Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials

Bibiche den Hollander; Marieke Rothuizen-Lindenschot; Lisa Geertjens; Frédéric M Vaz; Marion M Brands; Hoang Lan Le; Agnies M van Eeghen; Peter M van de Ven; Martina C Cornel; Bart A W Jacobs; Hilgo Bruining; Clara D van Karnebeek

doi:10.1016/j.conctc.2023.101233

Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials

Contemp Clin Trials Commun. 2023 Nov 17:36:101233. doi: 10.1016/j.conctc.2023.101233. eCollection 2023 Dec.

Authors

Bibiche den Hollander^{1

2

3}, Marieke Rothuizen-Lindenschot⁴, Lisa Geertjens^{5

6}, Frédéric M Vaz^{3

7

8

9}, Marion M Brands^{1

2

3}, Hoang Lan Le^{10

11}, Agnies M van Eeghen^{2

12

13

14}, Peter M van de Ven¹⁵, Martina C Cornel^{2

16}, Bart A W Jacobs^{11

17}, Hilgo Bruining^{2

5

6}, Clara D van Karnebeek^{1

2

3

16}

Affiliations

¹ Amsterdam UMC Location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands.
² Emma Personalized Medicine Center, Amsterdam UMC, Amsterdam, the Netherlands.
³ United for Metabolic Diseases, Amsterdam, the Netherlands.
⁴ HAN University of Applied Sciences, Nijmegen, the Netherlands.
⁵ Amsterdam UMC Location Vrije Universiteit Amsterdam, Child and Adolescent Psychiatry and Psychosocial Care, Emma Children's Hospital, Boelelaan 1117, Amsterdam, the Netherlands.
⁶ Amsterdam UMC Location University of Amsterdam, N=You Neurodevelopmental Precision Center, Amsterdam Neuroscience, Amsterdam Reproduction and Development, Meibergdreef 9, Amsterdam, the Netherlands.
⁷ Amsterdam UMC Location University of Amsterdam, Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Meibergdreef 9, Amsterdam, the Netherlands.
⁸ Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, the Netherlands.
⁹ Amsterdam UMC Location University of Amsterdam, Department of Core Facility Metabolomics, Meibergdreef 9, Amsterdam, the Netherlands.
¹⁰ Amsterdam UMC Location University of Amsterdam, Department of Hospital Pharmacy, Meibergdreef 9, Amsterdam, the Netherlands.
¹¹ Medicine for Society, Platform at Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
¹² Advisium, 's Heerlen Loo Zorggroep, Amersfoort, the Netherlands.
¹³ Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Public Health Research Institute, Methodology and Mental Health and Personalized Medicine, Meibergdreef 9, Amsterdam, the Netherlands.
¹⁴ Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Reproduction & Development, Child Development, Meibergdreef 9, Amsterdam, the Netherlands.
¹⁵ University Medical Center Utrecht, Department of Data Science and Biostatistics, Julius Center for Health Sciences and Primary Care, Heidelberglaan 100, Utrecht, the Netherlands.
¹⁶ Amsterdam UMC Location Vrije Universiteit van Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development, Meibergdreef 9, Amsterdam, the Netherlands.
¹⁷ Antoni van Leeuwenhoek, Department of Pharmacy and Clinical Pharmacology, Plesmanlaan 121, Amsterdam, the Netherlands.

Abstract

Rationale: Loss-of-function (LoF) mutations in GRIN2B result in neurologic abnormalities due to N-methyl-D-aspartate receptor (NMDAR) dysfunction. Affected persons present with various symptoms, including intellectual developmental disability (IDD), hypotonia, communication deficits, motor impairment, complex behavior, seizures, sleep disorders and gastrointestinal disturbance. Recently, in vitro experiments showed that D-serine mitigates function to GluN2B (mutation)-containing NMDARs. 11 previous case reports are published on (experimental) L-serine treatment of patients between 1.5 and 12 years old with GRIN2B missense or null mutations, some of whom showed notable improvement in motor and cognitive performance, communication, behavior and abnormalities on electro encephalography (EEG). Our objective is to further evaluate the effectiveness of L-serine for GRIN2B-related neurodevelopmental disorder (GRIN2B-NDD), using an n-of-1 trial design, increasing the level of evidence.

Methods/design: These n-of-1 trials, consisting of 2 cycles of 6 months, will be performed to evaluate the effect of L-serine compared to placebo in 4 patients with a GRIN2B LoF mutation. The aggregation of multiple n-of-1 trials will provide an estimate of the average treatment effects.The primary outcome is the Perceive-Recall-Plan-Perform of Task Analysis, assessing developmental skills. Secondary outcomes include Goal Attainment Scaling, seizure log books, EEGs, sleep log books, the irritability subscale of the Aberrant Behavior Checklist, the Bristol Stool Scale and the Pediatric Quality of Life Inventory.

Conclusion: This study employs an innovative methodological approach to evaluate the effectiveness of L-serine for patients with a GRIN2B LoF mutation. The results will establish a foundation for implementing L-serine as a disease-modifying treatment in GRIN2B-NDD.

Keywords: GRIN2B1; Intellectual developmental disability3; L-serine2; N-methyl-D-aspartate receptor4; Personalized medicine5; n-of-16.