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.

RECAPACITA PROJECT: Impact of the New York Convention on capacity modification judgments in persons with severe mental disorders: A comparative study using mixed methodology.

In 2013, Spain aligned its capacity modification processes (CM) legislation with the UN Convention on the rights of persons with disabilities, specifically for individuals with severe mental disorders (SMD). The reforms replaced incapacity verdicts with support provision and introduced the term "CM". However, the social impact of these changes remains uncertain. The RECAPACITA project was initiated to generate knowledge on SMD and CM, and this study aims to investigate modifications in CM sentences and associated terminology. Using a qualitative-quantitative methodology, content analysis was conducted on 56 sentences from individuals with SMD. Terminology analysis utilized 19 sentences to achieve information saturation. A comparison was made between sentences prior to 2013 and those spanning 2014 to 2023, analyzing the data through ANOVA and Bonferroni tests (significance level: 0.05). The analysis revealed that psychiatric illness, its evolution, lack of self-governance, and economic management were frequently mentioned aspects in the sentences. However, no significant correlations were found. Qualitatively, mentions of self-governance were more prevalent in sentences before 2013. Conversely, after 2013, there was an increased focus on substances use, lack of insight and medical adherence, and the need for support in daily life. The term "incapable person" appeared in 100% of the sentences, indicating no differences in terminology. The study suggests that current CM sentences provide increasingly individualized information, addressing the specific support needs of individuals. To enhance future legal proceedings, incorporating neuroscience in studying SMD individuals and reconsidering terminology based on Convention guidelines is recommended.

The RECAPACITA project: Description of the clinical, neuropsychological and functional profile of a sample of people with severe mental disorder and legal capacity modification in Spain.

Severe mental disorder (SMD) includes people with long-term mental disorders, disability and social dysfunction. The mental capacity evaluation of the people has been a key aspect in legislative systems around the world and different proposals have been made. In countries like Spain, until 2021, the mental capacity of individuals was assessed by means of legal proceedings. In the last years, there has been a notable increase in the number of claims for legal incapacity, but no data are available on the total number of persons with CM, neither on the specific pathologies, or clinical and cognitive profiles. In view of the total absence of data on the profile of people with SMD and modification of capacity, the RECAPACITA study was born. This study includes patients with SMD and CM, as well as those without CM, with the aim to describe exhaustively their clinical, neuropsychological and functional profile of people with SMD and CM, as well as obtaining a basic description of the social environment. OBJECTIVES: To describe CM in SMD, to identify clinical diagnoses, clinical severity and neuropsychological deterioration. METHODS: Cross-sectional descriptive study. 77 adult patients with SMD and CM, inpatients from the mental health sector of the Parc Sanitari Sant Joan de Déu (Spain), outpatients linked to the community rehabilitation services (CRS), and penitentiary inmates. CM, sociodemographic, clinical, functional and neuropsychological data are collected. RESULTS: In the sample, 59.5% present total CM. 74.7% are men (mean: 52.5 years). 87,0% have a diagnosis of schizophrenia. The estimated premorbid IQ is 91.4. The Global Assessment of Functioning (GAF) had a mean of 50.5, the "Clinical Global Impression Scale" (CGI) was 4.6 and Scale Unawareness of Mental Disorders (SUMD) was 9.28. The cognitive results shows a profile with slow proceeding speed (mean scale score: 6.6), good working memory (mean SC: 8.3) and adequate verbal comprehension (mean SC: 7.3). In memory, coding is altered (Pz: -1.9), and long-term spontaneous recall (Pz: -2.3). In abstract reasoning, a slight alteration is obtained (Mean SC: 6), as well as in semantic fluency (Mean SC: 6.3), phonological (Mean SC: 5.9), and inhibitory capacity (Mean SC: 5.7). CONCLUSIONS: Most of the sample are men with schizophrenia, with a total MC assumed by a tutelary foundation. They show a moderate alteration in global functioning and clinical global impression, with partial awareness of the disease. They present dysexecutive mild cognitive impairment, with poor memory coding and free retrieval capacity, and a normal IQ, adequate verbal comprehension and working memory. This study is the first to present objective data on the psychiatric, functional and cognitive status of a group of patients with CM. Such research could be a good starting point to address a topic of great interest from the health, social and legal point of view of the CM processes of people with SMD.

Prevalence of, and risk factors for, dental sequelae in adolescents who underwent cancer therapy during childhood.

INTRODUCTION: The increase in survival rates in children treated for cancer has been accompanied by a rise in sequelae in permanent teeth. The aim of the study was to correlate the type of cancer therapy administered to patients during early childhood and the dental sequelae recorded in survivors. MATERIAL AND METHODS: Single-center retrospective cohort study carried out at the Children's University Hospital of Sant Joan de Déu in Barcelona, Spain. Hundred and nine patients who had received cancer treatment during early childhood were randomly examined and grouped according to diagnosis and cancer therapy received. The type of therapy was correlated with the number and severity of dental lesions that patients presented in adolescence. RESULTS: Dental sequelae of some kind were present in 85.3% of patients. Microdontia was the most prevalent (52.3%). Treatment with alkylating agents had a relative risk of presenting moderate lesions of 3.36 (1.18-9.60), and one of 2.29 (1.07-4.91) of presenting severe lesions. Topoisomerase inhibitors and cytotoxic antibiotics presented relative risks of 1.6 (1.07-2.38) and 2.08 (1.02-4.26) of root alterations and agenesis, respectively. CONCLUSIONS: Treatment with alkylating agents together with cytotoxic antibiotics and topoisomerase inhibitors was associated with a higher relative risk of microdontia, agenesis, and root shortening.