Early-onset dysphagia and severe neurodevelopmental disorder as early signs in a patient with two novel variants in NARS1: a case report and brief review of the literature.

Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.[662 A > G]; [1155dup], p.[(Asn221Ser)]; [(Arg386Thrfs*19)], inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.

Brain and spine malformations and neurodevelopmental disorders in a cohort of children with CAKUT.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.

Desarrollo infantil y sus principales desafíos en los primeros años de vida: lugar e importancia de los centros de educación y protección del Instituto del Niño y Adolescente del Uruguay / Child development and its main challenges in the first years of life: place and importance of the education and protection centers of the Children and Adolescents Institute of Uruguay

Existe un aumento progresivo de los problemas del neuropsicodesarrollo. Las intervenciones psicoeducativas y sociales oportunas con soporte en evidencias mejoran la evolución a lo largo de la vida de los niños. Los Centros Educativos en Primera Infancia tienen el potencial de identificar precozmente a niños con riesgos de alteraciones en el neuropsicodesarrollo. El Centro de Formación y Estudios del Instituto del Niño y Adolescente del Uruguay convoca a la Unidad Académica de Psiquiatría Pediátrica para la formación y actualización en esta problemática. El objetivo del trabajo es implementar un Programa de Capacitación en desarrollo normal, sus variaciones y desafíos; oportunidades de estimulación, identificación precoz de alteraciones e intervenciones en Centros Educativos en Primera Infancia; simultáneamente capacitar en habilidades de comunicación y trabajo interdisciplinario a posgrados de psiquiatría pediátrica y otras disciplinas de salud mental. Está dirigido a trabajadores del Instituto del Niño y Adolescente del Uruguay que trabajan con niños de 0 a 3 años. La implementación se realiza a través de tres modalidades articuladas, escalando progresivamente en contenidos: 1) Conferencias abiertas. 2) Curso introductorio a través de talleres virtuales sincrónicos. 3) Instancias docentes de profundización con equipos de Centros Educativos en Primera Infancia. Resultados: 2800 inscriptos. Se realizaron dos conferencias (4500 participantes en total), ocho cursos introductorios y se está implementando la modalidad 3 para el año 2024. Las encuestas de satisfacción han sido entre muy buenas-excelente. Se concluye que la implementación de este Programa de Capacitación permite la difusión de conocimientos y el intercambio interdisciplinario, por lo que es necesario continuar la cooperación entre Unidades Académicas, explorar otras modalidades pedagógicas y estudiar el impacto de la capacitación.

A progressive increase in neuro-psycho- developmental problems has taken place; timely evidence-based psycho-educational and social interventions improve children's lifelong development. Early Childhood Educational Centers have the potential for early identification of children at risk for neurodevelopmental disorders. The Training and Studies Center of the Institute of Childhood and Adolescence of Uruguay convenes the Academic Unit of Pediatric Psychiatry for training and updating on this issue. The objective is to implement a Training Program on normal development, its variations and challenges; stimulation opportunities, early identification of changes and interventions in Early Childhood Educational Centers, while training pediatric psychiatry postgraduates and other mental health disciplines in communication skills and interdisciplinary work. Methodology: Aimed at workers of the Institute of Childhood and Adolescence of Uruguay, working with children from 0 to 3 years old. Three articulated modalities, progressively increasing in content: 1) Open lectures. 2) Introductory course: synchronous virtual workshops. 3) Teaching instances with teams from Early Childhood Educational Centers. Results: 2800 participants. Two conferences (4500 participants) and eight introductory courses were held. Modality 3 is being organized for 2024. Satisfaction surveys show very good to excellent results. It is concluded that the implementation of this training Program makes knowledge dissemination and interdisciplinary exchange possible, so it is necessary to continue cooperation between academic units, explore other pedagogical modalities and study training impact.

Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.

