Tolerability and Efficacy of L-Serine in Patients With GRIN-related Encephalopathy
试验速览
- 阶段
- 不适用
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Number of participants with any adverse event
研究概览
简要总结
GRIN-related disorders encompass a new group of Inborn Errors of Metabolism according to the recent nosology published by Ferreira et al (Genet Med, 2019).
These rare conditions represent a subtype of paediatric encephalopathies leading to intellectual disability, hypotonia, communication deficits and motor impairment (Orphanet entries: 178469, 289266, 101685, for GRIN1, GRIN2A and GRIN2B, respectively).
Mutations leading to glutamatergic hypotransmission can be potentially treated with L-Serine leading to significant clinical benefits in patients according to a pilot study published by our group (Soto et al, 2019).
In our study, the investigators will include about 20 spanish patients older than 2 years of age, harbouring GRIN variants functionally anotated as loss-of-function pathogenic variants. The investigators will evaluate dose tolerability, efficacy of the treatment according to neurocognitive and motor scales, as well as the effects of L-serine in microbiome composition.
详细描述
GRIN-related disorders, a novel group of IEM (inborn errors of metabolism): Mutations on GRIN genes, encoding for the N-methyl-D-Aspartate receptor (NMDAR) subunits, have been recently associated with autosomic dominant GRIN-related disorders (Lemke et al., 2016; Platzer et al., 2017; XiangWei et al., 2018; Strehlow et al., 2019). These rare conditions represent a subtype of paediatric encephalopathies leading to intellectual disability, hypotonia, communication deficits and motor impairment (Orphanet entries: 178469, 289266, 101685, for GRIN1, GRIN2A and GRIN2B, respectively).
There are about 200 patients affected with these diseases in Europe according to a data collection study conducted by the patients' families and presented at the first European meeting of GRIN disorders in October 2018 (Barcelona, Hospital Sant Joan de Déu).
Along the last years, our research efforts were focused to delineate the pathophysiology and personalized therapies for these diseases that are now considered as a new category of IEM. In particular, the recent nosology of inherited metabolic disorders (Ferreira et al, 2018) classifies GRIN-related disorders in the category: "DISORDERS OF NITROGEN CONTAINING COMPOUNDS", and the subgroup: "20. Disorders of glutamate metabolism":
GRIN1 (OMIM138249): Ionotropic glutamate receptor NMDA type subunit 1 dysregulation (AD, AR): Autosomal dominant mental retardation type 8; neurodevelopmental disorder with or without hyperkinetic movements and seizures. GRIN2A (OMIM138253): Ionotropic glutamate receptor NMDA type subunit 2A dysregulation (AD): Non related to human disease so far. GRIN2B (OMIM138252): Inotropic glutamate receptor NMDA type subunit 2B dysregulation (AD): Early infantile epileptic encephalopathy type 27; autosomal dominant mental retardation type 6. GRIN2D (OMIM602717): Ionotropic glutamate receptor NMDA type subunit 2D superactivity (AD): Early infantile epileptic encephalopathy type 46.
Indeed, in a proof-of-concept, the investigators have determined that a GRIN2B loss-of-function variant can be rescued in vitro, by means of elevated doses of D-serine (NMDAR coagonist) administration. More importantly, the investigators showed that L-serine (the D-serine natural precursor) dietary supplement was associated with a significant improvement of motor and communication skills of the patient harbouring GRIN2B hypofunctional variant (Soto et al., 2019).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of encephalopathy associated with genetic GRIN variant pathogenic or likely pathogenic, causing a loss-of-function
- •Parent(s)/legal representative give written informed consent for participation in the trial; patient assent (if possessing adequate understanding, in the investigator's)
- •Patient & caregiver are willing and able (in the investigator's opinion) to comply with all trial requirements (including the completion of all caregiver assessments by the same caregiver throughout the trial).
排除标准
- •Diagnosis of encephalopathy with absence of genetic GRIN variant pathogenic or likely pathogenic.
