TY - JOUR
T1 - Evidence for effect of L-serine, a novel therapy for GRIN2B-related neurodevelopmental disorder
AU - den Hollander, B.
AU - Veenvliet, A. R. J.
AU - Rothuizen-Lindenschot, M.
AU - van Essen, P.
AU - Peters, G.
AU - Santos-Gómez, A.
AU - Olivella, M.
AU - Altafaj, X.
AU - Brands, M. M.
AU - Jacobs, B. A. W.
AU - van Karnebeek, C. D.
N1 - Funding Information: l -serine was manufactured and provided by Nutricia. This work was supported by United for Metabolic Disease [ UMD-CG-2021-019, 2021 ] and Stichting Metakids NL [ 2020-01-UMD, 2020 ] to CvK and MB. B.A.W. Jacobs is member of the platform Medicine for Society, for which funding is provided by the Postcodeloterij . Functional annotation studies and computational studies were supported by ISCIII , co-funded by European Regional Development Fund (ERDF), a way to build Europe (grant PI19/00348 ) to XA. Funding Information: L-serine was manufactured and provided by Nutricia. This work was supported by United for Metabolic Disease [UMD-CG-2021-019, 2021] and Stichting Metakids NL [2020-01-UMD, 2020] to CvK and MB. B.A.W. Jacobs is member of the platform Medicine for Society, for which funding is provided by the Postcodeloterij. Functional annotation studies and computational studies were supported by ISCIII, co-funded by European Regional Development Fund (ERDF), a way to build Europe (grant PI19/00348) to XA. Publisher Copyright: © 2023
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Rationale: To date, causal therapy is potentially available for GRIN2B-related neurodevelopmental disorder (NDD) due to loss-of-function (LoF) variants in GRIN2B, resulting in dysfunction of the GluN2B subunit-containing N-methyl-D-aspartate receptor (NMDAR). Recently, in vitro experiments showed that high doses of NMDAR co-agonist D-serine has the potential to boost the activity in GluN2B LoF variant-containing NMDARs. Initial reports of GRIN2B-NDD patients LoF variants, treated with L-serine using different regimens, showed varying effects on motor and cognitive performance, communication, behavior and EEG. Here, this novel treatment using a standardized protocol with an innovative developmental outcome measure is explored further in an open-label observational GRIN2B-NDD study. Methods: Initially, in vitro studies were conducted in order to functionally stratify two de novo GRIN2B variants present in two female patients (18 months and 4 years old). Functional studies showed that both variants are LoF, and thus the patients were treated experimentally according to an approved protocol with oral L-serine (500 mg/kg/day in 4 doses) for a period of 12 months. Both patients showed a heterogeneous clinical phenotype, however overlapping symptoms were present: intellectual developmental disability (IDD), behavioral abnormalities and hypotonia. Outcome measures included laboratory tests, quality of life, sleep, irritability, stool, and performance skills, measured by, among others, the Perceive-Recall-Plan-Perform System of Task Analysis (PRPP-Assessment). Results: Both patients tolerated L-serine without adverse effects. In one patient, improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPP mastery score 10% at baseline, 78% at twelve months). In the most severe clinically affected patient no significant objective improvement in validated outcomes was observed. Caregivers of both patients reported subjective increase of alertness and improved communication skills. Conclusion: Our observational study confirms that L-serine supplementation is safe in patients with GRIN2B-NDD associated with LoF variants, and may accelerate psychomotor development and ameliorate cognitive performance in some but not all patients. The PRPP-Assessment, a promising instrument to evaluate everyday activities and enhance personalized and value-based care, was not performed in the severely affected patient, meaning that possible positive results may have been missed. To generate stronger evidence for effect of L-serine in GRIN2B-NDD, we will perform placebo-controlled n-of-1 trials.
AB - Rationale: To date, causal therapy is potentially available for GRIN2B-related neurodevelopmental disorder (NDD) due to loss-of-function (LoF) variants in GRIN2B, resulting in dysfunction of the GluN2B subunit-containing N-methyl-D-aspartate receptor (NMDAR). Recently, in vitro experiments showed that high doses of NMDAR co-agonist D-serine has the potential to boost the activity in GluN2B LoF variant-containing NMDARs. Initial reports of GRIN2B-NDD patients LoF variants, treated with L-serine using different regimens, showed varying effects on motor and cognitive performance, communication, behavior and EEG. Here, this novel treatment using a standardized protocol with an innovative developmental outcome measure is explored further in an open-label observational GRIN2B-NDD study. Methods: Initially, in vitro studies were conducted in order to functionally stratify two de novo GRIN2B variants present in two female patients (18 months and 4 years old). Functional studies showed that both variants are LoF, and thus the patients were treated experimentally according to an approved protocol with oral L-serine (500 mg/kg/day in 4 doses) for a period of 12 months. Both patients showed a heterogeneous clinical phenotype, however overlapping symptoms were present: intellectual developmental disability (IDD), behavioral abnormalities and hypotonia. Outcome measures included laboratory tests, quality of life, sleep, irritability, stool, and performance skills, measured by, among others, the Perceive-Recall-Plan-Perform System of Task Analysis (PRPP-Assessment). Results: Both patients tolerated L-serine without adverse effects. In one patient, improvement in psychomotor development and cognitive functioning was observed after 12 months (PRPP mastery score 10% at baseline, 78% at twelve months). In the most severe clinically affected patient no significant objective improvement in validated outcomes was observed. Caregivers of both patients reported subjective increase of alertness and improved communication skills. Conclusion: Our observational study confirms that L-serine supplementation is safe in patients with GRIN2B-NDD associated with LoF variants, and may accelerate psychomotor development and ameliorate cognitive performance in some but not all patients. The PRPP-Assessment, a promising instrument to evaluate everyday activities and enhance personalized and value-based care, was not performed in the severely affected patient, meaning that possible positive results may have been missed. To generate stronger evidence for effect of L-serine in GRIN2B-NDD, we will perform placebo-controlled n-of-1 trials.
KW - GRIN2B
KW - Intellectual developmental disorder
KW - L-serine
KW - N-methyl-D-aspartate receptor
KW - Neurodevelopmental disorder
KW - Personalized medicine
UR - http://www.scopus.com/inward/record.url?scp=85147577034&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ymgme.2023.107523
DO - https://doi.org/10.1016/j.ymgme.2023.107523
M3 - Article
C2 - 36758276
SN - 1096-7192
VL - 138
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 3
M1 - 107523
ER -