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.

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.

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.

[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.

[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.

[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.