GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting
genes (mostly
,
and
genes), which encode for the GluN subunit of the
-methyl ...D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present.
In this study, we aimed to delineate the structural and functional alterations of
disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants.
Patients harbouring
disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms.
Our findings show a strong correlation between
variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders involving age-dependent gene dysregulation. Reelin is a glycoprotein that varies its expression throughout lifetime and ...controls cortical patterning and synaptogenesis. Brain and plasma reelin levels have been reported to be low in adults with autism; as well as in children with autism, but only when compared to control adults. Therefore, reelin expression levels in children with autism are unclear. For this reason, we compared plasma reelin levels in children with autism and children without autism (non-ASD) of similar ages to evaluate reelin expression in ASD during childhood. Plasma samples from 19 non-ASD (8.9 ± 0.8 years) and 40 children with autism (7.5 ± 0.5 years) were analyzed. We found that 50% of the children with autism displayed similar plasma reelin levels to the non-ASD group. However, the remaining 50% expressed more than 30 times more reelin compared to non-ASD levels. We also show that male children with autism displayed significantly higher reelin levels than females. The clinical presentation of this subgroup could not be distinguished from that of children with autism. Epilepsy or attention-deficit/hyperactivity disorder (ADHD) was not associated to reelin levels. We conclude that the high levels of plasma reelin might be an important hallmark in a subset of children with autism, previously unnoticed. As we could not find any correlation between reelin levels and ASD clinical presentations, our results may indicate transient reelin increases in the plasma or the characterization of a group of ASD individuals with a different pathophysiology.
The engrailed homeobox protein (EN) plays an important role in the regionalization of the neural tube. EN distribution regulates the cerebellum and midbrain morphogenesis, as well as retinotectal ...synaptogenesis. In humans, the
and
genes code for the EN family of transcription factors. Genetic alterations in the expression of
have been related to different neurologic conditions and more particularly to autism spectrum disorders (ASD). We aimed to study and compare the phenotypes of three series of patients: (1) patients with encephalic structural anomalies (ESA) and abnormalities in the genomic (DNA) and/or transcriptomic (RNAm) of
(EN2-g), (2) ESA patients having other gene mutations (OG-g), and (3) ESA patients free of these mutations (NM-g).
We have performed a descriptive study on 109 patients who suffer from mental retardation (MR), cerebral palsy (CP), epilepsy (EP), and behavioral disorders (BD), showing also ESA in their encephalic MRI. We studied genomic DNA and transcriptional analysis (cDNA) on
gene (EN2), and in other genes (OG):
, and
, as a routine genetic diagnosis in ESA patients.
From 109 patients, fifteen meet the exclusion criteria. From the remaining 94 patients, 12 (12.8%) showed mutations in
(EN2-g), 20 showed mutations in other studied genes (OG-g), and 62 did not showed any mutation (NM-g). All EN2-g patients, suffered from MR, nine EP, seven BD and four CP. The proportions of these phenotypes in EN2-g did not differ from those in the OG-g, but it was significantly higher when comparing EN2-g with NM-g (MR:
= 0.013; EP:
= 0.001; BD:
= 0.0001; CP:
= 0.07, ns). Groups EN2-g and OG-g showed a 100 and a 70% of comorbidity, respectively, being significantly (
= 0.04) greater than NM-group (62.9%).
Our series reflects a significant effect of
gene alterations in neurodevelopmental abnormalities associated to ESA. Conversely, although these
related anomalies might represent a predisposition to develop brain diseases, our results did not support direct relationship between
mutations and specific clinical phenotypes.
GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial ...(NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.
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