L-serine treatment in patients with GRIN-related encephalopathy: A phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52-weeks. Primary endpoints included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months treatment. Secondary outcomes included seizure frequency and intensity reduction and electroencephalography improvement. Assessments were performed 3 months and 1 day before starting treatment and 1-3-6-12 months after the beginning of the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Clinical phenotype showed: 91% intellectual disability (61% severe), 83% behavioral problems, 78% movement disorders and 58% with epilepsy. Based on Vineland Adaptive Behavior Composite standard score, nine children were classified as mildly impaired level group (cut-off > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in Daily Living Skills domain (P = 0,035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. Growth Score Values cognitive subdomain on the Bayley-III showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068) regardless of severity. L-serine normalized EEG pattern in five children, and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve the adaptive, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Neurodevelopmental Outcomes of Infants Younger Than 90 Days Old Following Enterovirus and Parechovirus Infections of the Central Nervous System.

Enteroviruses (EVs) and human parechoviruses (HPeVs) are a major cause of central nervous system (CNS) infection in young infants. They have been implicated in neurodevelopmental delay, however limited data are available. The aim of this study is to describe the clinical outcome of young infants and to assess and compare the medium-term neurodevelopment following CNS infections caused by EV and HPeV. A multicentre observational ambispective study was conducted between May 2013 and March 2018. Children under 3 months of age with EV or HPeV CNS infection excluding encephalitis were included. Infants were contacted 1 year after the acute infection and their neurological development was evaluated using the Ages and Stages Questionnaire-3 (ASQ-3). If any area assessed was abnormal during the first round of tests, a second round was completed 6 to 12 months later. Forty-eight young infants with EV and HPeV CNS infection were identified: 33 (68.8%) were positive for EV and 15 (31.3%) for HPeV. At first assessment 14 out of 29 EV (48.3%) and 3 out of 15 HPeV (20%) positive cases presented some developmental concern in the ASQ-3 test. EV-positive infants showed mild and moderate alteration in all domains analyzed and HPeV-positive infants showed mild alterations only in gross and fine motor domains. Significant alterations in communication were observed in EV-positive but not in HPeV-positive infants (31 vs. 0%, p = 0.016). At second assessment 4 out of 13 EV-positive patients (30.8%) showed mild to moderate concerns in communication and gross motor function domains and 3 out of 13 (23.1%) showed significant concern in fine motor function. Although CNS infections without associated encephalitis are generally assumed to be benign our study shows that at a median age of 18 months almost half of the EV-infected infants (48.3%) and 20% of HPeV-positive infants presented some developmental concern in the ASQ-3 test. We recommend monitor the neurological development of infants during the first years of life after HPeV CNS infection and especially after EV CNS infection, even in mild cases, for an early intervention and stimulation of psychomotor development if necessary.

Desarrollo psicomotor en prematuros tardíos a los dos años de edad: comparación con recién nacidos a término mediante dos herramientas diferentes / Psychomotor development in late preterms at two years of age: a comparison with full-term newborn infants using two different instruments

Introducción. Los prematuros tardíos constituyen actualmente el 70% de los nacimientos prematuros. Presentan mayor comorbilidad, incluyendo las alteraciones del neurodesarrollo, que pueden no manifestarse hasta la escolarización. Objetivo. Identificar dificultades en el desarrollo neurológico a los dos años de edad. Sujetos y métodos. Se valoró el desarrollo psicomotor a los dos años de los prematuros tardíos y del grupo control a término nacidos en nuestro centro entre enero y septiembre del año 2014 mediante la escala de Brunet-Lézine revisada y el cuestionario de edades y etapas para la detección de trastornos del neurodesarrollo Ages & Stages Questionnaires (ASQ-3). Resultados. Se incluyó a 88 niños. Los prematuros tardíos presentaron puntuaciones inferiores en el lenguaje y el desarrollo postural. Las niñas obtuvieron resultados superiores en la edad de desarrollo global, la coordinación oculomotriz, el lenguaje y la sociabilidad. El cuestionario ASQ-3 detectó las diferencias en comunicación y socioindividuales. Se identificaron como factores de riesgo para presentar alteración del desarrollo la prematuridad, para alteración del lenguaje, y el sexo masculino, para menor edad de desarrollo y alteración del lenguaje. La correlación entre la valoración del lenguaje con la escala de Brunet-Lézine revisada y el cuestionario ASQ-3 fue buena, con un coeficiente de correlación de Pearson de 0,7 (p < 0,001), lo que nuestra la utilidad del cuestionario. Conclusiones. Los prematuros tardíos presentan menor desarrollo del lenguaje a los dos años. La prematuridad y el sexo masculino son factores de riesgo para presentar alteración. La valoración del lenguaje con el cuestionario ASQ-3 puede ser útil para detectar alteraciones

