Scientific publications
L-serine treatment in patients with GRIN-related encephalopathy: A phase 2A, non-randomized study. Scientific Publication
Natalia Juliá-Palacios 1 , Mireia Olivella 2 3 , Mariya Sigatullina Bondarenko 1 , Salvador Ibáñez-Micó 4 , Beatriz Muñoz-Cabello 5 , Olga Alonso-Luengo 5 , Víctor Soto-Insuga 6 , Deyanira García-Navas 7 , Laura Cuesta-Herraiz 8 , Patricia Andreo-Lillo 9 , Sergio Aguilera-Albesa 10 , Antonio Hedrera-Fernández 11 , Elena González Alguacil 6 , Rocío Sánchez-Carpintero 12 , Fernando Martín Del Valle 13 , Erika Jiménez González 14 , Lourdes Cean Cabrera 4 , Ines Medina-Rivera 1 , Marta Perez-Ordoñez 15 , Roser Colomé 1 , Laura Lopez 16 , María Engracia Cazorla 16 , Montserrat Fornaguera 16 , Aida Ormazabal 17 , Itziar Alonso-Colmenero 18 , Katia Sofía Illescas 1 , Sol Balsells-Mejía 19 , Rosanna Mari-Vico 1 , Maria Duffo Viñas 1 15 , Gerarda Cappuccio 20 21 , Gaetano Terrone 20 , Roberta Romano 20 , Filippo Manti 22 , Mario Mastrangelo 23 24 , Chiara Alfonsi 22 , Bruna de Siqueira Barros 25 , Mathilde Nizon 26 , Cathrine Elisabeth Gjerulfsen 27 , Valeria L Muro 28 , Daniela Karall 29 , Fiona Zeiner 29 , Silvia Masnada 30 , Irene Peterlongo 30 , Alfonso Oyarzábal 1 , Ana Santos-Gómez 31 32 , Xavier Altafaj 31 32 , Ángeles García-Cazorla 1
Abstract
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.
CITATION Brain. 2024 Feb 21:awae041. doi: 10.1093/brain/awae041
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