Las funciones ejecutivas: su significado y aplicación clínica / Executive functions: meaning and clinical application

Las funciones ejecutivas generalmente se conceptualizan como un conjunto de procesos generales de control de orden superior que trabajan juntos para dirigir y gestionar las funciones cognitivas, emocionales y conductuales, especialmente durante la resolución activa de problemas. Su disfunción es frecuente de ser detectada como comorbilidad de otros trastornos del neurodesarrollo, causa o efecto? La detección precoz de la disfunción ejecutiva y su abordaje terapéutico temprano, mejora el pronóstico global madurativo en el periodo infantojuvenil. Esta sucinta revisión de las funciones ejecutivas intenta resaltar su importancia para el pediatra y su mirada de los trastornos del neurodesarrollo (AU)

Executive functions are typically understood as a set of general higher-order control processes that collectively direct and manage cognitive, emotional, and behavioral functions, especially during active problem solving. Their dysfunction is often detected as a comorbidity of other neurodevelopmental disorders; cause or effect? Early detection of executive dysfunction and a prompt therapeutic approach improves the overall developmental prognosis in childhood and adolescence. This brief review of executive functions aims to highlight their importance for the pediatrician and his/her view of neurodevelopmental disorder (AU)

Liquid Biopsy in Adverse Neurodevelopment of Children: Problems and Prospects.

Neurodevelopmental disorders in children have an important impact on the quality of life in the whole life cycle. Severe neurodevelopmental disorders will become a serious social and family burden and an important social and economic problem. The early and middle childhood is the critical period of children's neurodevelopment. Early diagnosis of neurological disorders plays an important role in guiding children's neurological development. Existing monitoring tools lack prenatal and even early assessment of children's neurodevelopment, so reliable biomarkers are conducive to personalized care at an earlier stage. In this review, we will discuss different methods of neurodevelopmental monitoring at different times and the role and evaluation of liquid biopsy in neurodevelopmental monitoring.

Missense variant in SRCAP with distinct DNA methylation signature associated with non-FLHS SRCAP-related neurodevelopmental disorder.

Floating-Harbor syndrome (FLHS) is a neurodevelopmental disorder (NDD) caused by truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein gene (SRCAP). Truncating variants proximal to this location in SRCAP result in a non-FLHS SRCAP-associated NDD; an overlapping but distinct NDD characterized by developmental delay with or without intellectual disability (ID), hypotonia, normal stature, and behavioral and psychiatric issues. Here, we report a young woman who initially presented in childhood with significant delays in speech and mild ID. In young adulthood, she developed schizophrenia. On physical examination, she had facial features suggestive of 22q11 deletion syndrome. After non-diagnostic chromosomal microarray and trio exome sequencing (ES), a re-analysis of trio ES data identified a de novo missense variant in SRCAP that was proximal to the FLHS critical region. Subsequent DNA methylation studies showed the unique methylation signature associated with pathogenic sequence variants in non-FLHS SRCAP-related NDD. This clinical report describes an individual with non-FLHS SRCAP-related NDD caused by an SRCAP missense variant, and it also demonstrates the clinical utility of ES re-analysis and DNA methylation analysis for undiagnosed patients, in particular, those with variants of uncertain significance.

Exome sequencing data screening to identify undiagnosed Aromatic l-amino acid decarboxylase deficiency in neurodevelopmental disorders.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the DDC gene and mainly characterized by developmental delay, hypotonia, and oculogyric crises. Early diagnosis is crucial for correct patient management; however, many patients remain misdiagnosed or undiagnosed due to the rarity and clinical heterogeneity of the disorder especially in the milder forms. Here, we applied exome sequencing approach by screening 2000 paediatric patients with neurodevelopmental disorders to identify possible new AADC variants and AADC deficiency patients. We identified five distinct DDC variants in two unrelated individuals. Patient #1 harboured two compound heterozygous DDC variants: c.436-12T > C and c.435 + 24A>C and presented with psychomotor delay, tonic spasms, and hyperreactivity. Patient #2 had three homozygous AADC variants: c.1385G > A; p.Arg462Gln, c.234C > T; p.Ala78 = , and c.201 + 37A > G and presented with developmental delay and myoclonic seizures. The variants were classified as benign class I variants and therefore non-causative according to the ACMG/AMP guidelines. Since the AADC protein is a structural and functional obligate homodimer, we evaluated the possible AADC polypeptide chain combinations in the two patients and determined the effects resulting from the amino acid substitution Arg462Gln. Our patients carrying DDC variants presented clinical manifestations not precisely overlapped to the classical symptoms exhibited by the most severe AADC deficiency cases. However, screening data derived from exome sequencing in patients featuring wide-range symptoms related to neurodevelopmental disorders may help to identify AADC deficiency patients, especially when applied to larger cohorts.