Introduction. Late preterm infants currently constitute 70% of preterm infant births. They present greater comorbidity, including neurodevelopment disorders, which may not manifest until the school age. Aim. To identify the existence of difficulties in the neurodevelopment at the age of two years. Subjects and methods. The psychomotor development was performed at two years of age in late preterm infants and term control group born at our center between January and September 2014, with Brunet-Lezine Revised test and Ages & Stages Questionnaires (ASQ-3) questionnaire. Results. 88 children were included. Late preterm infants had lower scores in the language area and postural developmental. Girls achieved better results than males at global developmental age, oculo-motor coordination, language area and sociability. The ASQ-3 questionnaire detected differences in communication and socio-individual. Prematurity and male sex were identified as an independent risk factor to present a developmental disorder, prematurity for language impairment and male sex for younger developmental age and language impairment. The correlation between language assessment with the Brunet-Lezine Revised test and the ASQ-3 questionnaire was good, with a Pearson correlation coefficient of 0.7 (p < 0.001), showing the usefulness of the questionnaire. Conclusions. Late preterm infants have a lower developmental age in the language area at two years. Prematurity and male sex are risk factors for developmental disorder. Language assessment with the ASQ-3 questionnaire may be a useful tool to detect disorders and intervene early

Mutación puntual de novo en el gen KCND3 en un paciente con ataxia crónica de inicio precoz / De novo sporadic mutation in the KCND3 gene in a patient with early onset chronic ataxia

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Neurodevelopment medium-term outcome after parechovirus infection.

AIM: Human parechoviruses (HPeV) are responsible for fever without a source (FWS), sepsis-like illness and encephalitis in neonates and children under 3 months of age. Short-term outcome is generally good, but there is great concern about medium and long- term outcome of infants after HPeV infection. The aim of this study is to assess the medium-term outcome in infants following HPeV infection without encephalitis. METHODS: Patients who suffered HPeV infection involving cerebrospinal fluid were evaluated twice using Ages and Stages Questionnaire-3 (ASQ-3). The first evaluation was conducted at least one year after the infection and the second one year later. RESULTS: Sixteen patients were evaluated in the first assessment, and three of them presented mild alterations in motor function domains. Moreover, hypotonia was observed in the neurologic exam in one case, and hemiparesis in another case. In the second assessment fifteen patients were included, and only the patient with hemiparesis continued presenting gross motor disfunction, with complete recovery of the remaining patients. INTERPRETATION: We have observed a good medium-term prognosis in infants after HPeV infections, with improvement of mild motor alterations after at-home intervention. Infants who suffer HPeV infection without encephalitis seem to have a better prognosis than those with encephalitis.

Características epidemiológicas y clínicas de los lactantes hospitalizados por infecciones por parechovirus humanos. Estudio prospectivo en España / Epidemiological and clinical characteristics of infants admitted to hospital due to human parechovirus infections: A prospective study in Spain

Introducción: Los parechovirus humanos (HPeV) son virus de la familia Picornaviridae, recientemente descritos, a los que se atribuyen cuadros de fiebre sin foco (FSF), sepsis clínica, gastroenteritis, meningitis o encefalitis fundamentalmente en lactantes pequeños. Nuestro objetivo fue describir la epidemiología y las características clínicas de las infecciones por HPeV en nuestro medio. Pacientes y métodos: Estudio multicéntrico prospectivo, llevado a cabo en 12 hospitales a nivel nacional, entre 2013-2015, en niños < 3 años con FSF, sepsis clínica o patología neurológica. Se realizó determinación de HPeV mediante RT-PCR en el Centro Nacional de Microbiología en suero, heces o líquido cefalorraquídeo. Resultados: Se analizan 47 infecciones por HPeV de un total de 850 muestras (5,52%), siendo HPeV-3 el más frecuente (29 casos), con predominio en mayo y julio, con una distribución bienal. El 57% eran neonatos y solo 2 > 3 meses. Todos los pacientes presentaron fiebre, el 45% irritabilidad, el 18,6% exantema y el 14% diarrea. No se observa ninguna alteración específica en las pruebas bioquímicas. El diagnóstico final más frecuente fue FSF (61%) seguido de sepsis clínica (29%). Aunque un 29% de los niños precisaron ingreso en cuidados intensivos, solo un paciente presentó secuelas. Conclusiones: Los HPeV circulan en nuestro país, afectando fundamentalmente a lactantes < 2 meses y se asocian a FSF y sepsis clínica, con un predominio en primavera y verano. Sería de interés implementar las técnicas moleculares de diagnóstico en todos los hospitales para reconocer y manejar adecuadamente estas infecciones (AU)

