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 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 endpoints 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, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months treatment. Secondary outcomes included seizure frequency and intensity reduction and electroencephalography improvement. Assessments were performed 3 months and 1 day before starting treatment and 1-3-6-12 months after the beginning of 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). Clinical phenotype showed: 91% intellectual disability (61% severe), 83% behavioral problems, 78% movement disorders and 58% with epilepsy. Based on Vineland Adaptive Behavior Composite standard score, nine children were classified as mildly impaired level group (cut-off > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in Daily Living Skills domain (P = 0,035) 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. Growth Score Values cognitive subdomain on the Bayley-III 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 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 the adaptive, motor function and quality of life, with a better response to the treatment in mild phenotypes.

中文翻译：

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L-丝氨酸治疗 GRIN 相关脑病患者：2A 期非随机研究

GRIN 相关疾病是罕见的发育性脑病，其表现多样且治疗选择有限。在这里，我们提出了第一个非随机、开放标签、单臂试验 (NCT04646447)，旨在评估 L-丝氨酸对 GRIN 基因变异导致功能丧失的儿童的耐受性和疗效。在这项 2A 期试验中，患有 GRIN 功能丧失致病变异的 2-18 岁患者接受了为期 52 周的 L-丝氨酸治疗。主要终点包括安全性和有效性，通过测量 Vineland 适应性行为量表、贝利量表、适合年龄的韦克斯勒量表、粗大运动功能 88、儿童睡眠障碍量表、儿科生活质量、儿童行为检查表和看护者-教师的变化来衡量12 个月治疗后的报告表。次要结果包括癫痫发作频率和强度降低以及脑电图改善。评估在开始治疗前 3 个月零 1 天以及开始补充后 1-3-6-12 个月进行。共有 24 名参与者入组（13 名男性/11 名女性，平均年龄 9.8 岁，SD 4.8），其中 23 名完成了研究。患者具有 GRIN2B、GRIN1 和 GRIN2A 变异（分别为 12、6 和 5 例）。临床表型显示：91% 为智力障碍（61% 为严重），83% 为行为问题，78% 为运动障碍，58% 为癫痫。根据Vineland适应性行为综合标准评分，9名儿童被分类为轻度受损水平组(截止值＞55)，而14名儿童被分配为临床严重组。轻度组内的 Vineland 量表的日常生活技能领域有所改善（P = 0,035）。整个队列的表达能力（P = 0.005）、个人能力（P = 0.003）、社区能力（P = 0.009）、人际能力（P = 0.005）和精细运动能力（P = 0.031）子领域均有所改善，尽管改善主要出现在轻度患者中团体。Bayley-III 的生长评分认知子域在严重组中显示出显着改善（P = 0.016），平均提高了 21.6 分。无论严重程度如何，L-丝氨酸治疗与中位粗大运动功能 88 总分 (P = 0.002) 和平均儿科生活质量总分 (P = 0.00068) 的显着改善相关。L-丝氨酸使五名儿童的脑电图模式正常化，并使一名临床受影响儿童的癫痫发作频率正常化。一名患者因烦躁和失眠而停止治疗。该试验提供的证据表明，L-丝氨酸对于患有 GRIN 功能丧失变异的儿童来说是一种安全的治疗方法，有可能改善适应性、运动功能和生活质量，并且对轻度表型的治疗有更好的反应。