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 the 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 end points 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 Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning 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). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) 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. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale 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 the 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 adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Nivel formativo sobre trastornos del espectro autista (TEA) entre los pediatras de atención hospitalaria / Level of training in autistic spectrum disorders among hospital paediatricians

Introducción: La formación en trastornos del espectro autista (TEA) por parte de los pediatras es esencial para su diagnóstico precoz. Sin embargo, son escasos los estudios que han cuantificado este conocimiento, por lo que el objetivo principal es determinar el nivel formativo sobre TEA entre pediatras de atención hospitalaria en diferentes comunidades e identificar aspectos a mejorar. Material y métodos: Un total de 157 pediatras de atención hospitalaria de 3 comunidades autónomas completó el cuestionario online sobre TEA, estructurado en 3 partes (sociodemográfico, nivel formativo y opinión). Los datos fueron analizados con SPSS (versión 15). Resultados La media ± desviación estándar de puntuaciones en el cuestionario fue 20,34±2,43 (puntuación máxima posible: 23). Un 65% puntúa en todos los dominios igual o superior a la media. Los conceptos menos conocidos son: patrones restringidos de conducta, concepto general TEA y comorbilidades posibles. No hay diferencias estadísticamente significativas en cuanto a las puntuaciones entre diferentes grupos de pediatras según variables sociodemográficas. Un 64% de los pediatras opina que su conocimiento sobre TEA es limitado. Destaca un desconocimiento importante sobre la disponibilidad de recursos, presente en todas las comunidades estudiadas. Conclusiones Existe un adecuado nivel general de conocimientos sobre TEA entre los pediatras, pero un deficiente conocimiento en la parte práctica del manejo de estos pacientes y en la coordinación entre los diferentes equipos que participan en el cuidado de estos. Los esfuerzos deberían centrarse en lograr una buena comunicación entre estos equipos y en mantener actualizados los conocimientos sobre TEA a todos los niveles (AU)

Background: Training in autistic spectrum disorders is crucial in order to achieve an early diagnosis. However, the number of papers describing this training is limited. This study describes this level of knowledge among paediatricians from tertiary care hospitals in different regions of Spain and detects areas that need improvement. Material and method: A total of one hundred and fifty-seven (157) paediatricians working in tertiary healthcare hospitals located in three different regions in Spain consented to complete an online questionnaire divided in three sections (socio-demographic, knowledge about childhood autism, and opinion). Data were analysed using SPSS version 15. Results: The total mean score of participating paediatricians in the questionnaire was 20.34 (± 2.43 SD) out of a total possible score of 23. Approximately two-thirds (65%) of paediatricians scored more or equal to the mean score. The knowledge gap was found to be higher with symptoms of repetitive behaviour patterns, concept of autism, and comorbidity, with no statistical significance. There were no differences in paediatrician scores within different socio-demographic groups. Just under two-thirds (64%) of paediatricians subscribed to the opinion that their own knowledge about autism is limited, and there is a significant lack of knowledge about facilities in every region. Conclusions: There is a sufficient level of knowledge about autism among paediatricians in tertiary healthcare, although a lack of awareness about the management of these patients, with poor coordination between the different specialists that are involved in their treatment. Efforts should focus on achieving a better coordination between these specialists, and update the knowledge gaps identified (AU)

[Level of training in autistic spectrum disorders among hospital paediatricians]. / Nivel formativo sobre trastornos del espectro autista (TEA) entre los pediatras de atención hospitalaria.

BACKGROUND: Training in autistic spectrum disorders is crucial in order to achieve an early diagnosis. However, the number of papers describing this training is limited. This study describes this level of knowledge among paediatricians from tertiary care hospitals in different regions of Spain and detects areas that need improvement. MATERIAL AND METHOD: A total of one hundred and fifty-seven (157) paediatricians working in tertiary healthcare hospitals located in three different regions in Spain consented to complete an online questionnaire divided in three sections (socio-demographic, knowledge about childhood autism, and opinion). Data were analysed using SPSS version 15. RESULTS: The total mean score of participating paediatricians in the questionnaire was 20.34 (± 2.43 SD) out of a total possible score of 23. Approximately two-thirds (65%) of paediatricians scored more or equal to the mean score. The knowledge gap was found to be higher with symptoms of repetitive behaviour patterns, concept of autism, and comorbidity, with no statistical significance. There were no differences in paediatrician scores within different socio-demographic groups. Just under two-thirds (64%) of paediatricians subscribed to the opinion that their own knowledge about autism is limited, and there is a significant lack of knowledge about facilities in every region. CONCLUSIONS: There is a sufficient level of knowledge about autism among paediatricians in tertiary healthcare, although a lack of awareness about the management of these patients, with poor coordination between the different specialists that are involved in their treatment. Efforts should focus on achieving a better coordination between these specialists, and update the knowledge gaps identified.

