TY - JOUR
T1 - Effectiveness of L-serine supplementation in children with a GRIN2B loss-of-function mutation
T2 - Rationale and protocol for single patient (n-of-1) multiple cross-over trials.
AU - den Hollander, Bibiche
AU - Rothuizen-Lindenschot, Marieke
AU - Geertjens, Lisa
AU - Vaz, Frédéric M.
AU - Brands, Marion M.
AU - le, Hoang Lan
AU - van Eeghen, Agnies M.
AU - van de Ven, Peter M.
AU - Cornel, Martina C.
AU - Jacobs, Bart A. W.
AU - Bruining, Hilgo
AU - van Karnebeek, Clara D.
N1 - Funding Information: L-serine and placebo capsules were supported by platform Medicine for Society. This work was supported by United for Metabolic Disease [UMD-CG-2021-019, 2021], ‘s Heeren Loo. Stichting Metakids NL [2020-01-UMD, 2020], and Ladies Circle Nederland to CK and MB. BJ is member of the platform Medicine for Society, for which funding is provided by the Postcodeloterij. AvE is member of the European Reference Network ITHACA. LG and HG are supported by NWA.1160.18.200 NewTDech from NWO (Dutch Science Organisation).The current study has been approved by the Medical Ethics Board of the Amsterdam UMC location University of Amsterdam (registration number: 2022.0271). Funding Information: L-serine and placebo capsules were supported by platform Medicine for Society. This work was supported by United for Metabolic Disease [ UMD-CG-2021-019, 2021 ], ‘s Heeren Loo. Stichting Metakids NL [ 2020-01-UMD, 2020 ], and Ladies Circle Nederland to CK and MB. BJ is member of the platform Medicine for Society, for which funding is provided by the Postcodeloterij. AvE is member of the European Reference Network ITHACA. LG and HG are supported by NWA.1160.18.200 NewTDech from NWO (Dutch Science Organisation). Publisher Copyright: © 2023 The Authors
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
KW - GRIN2B
KW - Intellectual developmental disability
KW - L-serine
KW - N-methyl-D-aspartate receptor
KW - Personalized medicine
KW - n-of-1
UR - http://www.scopus.com/inward/record.url?scp=85179057965&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.conctc.2023.101233
DO - https://doi.org/10.1016/j.conctc.2023.101233
M3 - Article
C2 - 38144875
SN - 2451-8654
VL - 36
SP - 101233
JO - Contemporary Clinical Trials Communications
JF - Contemporary Clinical Trials Communications
M1 - 101233
ER -