Intervenciones parentales para el desarrollo lingüístico- comunicativo en preescolares con Trastornos del Neurodesarrollo: una revisión sistemática / Parental interventions for linguistic-communicative development in preschoolers with Neurodevelopmental Disorders: a systematic review

Resumen En el actual escenario sociosanitario enfrentado a raíz de la pandemia por SARS-CoV-2, múltiples actividades se han visto mermadas, e incluso, suspendidas por los largos periodos de aislamiento social y las medidas de cuidado para evitar contagios. En este sentido, muchas personas han dejado de recibir con la misma regularidad, o bajo las mismas circunstancias, sus tratamientos, incluyendo a niños con Trastornos del Neurodesarrollo (TND). Es así como surgen las intervenciones Parentales. Estas son programas donde los padres o cuidadores primarios son entrenados para llevar a cabo acciones terapéuticas con el niño y cuyo objetivo puede estar orientado a promover múltiples habilidades. El objetivo de la presente revisión sistemática fue determinar el efecto de estas intervenciones para promover el lenguaje y la comunicación en niños con diagnóstico de TND de entre 2 y 5 años. Se realizó una búsqueda sistemática en las bases de datos ERIC, MEDLINE y PubMed, considerando publicaciones de entre enero del 2010 y marzo de 2022. De las 9885 referencias iniciales, y posterior a las etapas de tamizaje y elegibilidad, 5 fuentes primarias cumplieron con los criterios de selección. Los resultados indican que las intervenciones parentales para habilidades de comunicación serían efectivas e incluso se mantendrían los efectos en medidas de seguimiento. En cuanto a las habilidades de lenguaje, los resultados a través de los estudios son contradictorios. Por otra parte, ninguno de los estudios reporta efectos adversos para los niños. En cuanto a efectos beneficios o adversos para padres o cuidadores primarios, ninguno de los estudios incluidos reporta medidas asociadas.

Abstract In the current socio-sanitary scenario that we are facing as a result of the SARS-CoV-2 Pandemic, there have been many activities that have been reduced and even suspended due to long periods of social isolation and care measures to avoid contagion. In this sense, many people have stopped receiving their treatments with the same regularity or under the same circumstances, including children with Neurodevelopmental Disorders. This is how parental interventions correspond to programs where parents or primary caregivers are trained to carry out therapeutic actions with the child and whose objective may be aimed at promoting multiple skills. The objective of this systematic review was to determine the effect of these interventions to promote language and communication in children diagnosed with Neurodevelopmental Disorders between 2 and 5 years of age. A systematic search was carried out in the ERIC, MEDLINE and PubMed databases including publications between January 2010 and March 2022. Of the 9885 initial references, and after the screening and eligibility stages, 5 primary sources met the selection criteria. The results indicate that parental interventions for communication skills would be effective, and the effects would even be maintained in follow-up measures. Regarding language skills, the results across studies are contradictory. On the other hand, none of the studies reported adverse effects for children. Regarding beneficial or adverse effects for parents or primary caregivers, none of the included studies reported associated measures.

Before the first seizure: The developmental imprint of infant epilepsy on neurodevelopment.

In light of the heterogeneity of epilepsy, both from a clinical and from an etiological perspective, it is difficult to establish a link between epilepsy and development that can be generalized to all infantile epilepsies. In general however, early-onset epilepsy has a poor developmental prognosis that is significantly linked to several parameters: age at first seizure, drug resistance, treatment, and etiology. This paper discusses the relationship between visible epilepsy parameters (those that allow the diagnosis of epilepsy) and neurodevelopment in infants, with special focus on Dravet syndrome and KCNQ2-related epilepsy, two common developmental and epileptic encephalopathies; and focal epilepsy caused by focal cortical dysplasia, which often begins during infancy. There are a number of reasons why it is difficult to dissect the relationship between seizures and their causes, and we suggest a conceptual model in which epilepsy is a neurodevelopmental disorder whose severity is determined by how the disease imprints itself on the developmental process rather than by the symptoms or etiology. The precocity of this developmental imprint may explain why treating seizures once they occur can have a very slight beneficial effect on development.