Crisis febriles complejas: ¿debemos cambiar nuestro modo de actuación? / Complex febrile crises: should we change the way we act?

Introducción. Las convulsiones febriles son una de las causas más frecuentes de consulta. Hasta ahora, los pacientes con convulsiones febriles complejas (CFC) deben ingresar, dado el mayor porcentaje de epilepsia y complicaciones agudas descrito clásicamente. En la actualidad hay estudios que apoyan ser menos invasivos en el abordaje de estos pacientes. Objetivo. Describir las características de los pacientes ingresados por CFC y proponer un nuevo protocolo de actuación. Pacientes y métodos. Análisis retrospectivo de historias clínicas de ingresados por CFC (enero de 2010-diciembre de 2013). Se ofrecen datos epidemiológicos, clínicos, pruebas complementarias y evolución. Resultados. Las CFC suponían un 4,2% de los ingresos de neuropediatría (n = 67). Edad media al evento: 25 meses. El 47% tenía antecedentes familiares patológicos, y el 31%, antecedentes personales de convulsión febril previa. En el 54% de los pacientes, la CFC duró menos de cinco minutos; hubo recurrencia, la mayoría con un total de dos crisis y durante el primer día (las CFC por recurrencia son las más frecuentes). De las pruebas complementarias realizadas, ninguna de ellas sirvió como apoyo diagnóstico en el momento agudo. Durante su seguimiento, cinco pacientes presentaron complicaciones. Los pacientes con antecedentes familiares de convulsiones febriles presentan mayor riesgo de epilepsia o recurrencia (p =0,02), sin diferencias significativas respecto a la edad, número de crisis, intervalo de fiebre, estado epiléptico o tipo de CFC. Conclusiones. Las CFC no asocian mayores complicaciones agudas; las exploraciones complementarias no permiten discriminar precozmente a los pacientes de riesgo. Su ingreso podría evitarse en ausencia de otros signos clínicos y limitarse a casos seleccionados (AU)

Introduction. Febrile seizures are one of the most frequent reasons why patients visit the healthcare specialist. Up until now, patients with complex febrile seizures (CFS) have been hospitalised, bearing in mind the higher percentages of epilepsy and acute complications that were classically reported. Today there are studies that back the idea of being less invasive in the management of these patients. Aims. To describe the characteristics of patients hospitalised due to CFS and to propose a new protocol to be followed in dealing with such cases Patients and methods. The medical records of patients hospitalised because of CFS (January 2010-December 2013) were analysed retrospectively. Epidemiological and clinical data are presented, together with information from complementary tests and about development. Results. CFS account for 4.2% of all neuropaediatric cases of admittance to hospital in (67 patients). Mean age at the time of the event: 25 months. A pathological family history existed in 47% of cases, and 31% had a previous personal history of febrile seizures. The CFS lasted less than five minutes in 54% of patients; there were also recurrences, most of them with a total of two crises and during the first day (CFS due to recurrence are the most frequent). None of the complementary tests that were carried out were of any use as a diagnostic aid during the acute phase. During their follow-up, five patients presented complications. Patients with a family history of febrile seizures presented a higher risk of epilepsy or recurrence (p = 0.02), with no significant differences as regards age, number of seizures, febrile interval, epileptic status or type of CFS. Conclusions. The CFS are not associated with greater acute complications, and the complementary examinations do not allow high-risk patients to be distinguished at an early stage. Hospitalising them could be avoided in the absence of other clinical signs and symptoms, and thus be limited to selected cases (AU)