Introduction: Human parechovirus (HPeV) is one of the recently described picornaviridae viruses that have been associated with fever of unknown origin (FUO), clinical sepsis, gastroenteritis, meningitis, or encephalitis in very young infants. The aim of this study is to describe the epidemiology and clinical features of these viruses. Patients and methods: A prospective multicentre 3-year study was conducted in 12 hospitals in Spain. Out of 850 specimens examined, 47 were positive (5.52%), with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae. Results: Out of 850 specimens examined, 47 were positive (5.52%) for HPeV, with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae. Conclusions: HPeV circulates in our country, mainly during spring and summer, and affects young infants with a FUO and clinical sepsis. Molecular diagnostic techniques in all hospitals could help in improving the management of patients with these infections (AU)

[Epidemiological and clinical characteristics of infants admitted to hospital due to human parechovirus infections: A prospective study in Spain]. / Características epidemiológicas y clínicas de los lactantes hospitalizados por infecciones por parechovirus humanos. Estudio prospectivo en España.

INTRODUCTION: Human parechovirus (HPeV) is one of the recently described picornaviridae viruses that have been associated with fever of unknown origin (FUO), clinical sepsis, gastroenteritis, meningitis, or encephalitis in very young infants. The aim of this study is to describe the epidemiology and clinical features of these viruses. PATIENTS AND METHODS: A prospective multicentre 3-year study was conducted in 12 hospitals in Spain. Out of 850 specimens examined, 47 were positive (5.52%), with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae. RESULTS: Out of 850 specimens examined, 47 were positive (5.52%) for HPeV, with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae CONCLUSIONS: HPeV circulates in our country, mainly during spring and summer, and affects young infants with a FUO and clinical sepsis. Molecular diagnostic techniques in all hospitals could help in improving the management of patients with these infections.

Síndrome de piernas inquietas en pacientes diagnosticados de trastorno por déficit de atención/hiperactividad / Restless legs syndrome in patients diagnosed with attention deficit hyperactivity disorder

Introducción. El síndrome de piernas inquietas (SPI) es una patología neurológica común. Se ha relacionado con diferentes trastornos psiquiátricos, especialmente con el trastorno por déficit de atención/hiperactividad (TDAH). Objetivos. El objetivo principal fue describir la frecuencia del SPI en pacientes pediátricos diagnosticados de TDAH. Los objetivos secundarios del estudio fueron describir otros trastornos del sueño en pacientes con TDAH. Pacientes y métodos. Se realizó un estudio descriptivo prospectivo multicéntrico en nueve centros españoles de niños de 6-18 años con diagnóstico de TDAH entre enero y junio de 2015. Los datos fueron recogidos por 13 médicos investigadores mediante entrevista con el padre/cuidador y con el menor. Para valorar el grado de funcionamiento de los pacientes con TDAH se utilizó la Children’s Global Assessment Scale. Se aplicó la Sleep Disturbance Scale for Children de Bruni para el cribado del trastorno de sueño de la infancia. Resultados. Se recogió una muestra de 73 pacientes. Cinco pacientes (6,8%) cumplen criterios diagnósticos de SPI: cuatro de ellos definitivos y uno probable. Conclusiones. El SPI es una entidad frecuente en la edad adulta, pero también en la adolescencia y en la infancia. Los pacientes con TDAH tienen un riesgo aumentado de presentar de manera concomitante un SPI (AU)

