3.3 points higher than Natural History (95% CI: 0.59, 5.93;p=0.02). High dose allogeneic CB, but not hCT-MSC, infusion is associated with gross motor improvement in young children with CP, consistent with the dose effect in a prior study of autologous CB. A phase 3 randomized placebo-controlled study should be performed to confirm the CB observation.

Background Youth with special health care needs often experience difficulty transitioning from pediatric to adult care. These difficulties may derive in part from lack of physician training in transition care and the challenges health care providers experience establishing interdisciplinary partnerships to support these patients. Objective This educational innovation sought to improve pediatrics and adult medicine residents' interdisciplinary communication and collaboration. Methods Residents from pediatrics, medicine-pediatrics, and internal medicine training programs participated in a transitions clinic for patients with chronic health conditions aged 16 to 26 years. Residents attended 1 to 4 half-day clinic sessions during 1-month ambulatory rotations. Pediatrics/adult medicine resident dyads collaboratively performed psychosocial and medical transition consultations that addressed health care navigation, self-care, and education and vocation topics. Two to 3 attending physicians supervised each clinic session (4 hours) while concurrently seeing patients. Residents completed a preclinic survey about baseline attitudes and experiences, and a postclinic survey about their transitions clinic experiences, changes in attitudes, and transition care preparedness. Results A total of 46 residents (100% of those eligible) participated in the clinic and completed the preclinic survey, and 25 (54%) completed the postclinic survey. A majority of respondents to the postclinic survey reported positive experiences. Residents in both pediatrics and internal medicine programs reported improved preparedness for providing transition care to patients with chronic health conditions and communicating effectively with colleagues in other disciplines. Conclusions A dyadic model of collaborative transition care training was positively received and yielded improvements in immediate self-assessed transition care preparedness.

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

The Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

Aim To characterize motor function profiles in alternating hemiplegia of childhood, and to investigate interrelationships between these domains and with age. Method We studied a cohort of 23 patients (9 males, 14 females; mean age 9y 4mo, range 4mo–43y) who underwent standardized tests to assess gross motor, upper extremity motor control, motor speech, and dysphagia functions. Results Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure-88 (GMFM-88), Manual Ability Classification System (MACS), and Revised Melbourne Assessment (MA2) scales manifested predominantly mild impairments; motor speech, moderate to severe; Modified Dysphagia Outcome and Severity Scale (M-DOSS), mild-to moderate deficits. GMFCS correlated with GMFM-88 scores (Pearson's correlation, p=0.002), MACS (p=0.038), and MA2 fluency (p=0.005) and accuracy (p=0.038) scores. GMFCS did not correlate with motor speech (p=0.399), MA2 dexterity (p=0.247), range of motion (p=0.063), or M-DOSS (p=0.856). Motor speech was more severely impaired than the GMFCS (p

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by alterations in social functioning, communicative abilities, and engagement in repetitive or restrictive behaviors. The process of aging in individuals with autism and related neurodevelopmental disorders is not well understood, despite the fact that the number of individuals with ASD aged 65 and older is projected to increase by over half a million individuals in the next 20 years. To elucidate the effects of aging in the context of a modified central nervous system, we investigated the effects of age on the BTBR T + tf/j mouse, a well characterized and widely used mouse model that displays an ASD-like phenotype. We found that a reduction in social behavior persists into old age in male BTBR T + tf/j mice. We employed quantitative proteomics to discover potential alterations in signaling systems that could regulate aging in the BTBR mice. Unbiased proteomic analysis of hippocampal and cortical tissue of BTBR mice compared to age-matched wild-type controls revealed a significant decrease in brain derived neurotrophic factor and significant increases in multiple synaptic markers (spinophilin, Synapsin I, PSD 95, NeuN), as well as distinct changes in functional pathways related to these proteins, including Neural synaptic plasticity regulation and Neurotransmitter secretion regulation. Taken together, these results contribute to our understanding of the effects of aging on an ASD-like mouse model in regards to both behavior and protein alterations, though additional studies are needed to fully understand the complex interplay underlying aging in mouse models displaying an ASD-like phenotype.

Low bone mass density (BMD), a classical age-related health issue and a known health concern for fair skinned, thin, postmenopausal Caucasian women, is found to be common among individuals with developmental/intellectual disabilities (D/IDs). It is the consensus that BMD is decreased in both men and women with D/ID. Maintaining good bone health is important for this population as fractures could potentially go undetected in nonverbal individuals, leading to increased morbidity and a further loss of independence. This paper provides a comprehensive overview of bone health of adults with D/ID, their risk of fractures, and how this compares to the general aging population. We will specifically focus on the bone health of two common developmental disabilities, Down syndrome (DS) and cerebral palsy (CP), and will discuss BMD and fracture rates in these complex populations. Gaining a greater understanding of how bone health is affected in individuals with D/ID could lead to better customized treatments for these specific populations.

We report on a preterm neonate of 30 weeks gestational age who presented with marked muscular hypotonia and severe respiratory failure at birth and was diagnosed with congenital myotonic dystrophy. Neuroimaging at 36 gestational weeks demonstrated diffuse T2-hyperintense signal of the supratentorial white matter and a simplified gyration and sulcation pattern. Follow-up imaging showed progressive myelination, brain maturation and decrease in T2-signal of the white matter. We discuss possible pathomechanisms for white matter signal abnormalities in this neonate.