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

Autor:	Juliá-Palacios N; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Olivella M; Bioinformatics and Bioimaging Group. Faculty of Science, Technology and Engineering, University of Vic-Central University of Catalonia, 08500 Vic, Spain.; Institute for Research and Innovation in Life and Health Sciences (IRIS-CC), University of Vic-Central University of Catalonia, 08500 Vic, Spain., Sigatullina Bondarenko M; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Ibáñez-Micó S; Pediatric Neurology Unit, Arrixaca Universitary Hospital, 30120 Murcia, Spain., Muñoz-Cabello B; Department of Pediatrics, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain., Alonso-Luengo O; Department of Pediatrics, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain., Soto-Insuga V; Neurology Service, Hospital Niño Jesús, 28009 Madrid, Spain., García-Navas D; Department of Pediatric Neurology, Complejo Hospitalario Universitario de Cáceres, 10003 Cáceres, Spain., Cuesta-Herraiz L; Department of Paediatrics Neurology, Hospital de Manises, 46940 Valencia, Spain., Andreo-Lillo P; Neuropediatric Unit, Pediatric Department, University Hospital of Sant Joan d'Alacant, 03550 Sant Joan d'Alacant, Spain., Aguilera-Albesa S; Paediatric Neurology Unit, Department of Pediatrics, Hospital Universitario de Navarra, 31008, Pamplona, Spain., Hedrera-Fernández A; Child Neurology Unit, Pediatrics Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain., González Alguacil E; Neurology Service, Hospital Niño Jesús, 28009 Madrid, Spain., Sánchez-Carpintero R; Pediatric Neurology Unit, Clínica Universidad de Navarra, 31080, Pamplona, Spain., Martín Del Valle F; Department of Pediatrics, Hospital Universitario Severo Ochoa, 28911 Leganés, Madrid, Spain., Jiménez González E; Department of Pediatrics, Hospital Rey Juan Carlos, 28933 Móstoles, Madrid, Spain., Cean Cabrera L; Pediatric Neurology Unit, Arrixaca Universitary Hospital, 30120 Murcia, Spain., Medina-Rivera I; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Perez-Ordoñez M; Child and Adolescent Mental Health Area, Psychiatry and Psychology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain., Colomé R; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Lopez L; Department of Rehabilitation, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain., Engracia Cazorla M; Department of Rehabilitation, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain., Fornaguera M; Department of Rehabilitation, Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain., Ormazabal A; Department of Clinical Biochemistry, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.; European Reference Network for Hereditary Metabolic Diseases (MetabERN), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid 28029, Spain., Alonso-Colmenero I; Pediatric Neurology Department, Hospital Sant Joan de Déu, Full Member of ERN EpiCare, Barcelona University, 08950 Barcelona, Spain., Illescas KS; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Balsells-Mejía S; Department of Research Promotion and Management. Statistical Support, Hospital Sant Joan de Déu (HSJD), 08950 Barcelona, Spain., Mari-Vico R; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Duffo Viñas M; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain.; Child and Adolescent Mental Health Area, Psychiatry and Psychology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain., Cappuccio G; Department of Translational Medical Sciences, Università degli Studi di Napoli 'Federico II', 80125 Naples, Italy.; Telethon Institute of Genetics and Medicine, Department of Pediatrics, Pozzuoli, 80131 Naples, Italy., Terrone G; Department of Translational Medical Sciences, Università degli Studi di Napoli 'Federico II', 80125 Naples, Italy., Romano R; Department of Translational Medical Sciences, Università degli Studi di Napoli 'Federico II', 80125 Naples, Italy., Manti F; Department of Human Neuroscience, University of Rome La Sapienza, 00185 Roma, Lazio, Italy., Mastrangelo M; Department of Women and Child Health and Uroginecological Sciences, Sapienza University of Rome, 00185 Rome, Italy.; Child Neurology and Psychiatry Unit, Department of Neuroscience/Mental Health, Azienda Ospedaliero-Universitaria Policlinico Umberto I, 00161 Rome, Italy., Alfonsi C; Department of Human Neuroscience, University of Rome La Sapienza, 00185 Roma, Lazio, Italy., de Siqueira Barros B; Núcleo de Estudos da Saúde do Adolescente, Programa de Pós-Graduação em Ciências Médicas, Universidade do Estado do Rio de Janeiro, Faculdade de Ciência Médicas, 56066 Rio de Janeiro, RJ, Brazil., Nizon M; Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France., Gjerulfsen CE; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark., Muro VL; Pediatric Neurology Unit, Hospital Britanico Buenos Aires, C1280AEB Buenos Aires, Argentina., Karall D; Clinic for Paediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria., Zeiner F; Clinic for Paediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria., Masnada S; Department of Child Neurology, V. Buzzi Children's Hospital, 20125 Milan, Italy., Peterlongo I; Department of Child Neurology, V. Buzzi Children's Hospital, 20125 Milan, Italy., Oyarzábal A; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain., Santos-Gómez A; Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain.; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain., Altafaj X; Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain.; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain., García-Cazorla Á; Neurometabolic Unit and Synaptic Metabolism Lab, Department of Neurology, Hospital Sant Joan de Déu-IRSJD, CIBERER and MetabERN, 08950 Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 May 03; Vol. 147 (5), pp. 1653-1666.
DOI:	10.1093/brain/awae041
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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