l -Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B -related pediatric encephalopathy

Abstract

Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.

Long-term use of fluoxetine accelerates bone loss through the disruption of sphingolipids metabolism in bone marrow adipose tissue

“…In this study, we treated the patients with a dose of 250 mg/kg/d and plasma L-serine level of 1000 ± 127 µM in patients. This dose had been shown to ameliorate GRIN2B-related severe encephalopathy in a clinical trial 52 . The dose appears to be safe, and no obvious side effects were observed during the treatment.…”

Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

“…Other, refers to chromosome deletions, insertions, duplications that affect GRIN2A or GRIN2B genes. References 21, 73, 75, 76, 80, 82– 86, 89– 92, 94, 96, 98– 101, 103– 153.…”

“…Over 200 variants in GRIN2B are found in patients from cohorts with any one of several neurodevelopmental disorders 71 such as ID (including DD) 14, 75, 80, 82– 84, 91, 94– 96, 98, 103– 108, 111, 112, 114, 120, 122, 123, 128, 130, 135, 139– 147, 149– 153 , ASD 75, 80, 82, 84, 91, 98, 104, 105, 108, 111, 135, 140, 144, 148, 151– 153 , EE and seizure disorders 21, 80, 82, 84, 98, 103, 120, 130, 135, 138, 139, 141, 145 , schizophrenia 71, 111, 114, 137, 148 , and, to a lesser extent, attention-deficit/hyperactivity disorder 80, 84, 106 , cerebral visual impairment 158, 146 , and Alzheimer’s disease 159 have been reported in the literature. For these various phenotypes, virtually all of the patients display mild to profound DD or ID or both.…”

“…GRIN2B has been linked as a potential gene in which variations could increase the risk of autism 104, 105, 160 . A number of other characteristics, including microcephaly, movement disorders, Rett-like syndrome, language disorders have been observed in some patients 75, 96, 115, 142, 158 .…”

NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity

“…Given the rigid secondary structure of proline, we inserted glycines on either side of these prolines. Numerous disease-associated missense mutations have been identified at the membrane proximal prolines (Ogden et al, 2017;Soto et al, 2019). To assay receptor function, we initially recorded the activity of single channel patches in the on-cell mode (See Materials & Methods).…”