Introduction. Restless legs syndrome (RLS) is a common neurological disease. RLS has been linked to various psychiatric disorders, especially with attention deficit hyperactivity disorder (ADHD). Aims. The main objective was to describe the frequency of RLS in pediatric patients diagnosed with ADHD. Secondary objectives of the study were describe other sleep disorders in ADHD patients. Patients and methods. A multicentre prospective study was conducted in nine Spanish centers. We included children aged 6-18 years diagnosed with ADHD between January and June 2015. Data were collected by 13 researchers doctors through an interview with the parent/caregiver and with the child. To assess the degree of functioning of patients with ADHD we used the Children’s Global Assessment Scale. The Sleep Disturbance Scale for Children was applied to screening sleep disorders in childhood. Results. A sample of 73 patients was collected. Five patients (6.8%) met diagnostic criteria for RLS: four of them definitive and one probable. Conclusions. RLS is a frequent condition in adulthood but also in adolescence and childhood. ADHD patients have an increased risk of an RLS (AU)

[The importance of sleep problems in children with headache and other neurodevelopmental disorders in neuropaediatric services]. / Importancia de los problemas de sueño en los niños con cefalea y otros trastornos del neurodesarrollo en las consultas de neuropediatria.

INTRODUCTION: Sleep disorders are common in children with neurological disorders. The aim of this study is to know the opinion of neuropediatricians and the prevalence of these disturbances in Spain. PATIENTS AND METHODS: Multicenter cross-sectional study (12 Spanish hospitals, 15 researchers). BEARS survey was collected in three groups: A (2-5 years), (6-12 years), and C (> 12 years). The opinion of neuropediatricians was also collected. RESULTS: 939 questionnaires were filled. The main results in groups B and C were ADHD (32.4% and 30.1% respectively) and headache (25.1% and 27.6% respectively), whereas in group A neurodevelopmental disorders (32.4%) and epilepsy (21.4%) were the main diagnoses. Disturbances in at least one area of sleep were found in 92% of children in group A (n = 209, mean 3 years), 64.2% in group B (n = 534, mean 9.4 years) and 58.2% in group C (n = 196, mean 13.7 years). Sixty-one surveys were answered by neuropediatricians (16.75% of the total sent), estimating that less than a quarter of the patients (24.5%) suffered. Even, up to 23% of doctors claimed that the prevalence of sleep disorders was < 10%. CONCLUSIONS: 58-92% of parents-patients under follow up at a neuropediatrician office in Spain have some degree of disturbed sleep. Although most neurologists emphasize the importance of an early diagnosis and treatment of sleep disorders in children with neurological disorders, its frequency is often underestimated (risk of underdiagnosis).

TITLE: Importancia de los problemas de sueño en los niños con cefalea y otros trastornos del neurodesarrollo en las consultas de neuropediatria.Introduccion. Los trastornos de sueño son frecuentes en niños con trastornos neurologicos. El objetivo del estudio es conocer la opinion de los neuropediatras y su prevalencia real en España. Pacientes y metodos. Estudio transversal multicentrico (12 hospitales españoles, 15 investigadores). Se administro la encuesta Bedtime, Excesive Daytime Sleepiness, Awakenings, Regularity, Sleep-Disordered Breathing (BEARS) y se definieron tres grupos: A (2-5 años), B (6-12 años) y C (> 12 años). Asimismo, se recogio la opinion de neuropediatras de la Sociedad Española de Neuropediatria mediante una encuesta anonima. Resultados. Se recogieron 939 encuestas. Los principales motivos de consulta en los grupos B y C fueron trastorno por deficit de atencion/hiperactividad (32,4% y 30,1%, respectivamente) y cefalea (25,1% y 27,6%, respectivamente), y en el grupo A, los trastornos del neurodesarrollo (32,4%) y la epilepsia (21,4%). Al menos un area del sueño alterada se encontro en el 92,9% de niños del grupo A (n = 209; media: 3 años), en el 64,2% del grupo B (n = 534; media: 9,4 años) y en el 58,2% del grupo C (n = 196; media: 13,7 años). Se recibieron 61 encuestas respondidas por los neuropediatras (16,75% de las enviadas), quienes estimaban que los trastornos del sueño afectaban a menos de una cuarta parte de sus pacientes (24,5%), y hasta un 23% afirmo que la prevalencia era inferior al 10%. Conclusion. El 58-92% de los padres-pacientes que acuden a consultas de neuropediatria refiere tener algun aspecto del sueño alterado. Aunque la mayoria de los neuropediatras subraya la importancia de un diagnostico y tratamiento de los trastornos de sueño de los niños con trastornos neurologicos, se suele infraestimar su frecuencia e importancia.