Consultas de demanda espontánea sobre trastornos del desarrollo en el Hospital Garrahan / Spontaneous consultations for developmental disorders at Garrahan Hospital

Introducción: Los trastornos del desarrollo (TD) constituyen un motivo de consulta muy frecuente en la práctica pediátrica. El Hospital Garrahan recibe por demanda espontánea al servicio de Mediano Riesgo (MR) consultas de cuidadores con preocupaciones sobre el desarrollo de los niños, niñas y adolescentes (NNyA). Allí son valorados por pediatras clínicos, quienes realizan la interconsulta al servicio de Clínicas Interdisciplinarias del Neurodesarrollo (CIND) según necesidad (representan el 10% del total de consultas en MR). El objetivo del trabajo es comparar las características de los pacientes de MR que fueron consultados al área de Maduración de CIND durante el bimestre marzo/abril de 2016, 2021 y 2022. Materiales y métodos: estudio retrospectivo, observacional y comparativo. Se revisaron las historias clínicas analizando las siguientes variables: edad, procedencia, contar con pediatra de cabecera, cobertura de salud, motivo de consulta y sospecha diagnóstica. Resultados: La cantidad de consultas aumentó por encima del 20%, con un descenso en la mediana de edad de alrededor de un año. Aproximadamente el 70% de los pacientes procedían del conurbano en los tres períodos. Observamos un descenso respecto al número de NNyA con seguimiento pediátrico y cobertura social. El lenguaje y la conducta fueron los motivos más frecuentes de consulta y la mayor sospecha diagnóstica fue el Trastorno del Espectro Autista (TEA). Conclusiones: Los datos observados pueden relacionarse con el impacto de la pandemia así como también con las condiciones socio-económicas de los últimos cinco años, con un mayor conocimiento acerca del desarrollo y un probable aumento de la prevalencia de los TD (AU)

Introduction: Developmental disorders (DD) are a frequent reason for consultation in pediatric practice. The Garrahan Hospital receives spontaneous consultations at the department of Intermediate Risk (IR) from caregivers with concerns about the development of children and adolescents. At the IR department, children and adolescents are evaluated by clinical pediatricians, who consult with specialists at the Interdisciplinary Neurodevelopmental Clinic (INDC) as needed (accounting for 10% of the total number of consultations at the IR department). The aim of this study was to compare the characteristics of IR patients who were consulted at the INDC during the bimonthly period March/April 2016, 2021, and 2022. Materials and methods: a retrospective, observational, and comparative study was conducted. Medical records were reviewed analyzing the following variables: age, provenance, having a primary care pediatrician, healthcare insurance, reason for consultation, and diagnostic suspicion. Results: The number of consultations increased by over 20%, with a decrease in median age of around one year. Approximately 70% of the patients came from Greater Buenos Aires in the three periods. A decrease in the number of children and adolescents with pediatric follow-up and a social health insurance was observed. Language and behavior disorders were the most frequent reasons for consultation and autism spectrum disorder (ASD) was most often suspected. Conclusions: The observed data may be related to the impact of the pandemic as well as socio-economic conditions over the last five years, together with increased knowledge about development and a probable increase in the prevalence of ASD (AU)

Reanalysis of exome sequencing data reveals a treatable neurometabolic origin in two previously undiagnosed siblings with neurodevelopmental disorder.

