PMID- 34997442
OWN - NLM
STAT- MEDLINE
DCOM- 20220526
LR  - 20240204
IS  - 1878-7479 (Electronic)
IS  - 1933-7213 (Print)
IS  - 1878-7479 (Linking)
VI  - 19
IP  - 1
DP  - 2022 Jan
TI  - L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure 
      Frequency in Individuals with GRIN-Related Disorders Due to Null Variants.
PG  - 334-341
LID - 10.1007/s13311-021-01173-9 [doi]
AB  - Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of 
      function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation 
      gave rise to the hypothesis of successfully treating GRIN-related disorders due 
      to LoF variants with co-agonists of the NMDAR. In this respect, we describe a 
      retrospectively collected series of ten individuals with GRIN2A- or 
      GRIN2B-related disorders who were treated with L-serine, each within an 
      independent n-of-1 trial. Our cohort comprises one individual with a LoF missense 
      variant with clinical improvements confirming the above hypothesis and 
      replicating a previous n-of-1 trial. A second individual with a GoF missense 
      variant was erroneously treated with L-serine and experienced immediate temporary 
      behavioral deterioration further supporting the supposed functional 
      pathomechanism. Eight additional individuals with null variants (that had been 
      interpreted as loss-of-function variants despite not being missense) again showed 
      clinical improvements. Among all nine individuals with LoF missense or null 
      variants, L-serine treatment was associated with improvements in behavior in 
      eight (89%), in development in four (44%), and/or in EEG or seizure frequency in 
      four (44%). None of these nine individuals experienced side effects or adverse 
      findings in the context of L-serine treatment. In summary, we describe the first 
      evidence that L-serine treatment may not only be associated with clinical 
      improvements in GRIN-related disorders due to LoF missense but particularly also 
      null variants.
CI  - (c) 2022. The Author(s).
FAU - Krey, Ilona
AU  - Krey I
AUID- ORCID: 0000-0002-9168-7615
AD  - Institute of Human Genetics, University of Leipzig Medical Center, 
      Philipp-Rosenthal-Strasse 55, 04103, Leipzig, Germany. 
      ilona.krey@medizin.uni-leipzig.de.
FAU - von Spiczak, Sarah
AU  - von Spiczak S
AD  - DRK-Northern German Epilepsy Center for Children and Adolescents, Schwentinental, 
      Germany.
AD  - Department of Neuropediatrics, University Medical Center Schleswig-Holstein, 
      Campus Kiel, Kiel, Germany.
FAU - Johannesen, Kathrine M
AU  - Johannesen KM
AUID- ORCID: 0000-0002-7356-3109
AD  - Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy 
      Centre, Dianalund, Denmark.
AD  - Department of Regional Health Research, University of Southern Denmark, Odense, 
      Denmark.
FAU - Hikel, Christiane
AU  - Hikel C
AD  - Department of Children and Adolescents, GFO Kliniken Niederrhein, Dinslaken, 
      Germany.
FAU - Kurlemann, Gerhard
AU  - Kurlemann G
AD  - Hospital for Children, Bonifatius Hospital Lingen, Lingen, Germany.
FAU - Muhle, Hiltrud
AU  - Muhle H
AD  - Department of Neuropediatrics, University Medical Center Schleswig-Holstein, 
      Campus Kiel, Kiel, Germany.
FAU - Beysen, Diane
AU  - Beysen D
AD  - Department of Paediatric Neurology, Antwerp University Hospital, Antwerp, 
      Belgium.
FAU - Dietel, Tobias
AU  - Dietel T
AD  - Epilepsy Center Kork, Medical Faculty of the University of Freiburg, Kehl, 
      Germany.
FAU - Moller, Rikke S
AU  - Moller RS
AD  - Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy 
      Centre, Dianalund, Denmark.
AD  - Department of Regional Health Research, University of Southern Denmark, Odense, 
      Denmark.
FAU - Lemke, Johannes R
AU  - Lemke JR
AD  - Institute of Human Genetics, University of Leipzig Medical Center, 
      Philipp-Rosenthal-Strasse 55, 04103, Leipzig, Germany.
AD  - Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany.
FAU - Syrbe, Steffen
AU  - Syrbe S
AD  - Division of Paediatric Epileptology, Centre for Paediatrics and Adolescent 
      Medicine, University Hospital Heidelberg, Heidelberg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220107
PL  - United States
TA  - Neurotherapeutics
JT  - Neurotherapeutics : the journal of the American Society for Experimental 
      NeuroTherapeutics
JID - 101290381
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 452VLY9402 (Serine)
SB  - IM
MH  - Electroencephalography
MH  - Humans
MH  - Receptors, N-Methyl-D-Aspartate/genetics
MH  - Retrospective Studies
MH  - *Seizures/drug therapy/genetics
MH  - *Serine/genetics
PMC - PMC9130352
OTO - NOTNLM
OT  - Developmental and epileptic encephalopathy
OT  - Epilepsy
OT  - Precision medicine
OT  - Retrospective observational case series
OT  - Targeted treatment
COIS- The authors declare no competing interests.
EDAT- 2022/01/09 06:00
MHDA- 2022/05/27 06:00
PMCR- 2022/01/07
CRDT- 2022/01/08 06:11
PHST- 2021/12/18 00:00 [accepted]
PHST- 2022/01/09 06:00 [pubmed]
PHST- 2022/05/27 06:00 [medline]
PHST- 2022/01/08 06:11 [entrez]
PHST- 2022/01/07 00:00 [pmc-release]
AID - S1878-7479(23)00171-X [pii]
AID - 1173 [pii]
AID - 10.1007/s13311-021-01173-9 [doi]
PST - ppublish
SO  - Neurotherapeutics. 2022 Jan;19(1):334-341. doi: 10.1007/s13311-021-01173-9. Epub 
      2022 Jan 7.