- •Currently using or has used within the 30 days prior to screening L-Serine supplement
- •Patient has been previously randomized into this trial
结局指标
主要结局
Number of participants with any adverse event
时间窗: up to 12 months
Dose tolerability is based on subject interviews and scheduled assessment evaluating the presence or absence of adverse events. The presence of adverse events will be collected according the doses of L-serine: 250 mg / kg / day and 500 mg / kg / day. Pre-existing conditions (present before intake of study nutreceutical) or pretreatment AEs (onset before intake of study nutraceutical) are considered concomitant diseases and should not be recorded as AEs but should be recorded on the concomitant diseases eCRF page. However, if the subject experiences a worsening, increased frequency, or complication of such a concomitant disease, the worsening, increased frequency, or complication should be recorded as an AE.
Change in mental age with Vineland Adaptive Behavior Scales (VABS) (Vineland-3)
时间窗: Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention
Exploring the following domains: Communication, Daily Living Skills, Socialization and motor Skills (gross and fine) Once obtained the mental age equivalent, the neuropsychologist test or battery to assess the neurodevelopment will be selected
Change in bayley Scales of Infant and Toddler Development (BSID)
时间窗: Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention
The Bayley Scales of Infant and Toddler Development (BSID-III) are a set of standardized rating scales, which enable us to assess the cognition, receptive language, expressive language, fine motor and gross motor of children between 1 and 42 months. The Cognitive battery, which consists on the evaluation of the following items: visual perception, attention, memory, objects manipulation and exploration, communication skills and verbal comprehension. Bayley III has a raw score, scale score, composite score, and growth percentile score. All of these scores will be given in the study. A higher score means improvement is better. The high score for cognition is 91, 48 for receptive language, 49 for expressive language, 66 for fine motor and 72 for gross motor evaluation.
Efficiency of the treatment measured by change in the cognitive assessment (Wechsler Intelligence Scale.
时间窗: Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention
If the mental age is more than 42 months will be considering the followings neuropsychologist test: Specific test will be chosen according the age of the children. 1. The Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV): Age range: 2 years 6 months to 7 years 7 months. An index score can range from 40 to 160. A higher score means improvement is better. 2. The Wechsler Intelligence Scale for Children (WISC V): Age range: Children aged 6:0-16:11. It has 5 composite scores and a Full-Scale Intelligence Quotient (FSIQ) is generated based on seven subtests. The primary index scores range from 45 to 155; the FSIQ ranges from 40 to 160. A higher score means improvement is better. 3. The Wechsler Adult Intelligence Scale (WAIS-IV): Age range: 16 years to 90 years, 11 months. The test has 15 subtests, 10 of which are core subtests that are usually used to measure the four index scores and the FSIQ. A higher score means improvement is better.
Change in the Achenbach System of Empirically Based Assessment (ASEBA) System of Empirically Based Assessment (ASEBA)+
时间窗: Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention
The Achenbach System of Empirically Based Assessment (ASEBA) for parents and teachers offers a comprehensive approach to assessing adaptive and maladaptive functioning
Change in Gross Motor Function Measure-88
时间窗: -3 months, 0 months (start treatment), 3 months, 6 months, 12 months
Items span the spectrum of gross motor activities in five dimensions. A: Lying and Rolling, B: Sitting C: Crawling and Kneeling, D: Standing, and E: Walking, Running and Jumping.
Change in Social Communication Questionnaire (SCQ)
时间窗: Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention
Evaluates communication skills and social functioning in children who may have autism or autism spectrum disorders and The SCQ is a 40-item survey where each question is a 'yes' or 'no' answer. The total possible range of scores is 0-39 (verbal children) or 0-33 (non-verbal children) with higher scores indicative of greater frequency of symptoms. They are completed by parents or other primary caregiver.
Change in the Sleep Disturbance Scale for Children (SDSC)
时间窗: Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention
The Sleep Disturbance Scale for Children (SDSC) is a 27-item inventory rated on a 5 point Likert-type scale. 0 = least severe and 5 = most severe The instrument's purpose is to categorize sleep disorders in children. As well as giving an overall score the instrument uses five subdomains: disorders of initiating and maintaining sleep, sleep breathing disorders, disorders of arousal, sleep-wake transition disorders, disorders of excessive somnolence, and sleep hyperhidrosis.
次要结局
- Microbiota composition([ Time Frame: 12 months ])