Neurodevelopmental disorders (NDDs) have broad heterogeneity both clinically and genetically. Inborn errors of metabolism can be one of the reasons of neurodevelopmental disruption causing specific NDDs. Although there is tremendous advance in molecular identification via next-generation sequencing (NGS), there are still many unsolved patients with NDD. Reanalysis of NGS data with different pipelines can at least partially accomplish this challenge. Herein, we report clinic and genetic components of an adult sib-pair with an undiagnosed NDD condition, which has been solved through reanalysis of whole-exome sequencing (WES). Parallel analysis of SNP-based genotyping and WES was performed to focus on variants only in loci with positive logarithm of the odds scores. WES data was analyzed through three different pipelines with two distinct bed files. Reanalysis of WES data led us to detect a homozygous FOLR1 variant (ENST00000393676.5:c.610C > T, p.(Arg204Ter), rs952165627) in the affected sib-pair. Surprisingly, the variant could not be detected in the first analysis as the variant region is not included in the first bed file which may frequently be used. Biochemical tests of CSF have confirmed the genetic analysis, CSF folic acid levels were detected low in sib-pair, and intravenous folinic acid treatment improved the disease course for the first 6 months of follow-up even at late diagnosis age. Although combined analysis of SNP-based genotyping and WES is a powerful tool to reveal the genetic components of heterogeneous diseases, reanalysis of genome data still should be considered in unsolved patients. Also, biochemical screening helps us to decipher undiagnosed NDD that may be a treatable neurometabolic condition.

Detección precoz de desviaciones y promoción de las habilidades sociales del lactante con la escala ADBB durante el seguimiento pediátrico: experiencia en un centro de salud pública de alta vulnerabilidad social / Early detection of deviations and promotion of infant social skills using the ADBB scale during pediatric follow-up: experience at a public health center of high social vulnerability / Detecção precoce de desvios e promoção de habilidades sociais infantis utilizando a escala ADBB durante o acompanhamento pediátrico: experiência num centro público de saúde de alta vulnerabilidade social

Introducción: el retraimiento del lactante es un signo de riesgo de desviaciones en el desarrollo y la salud mental infantil asociado a perturbaciones sostenidas en la interacción padres-bebé. Para este estudio se amplió la formación de un grupo de pediatras, médicos de familia y otros profesionales del primer nivel de un centro de salud de una zona de alta vulnerabildad social en una perspectiva interdisciplinaria del impacto de las interacciones tempranas en el neurodesarrollo y en la salud psicoemocional de los primeros años de vida, junto con la aplicación de un instrumento validado internacionalmente para la detección de retraimiento (escala ADBB, Alarme Détresse Bébé, Guedeney 2001) y estrategias para promover las habilidades sociales del lactante durante el control pediátrico. Objetivo: el estudio fue para evaluar el efecto de este abordaje en el seguimiento pediátrico de un grupo de lactantes a través de la detección de retraimiento y en comparación con otro grupo atendido en el mismo centro de salud sin el abordaje propuesto. Material y métodos: se realizó la detección de retraimiento con ADBB a 101 lactantes de 2 a 11 meses filmados en controles pediátricos durante 2016-2017 en un centro de salud pública de Montevideo. De total, 58 tuvieron seguimiento pediátrico con cuatro pediatras y una médica de familia con el abordaje propuesto y fueron evaluados con ADBB en dos tiempos, entre los 2 y 5 meses y entre los 8 y 11 meses de edad. Los 43 restantes acudieron al control pediátrico habitual en el centro de salud y fueron evaluados con ADBB entre los 8 y 11 meses. Todos los lactantes fueron evaluados con ADBB por expertos independientes. Resultados: de los 58 lactantes atendidos con el abordaje propuesto, 22% presentó retraimiento entre los 2 y 5 meses, y 14% entre los 8 y 11 meses. En el grupo atendido en los controles pediátricos regulares sin el abordaje propuesto, se detectó 53% de retraimiento entre los 8 y 11 meses de edad (p <0,001). Conclusiones: La detección precoz de retraimiento junto con estrategias para la promoción de las habilidades sociales del lactante durante el segui- miento pediátrico podría favorecer una perspectiva más integral y preventiva de la salud, incidiendo en el cuidado del neurodesarrollo y de la salud mental infantil desde el primer nivel.

