L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

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.

Electroencephalographic assessment in patients with Rett syndrome during cognitive stimulation by means of eye tracking technology and alternative and augmentative communication systems.

Rett syndrome (RTT) is considered a rare disease despite being the leading genetic disorder to cause severe intellectual disability in women. There is no cure for RTT, so the treatment is symptomatic and supporting, requiring a multidisciplinary approach. Occupational therapy can help girls and their families to improve communication, being one of the main concerns when verbal language and intentional hand movement are impaired or lost. This paper presents a pilot study of cognitive training through the combined use of eye-tracking technology (ETT) and augmentative and alternative communication (AAC) using the Peabody Picture Vocabulary Test (PPVT-IV). The objective was to evaluate brain activation by means of electroencephalography (EEG) during the stimulation of non-verbal communication. EEG data were recorded during an eyes-open resting state (EO-RS) period and during cognitive stimulation via AAC activity. To assess their effect, both signals were compared at the spectral level, focusing on frequency, brain symmetry and connectivity. During the task, a redistribution of power towards fast frequency bands was observed, as well as an improvement in the brain symmetry index (BSI) and functional synchronicity through increased coherence. Therefore, the results of the spectral analysis showed a possible deviation from the pathological pattern, manifesting a positive effect in the use of non-verbal cognitive stimulation activities. In conclusion, it was observed that it is possible to establish a cognitive training system that produces brain activation and favors communication and learning despite intentional language loss.Clinical Relevance- This manifests a method of cognitive training that would induce brain activation in RTT patients with absence of intentional communication. The evaluation system through spectral analysis could complement the standardized protocols to asses communication that are based on verbal and motor production.

Choosing Strategies to Deal with Artifactual EEG Data in Children with Cognitive Impairment.

Rett syndrome is a disease that involves acute cognitive impairment and, consequently, a complex and varied symptomatology. This study evaluates the EEG signals of twenty-nine patients and classify them according to the level of movement artifact. The main goal is to achieve an artifact rejection strategy that performs well in all signals, regardless of the artifact level. Two different methods have been studied: one based on the data distribution and the other based on the energy function, with entropy as its main component. The method based on the data distribution shows poor performance with signals containing high amplitude outliers. On the contrary, the method based on the energy function is more robust to outliers. As it does not depend on the data distribution, it is not affected by artifactual events. A double rejection strategy has been chosen, first on a motion signal (accelerometer or EEG low-pass filtered between 1 and 10 Hz) and then on the EEG signal. The results showed a higher performance when working combining both artifact rejection methods. The energy-based method, to isolate motion artifacts, and the data-distribution-based method, to eliminate the remaining lower amplitude artifacts were used. In conclusion, a new method that proves to be robust for all types of signals is designed.