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 2-18â 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 12â months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3â months and 1â day before starting treatment and 1, 3, 6 and 12â months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8â 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.
Receptors, N-Methyl-D-Aspartate , Serine , Humans , Female , Male , Child , Child, Preschool , Adolescent , Serine/therapeutic use , Serine/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Brain Diseases/genetics , Brain Diseases/drug therapy , Treatment Outcome , Quality of Life
La ambliopía, vista desde el desarrollo, se comporta clínicamente diferente según el momento de la agresióny el tiempo que esta se mantuvo. Las funciones visuales y la sensibilidad del sistema tienen períodos críticos variables dependiendo del nivel de procesamientode la información visual y, por lo tanto, tendremosmanifestaciones clínicas correspondientes a cada una de estas etapas del desarrollo. Son conceptosimportantes para tener en cuenta a la hora de establecer un tratamiento.De acuerdo a Von Noorden (2002) la ambliopía es una disminución de la agudeza visual causada por deprivación de la visión o una interacción binocular anormal, en la que no pueden ser detectadas causas orgánicas en el examen físico del ojo y que, en los casos apropiados, es reversible por medios terapéuticos.Nigel (1998) habla de la ambliopía como el resultado de una gran variedad de anomalías sensoriales y motoras,que tiene causas y efectos múltiples.Las condiciones que producen la ambliopía son patologíasampliamente conocidas y las encontramos en la consulta diaria: estrabismo, anisometropía, viciosde refracción, cataratas y otras formas de deprivaciónvisual.
Amblyopia seen from developing clinically behaves differently depending on the time of the attack and the time that remained. The functions and the sensitivity of the visual system are critical periods varied depending on the level of processing visual information and therefore, will have clinical manifestations corresponding to each of these stages of development. These are important concepts to take into account when establishing a treatment.According to Von Noorden (2002), amblyopia is a vision loss caused by deprivation of vision and/or an abnormal interaction binocular, which can not be detected organic reasons to physical examination of the eye, and where to Where appropriate, is reversible by therapeutic means.Nigel (1998) spoke of amblyopia as the result of a variety of sensory and motor abnormalities, which has multiple causes and effects.The conditions that produce amblyopia pathologies are widely known and are in daily consultation: strabismus, anisometropía, refractive errors, cataracts and other forms of visual deprivation.
Amblyopia , Refractive Errors , Strabismus , Visual Cortex