Introduction: infant withdrawal is a sign of risk for deviations in child development and mental health associated with sustained disturbances in parent-infant interaction. For this study, a group of pediatricians, family doctors and other professionals of the Primary Care Level of a health center in an area of high social vulnerability was trained including an interdisciplinary perspective regarding the impact of early interactions on the neurodevelopment and psychological and emotional health of the first years of life. Similarly, we applied an internationally validated instrument for the detection of withdrawal (ADBB scale, Alarme Détresse Bébé, Guedeney 2001) and strategies to promote infant social skills during the pediatric check-ups. Objective: the study was to evaluate the effect of this approach in the pediatric follow-up of a group of infants through the detection of withdrawal and to compare it with another group assisted in the same center that did not receive the same approach. Material and methods: withdrawal with ADBB was detected in 101 infants aged 2 to 11 months filmed in pediatric controls during 2016-2017 in a public health center in Montevideo. In total, 58 had pediatric follow-up with four pediatricians and one family physician using the approach proposed in this study and were evaluated with ADBB in two stages, between 2 and 5 months and between 8 and 11 months of age. The remaining 43 attended the usual pediatric control at the health center and were evaluated with ADBB between 8 and 11 months. All infants were evaluated with ADBB by independent experts. Results: of the 58 infants treated with the approach proposed in this study, 22% presented withdrawal between 2 and 5 months, and 14% between 8 and 11 months. In the group attended in regular pediatric check-ups without using the proposed approach, 53% of withdrawal was detected between 8 and 11 months of age (p <0.001). Conclusions: the early detection of withdrawal to gether with strategies for the promotion of infant social skills during pediatric follow-up could favor a more comprehensive and preventive health perspective and enable practitioners to focus on the children neurodevelopmental and mental health from primary care assistance.

Introduccion: a abstinencia infantil é um sinal de risco para os desvios no desenvolvimento infantil e na saúde mental associados a distúrbios sustenta- dos na interação pais-bebê. Para este estudo, expandiuse a formação de um grupo de pediatras, médicos de família e outros profissionais do primeiro nível de um centro de saúde numa área de alta vulnerabilidade social, utilizando uma perspectiva interdisciplinar do impacto das interações precoces no neurodesenvolvimento e na saúde psicoemocional dos primeiros anos de vida, juntamente com a aplicação de um instrumento validado internacio- nalmente para a detecção de abstinência (escala ADBB, Alarme Détresse Bébé, Guedeney 2001) e estratégias para promover habilidades sociais infan- tis durante o controle pediátrico. Objetivo: do estudo foi avaliar o efeito dessa abordagem no acompanhamento pediátrico de um grupo de lactentes por meio da detecção de abstinência e comparálo com outro grupo atendido no mesmo centro de saúde, más sem utilizar a abordagem proposta. Material e Métodos: a abstinência com ADBB foi detectada em 101 lactentes com idades entre 2 e 11 meses filmados em controles pediátricos durante 2016-2017 num Centro de Saúde Pública em Montevidéu. No total, 58 tiveram acompanhamento pediátrico com quatro pediatras e um médico de família e receberam a abordagem proposta e foram avaliados com o ADBB em dois estágios, entre 2 e 5 meses e entre 8 e 11 meses de idade. Os 43 restantes compareceram ao controle pediátrico habitual no centro de saúde e foram avaliados com ADBB entre 8 e 11 meses. Todos os lactentes foram avaliados com o ADBB por especialistas independentes. Resultados: dos 58 lactentes tratados com a abordagem proposta, 22% apresentaram abstinência entre 2 e 5 meses e 14% entre 8 e 11 meses. No grupo atendido em check-ups pediátricos regulares sem a abordagem proposta, 53% de desistência (retraimiento) foi detectada entre 8 e 11 meses de idade (p <0,001). Conclusões: a detecção precoce da abstinência, aliada a estratégias de promoção de habilidades sociais infantis durante o acompanhamento pediá- trico, poderia favorecer uma perspectiva de saúde mais abrangente e preventiva, com foco no cuidado do neurodesenvolvimento e da saúde mental infantil desde o primeiro nível de saúde.

Resultados en el neurodesarrollo en la edad preescolar y escolar de los recién nacidos pretérminos asistidos en el CTI neonatal de la Asociación Médica de San José / Neurodevelopmental preschool and school results of preterm newborns assisted at the neonatal ICU of the San José department medical provider in Uruguay / Resultados neuro desenvolvimento em idade pré-escolar e escolar de recém-nascidos pré-termos atendidos na UTI neonatal da assistência médica do departamento do São José no Uruguai

Uruguay acompaña la tendencia mundial al descenso de la natalidad con un descenso de la mortalidad concomitante, siendo la primera causa de mortalidad infantil la prematurez. Enfocados en la prematurez, es de nuestro interés conocer qué ocurre con estos niños luego del alta de la unidad neonatal. Se realizó el estudio de una cohorte de niños entre 4 y 8 años, nacidos con 32 semanas o menos de edad gestacional y/o con pesos al nacer de 1.500 g o menos, asistidos en su período neonatal en la Asociación Médica de San José, a quienes se les realizó el test de Battelle. Se logró identificar las áreas con mayor dificultad en el desarrollo para cada grupo de edad, concluyendo que se pueden realizar planes específicos de acción para promover el desarrollo de estos niños en la edad preescolar y escolar.