Importancia de los problemas de sueño en los niños con cefalea y otros trastornos del neurodesarrollo en las consultas de neuropediatría / The importance of sleep problems in children with headache and other neurodevelopmental disorders in neuropaediatric services

Introducción. Los trastornos de sueño son frecuentes en niños con trastornos neurológicos. El objetivo del estudio es conocer la opinión de los neuropediatras y su prevalencia real en España. Pacientes y métodos. Estudio transversal multicéntrico (12 hospitales españoles, 15 investigadores). Se administró la encuesta Bedtime, Excesive Daytime Sleepiness, Awakenings, Regularity, Sleep-Disordered Breathing (BEARS) y se definieron tres grupos: A (2-5 años), B (6-12 años) y C (> 12 años). Asimismo, se recogió la opinión de neuropediatras de la Sociedad Española de Neuropediatría mediante una encuesta anónima. Resultados. Se recogieron 939 encuestas. Los principales motivos de consulta en los grupos B y C fueron trastorno por déficit de atención/hiperactividad (32,4% y 30,1%, respectivamente) y cefalea (25,1% y 27,6%, respectivamente), y en el grupo A, los trastornos del neurodesarrollo (32,4%) y la epilepsia (21,4%). Al menos un área del sueño alterada se encontró en el 92,9% de niños del grupo A (n = 209; media: 3 años), en el 64,2% del grupo B (n = 534; media: 9,4 años) y en el 58,2% del grupo C (n = 196; media: 13,7 años). Se recibieron 61 encuestas respondidas por los neuropediatras (16,75% de las enviadas), quienes estimaban que los trastornos del sueño afectaban a menos de una cuarta parte de sus pacientes (24,5%), y hasta un 23% afirmó que la prevalencia era inferior al 10%. Conclusión. El 58-92% de los padres-pacientes que acuden a consultas de neuropediatría refiere tener algún aspecto del sueño alterado. Aunque la mayoría de los neuropediatras subraya la importancia de un diagnóstico y tratamiento de los trastornos de sueño de los niños con trastornos neurológicos, se suele infraestimar su frecuencia e importancia (AU)

Introduction. Sleep disorders are common in children with neurological disorders. The aim of this study is to know the opinion of neuropediatricians and the prevalence of these disturbances in Spain. Patients and methods. Multicenter cross-sectional study (12 Spanish hospitals, 15 researchers). BEARS survey was collected in three groups: A (2-5 years), (6-12 years), and C (> 12 years). The opinion of neuropediatricians was also collected. Results. 939 questionnaires were filled. The main results in groups B and C were ADHD (32.4% and 30.1% respectively) and headache (25.1% and 27.6% respectively), whereas in group A neurodevelopmental disorders (32.4%) and epilepsy (21.4%) were the main diagnoses. Disturbances in at least one area of sleep were found in 92% of children in group A (n = 209, mean 3 years), 64.2% in group B (n = 534, mean 9.4 years) and 58.2% in group C (n = 196, mean 13.7 years). Sixty-one surveys were answered by neuropediatricians (16.75% of the total sent), estimating that less than a quarter of the patients (24.5%) suffered. Even, up to 23% of doctors claimed that the prevalence of sleep disorders was < 10%. Conclusions. 58-92% of parents-patients under follow up at a neuropediatrician office in Spain have some degree of disturbed sleep. Although most neurologists emphasize the importance of an early diagnosis and treatment of sleep disorders in children with neurological disorders, its frequency is often undesestimated (risk of underdiagnosis) (AU)

[Spinal muscular atrophy-type I with respiratory distress]. / Atrofia muscular espinal tipo 1 con distres respiratorio.

TITLE: Atrofia muscular espinal tipo 1 con distres respiratorio.

Atrofia muscular espinal tipo 1 con distrés respiratorio / Spinal muscular atrophy-type I with respiratory distress

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Síndrome de Panayiotopoulos de evolución parcialmente atípica: importancia de la correlación electroclínica / No disponible

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