Uruguay follows the global declining trend in birth rates along with decreasing mortality, being prematurity the main cause of infant mortality. We studied premature children who had undergone the Battelle Test and had been discharged from the neonatal unit, a cohort of children between 4 and 8 years of age, born at 32 weeks or less of gestational age and/or having a birth weight of 1500g or less, assisted in their neonatal period at the San José Department Medical Center. We could identify the main areas affecting development for each age group, and concluded that specific action plans can be carried out to promote the development of these children at preschool and school age.

O Uruguai acompanha a tendência mundial de declínio das taxas de natalidade com uma concomitante diminuição da mortalidade, sendo a prematuridade a principal causa de mortalidade infantil. Nos focamos na prematuridade e no estudo do que acontece com essas crianças após a alta da unidade neonatal. Realizamos um estudo de uma coorte de crianças entre 4 e 8 anos que tinham sido submetidas ao Teste de Battelle, nascidas com 32 semanas ou menos de idade gestacional e/ou com peso de nascimento igual ou inferior a 1500g, atendidas no período neonatal na Assistência Médica do Departamento de São José no Uruguai. Foi possível identificar as áreas de maior dificuldade de desenvolvimento para cada faixa etária, e concluir que podem se realizar planos de ação específicos para promover o desenvolvimento dessas crianças em idade pré-escolar e escolar.

Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes.

DYRK1A and Wiedemann-Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient-driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.

A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene.

Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome (FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (~2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5' transduction and hallmarks of target-primed reverse transcription. The 20-bp 5' transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.

Predictive validity of ESSENCE Q screening tool for early detection of neurodevelopmental disorder in children.

INTRODUCTION: Neurodevelopmental disorders (NDD) are a group of conditions that typically manifest early during the child's development with lifelong consequences. Early identification using efficient screening tools can positively modify the natural history of the disorder. ESSENCE Q is a simple questionnaire to detect ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations to reflect the co-existence of NDDs in children less than five years). There are limited studies on the validity of ESSENCE Q in detecting NDDs in young children in India. METHODS: We did a cross-sectional study in a tertiary care hospital to evaluate the validity of ESSENCE Q in detecting neurodevelopmental disorders. We translated the ESSENCE Q and subsequently used it to screen for NDD in 100 children aged 12-60 months. Clinical consensus diagnosis by two experienced experts was taken as the gold standard. RESULTS: 23% were diagnosed as having NDD as per the clinical consensus diagnosis. Around half the children (46%) were "at-risk for NDD" based on the ESSENCE Q scale. We found an optimal cut-off for ESSENCE Q of more than or equal to 4 with a sensitivity of 96%, a specificity of 82%, and a Youden index of 0.77. CONCLUSION: ESSENCE Q has good predictive validity to be used as a quick and easy screening tool to detect NDDs in young children under the age of 5 years.

Microdeletion of 16q24.1-q24.2-A unique etiology of Lymphedema-Distichiasis syndrome and neurodevelopmental disorder.

Interstitial deletions of 16q24.1-q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema-Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1-q24.2. This report extends the phenotype of both 16q24.1-q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3'-UTR part of FOXC2.

[Neurodevelopmental disorders: from the laboratory to the classroom]. / Desórdenes del neurodesarrollo: del laboratorio al aula de clase.

Neurodevelopmental disorders are the most common diagnosis in the clinical practice in child neurology. Since the 70's the terminology used for the diagnosis of these conditions, was developed with the goal of obtaining better services for those individuals affected. Over the years the classification has changed but the fundamental process for diagnosis continues the same. There is a new movement aiming to change the current classification and propose a new one based in the molecular deficits associated with the clinical phenotype rather than a collection of symptoms. This new approach focusses on the identification of the molecular defectcausing of the specific to design targeted interventions that will promise a curative approach, rather than the current symptom-based interventions available. Important progress has been done alrea dy, given the high association between cognitive/compartmental phenotype in some well-known genetic defects like Neurofibromatosis, TSC, Down syndrome, and the high association between different cognitive/compartmental phenotype in rare diseases. The future will hold opportunities to properly identify the molecular deficit and a tailored intervention for those conditions today called Neurodevelopmental disabilities.

Los desórdenes del Neurodesarrollo son en conjunto los diagnósticos más frecuentes en la práctica clínica en Neurología Infantil. De los años 70', se desarrolló una terminología usada para denominar estos desordenes, con el objetivo de obtener mejor atención en servicios médicos y educativos para los afectados. A lo largo de los años, las clasificaciones han cambiado, pero el proceso fundamental del diagnóstico sigue siendo el mismo. Existe actualmente un movimiento para cambiar y establecer una nueva clasificación, basada en los déficits biológicos asociados con el fenotípico clínico. Esta nueva aproximación diagnóstica tiene como objetivo entre tantos otros, el diseño de intervenciones específicas que prometerían un mayor potencial curativo, a diferencia de las actuales opciones de tratamiento, que se basan en el manejo de síntomas. Importantes progresos se han hecho ya en este campo. Por ejemplo, algunos fenotipos conductuales en condiciones genéticas ampliamente conocidas como el Síndrome de Down, síndrome de X Frágil, neurofibromatosis, esclerosis tuberosa entre otros, han permitido proponer correlaciones biológicas con fenotipos comunes en pacientes con autismo, trastornos por déficit de atención, entre otros. Adicionalmente, el extenso estudio que actualmente se lleva a cabo sobre las denominadas enfermedades raras, que se asocian hasta en un 80% con trastornos del neurodesarrollo, ha abierto la posibilidad para muchas más correlaciones biológicas-comportamentales. En el futuro, será posible esperar oportunidades para la identificación de déficits biológicos moleculares, asociados con fenotipos clínicos cognitivos-conductuales y que, a partir de ellos se puedan diseñar intervenciones individuales a los problemas que hoy conocemos globalmente como los desórdenes del neurodesarrollo.

Pre-operative neurodevelopmental assessment in young children undergoing cardiac surgery in central South Africa: feasibility and clinical value.

BACKGROUND: Pre-operative neurodevelopmental assessment in children with congenital heart disease may assist in the early identification of children at risk for or presenting with developmental delays. This study determined the pre-operative neurodevelopmental status of young children undergoing cardiac surgery in central South Africa. Feasibility and clinical value of pre-operative assessment were also evaluated. METHODS: Children 30 months and younger, scheduled to undergo cardiac surgery, were recruited into this prospective observational analytical study. Neurodevelopmental status was assessed using the Bayley-III and neuromotor examination. Variables associated with developmental performance were determined using ANOVAs. Sociodemographic and medical information were collected using a self-developed questionnaire. Pre-operative neurodevelopmental assessment was completed for 40 children at a median age of 7.4 months, including 30 children without and 10 with Down syndrome. Mean cardiac disease severity was moderate. The inclusion rate for pre-operative developmental assessment was 68%, limited mainly by environmental barriers. RESULTS: Children with Down syndrome had significantly poorer motor (p < 0.0001), cognitive (p < 0.0001) and language performance (p < 0.001) compared to children without Down syndrome. Apart from Down syndrome, disease severity (p = 0.02), younger age at first cardiac surgery (p < 0.01) and growth failure (p = 0.04) were significantly associated with poorer cognitive, language and motor performance, respectively. Just more than half of the children without (n = 16) and all children with Down syndrome (n = 10) scored below one standard deviation of the test mean score (scores < 85) on at least one of the Bayley-III subscales, meeting the criteria for referral to rehabilitation therapies, including physiotherapy, occupational therapy and/or speech therapy. CONCLUSION: Pre-operative neurodevelopmental assessment may be of high importance in South Africa to identify children at developmental risk, facilitating early referral to rehabilitation therapies.