Prevalence of High Plasmatic 3-O-Methyldopa Level in a Specific Population of Patients With a Symptomatology Compatible With AADC Deficiency (Aromatic L-Amino Acid Decarboxylase)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 388
- 试验地点
- 4
- 主要终点
- change of plasmatic 3-OMD level beyond 25% of reference value, by age group (0 - 30 days old, 31 - 365 days old, 1 - 10 years old, > 10 years old)
研究概览
简要总结
O-MethyDopa (3-OMD) is a metabolite of the Dopaminergic pathway that accumulates in case of a default in the neurotransmitter biosynthesis due to a key enzyme deficiency: Aromatic L-Amino Acid Decarboxylase (AADC) deficiency. 3-OMD is a validated biomarker specific for this AADC enzyme defect.
The purpose of this study is to assess the prevalence of the elevation of 3-OMD in a predominantly pediatric targeted population with symptoms compatible with AADC deficiency; that will allow us to specify the indications for this screening test according to the clinical symptoms of the patients with the aim, ultimately, of optimizing the diagnosis of AADC deficiency.
详细描述
-O-MethyDopa (3-OMD) is a metabolite of the Dopaminergic pathway that accumulates in case of a default in the neurotransmitter biosynthesis due to a key enzyme deficiency: Aromatic L-Amino Acid Decarboxylase (AADC) deficiency. 3-OMD is a validated biomarker specific for this AADC enzyme defect. (Chen et al., 2014, Chien et al., 2016, Brennenstuhl et al., 2019).
To date, the prevalence of the elevation of 3-OMD has been studied in neonatal screening of healthy newborns and in patients with a previously proven AADC deficiency but not in a target population. (Chen et al., 2014, Chien et al., 2016, Brennenstuhl et al., 2019, Kubaski et al., 2021). The prevalence of elevated plasma 3-OMD, a biomarker of cerebral monoamine neurotransmitters deficiency, has never been evaluated in a targeted population.
The AADC enzyme is encoded by the DDC (Dopa-Decarboxylase) gene. Pathogenic bi-allelic variations of the DDC gene are responsible for a dysfunction of the AADC enzyme, leading to a decrease in the synthesis of biogenic amine neurotransmitters (Dopamine, Serotonin).
AADC deficiency is a rare recessive genetic disease, with less than 200 cases published in the literature. The clinical signs begin in childhood are varied, with a broad phenotypic spectrum, reflecting the deficiency in biogenic amine neurotransmitters: motor impairment, neurodevelopmental abnormalities (delay in acquisitions, cognitive disorders and / or disorders of social interactions), dysautonomia, epileptic seizures. However, there are no specific clinical symptoms and evoking this diagnosis is tricky (Pearson et al., 2020).
A confirmation of the diagnosis requires at least 2 positive tests among: (i) analysis of the profile of cerebrospinal fluid (CSF) neurotransmitters by lumbar puncture (ii) enzymatic study of AADC (iii) genetic study of the DDC gene (Wassenberg et al. al., 2017). The cerebrospinal fluid (CSF) analysis is an invasive examination and the enzymatic study is performed in only a few laboratories. Therefore, it is largely admitted that this pathology is underdiagnosed (Brun et al, 2010, Brennenstuhl et al, 2019, Hyland 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
- Other
- 盲法
- None
入排标准
- 年龄范围
- 0 Days 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient with a neurodevelopmental disorder and presenting one of the following criteria:
- •Motor development delay
- •Cerebral palsy
- •Hypotonia / hypertonia
- •Movement disorders: Oculogyric crises, dystonia, hypokinesia / bradykinesia
- •Catatonia
- •Dysautonomia: ptosis, excessive sweating, intermittent hypothermia, nasal congestion, fluctuating blood pressure
- •Epileptic encephalopathy
- •Autism spectrum disorder
- •Absence of cerebral structural abnormality on MRI apart from corpus callosum abnormality, white matter non-specific abnormality or cerebral atrophy
- •Collection of informed consent signed by both parents or legal guardians and by the child if possible or formed consent signed by adult
- •Patient benefiting from a social security scheme
- •exclusion criteria
- •Patient who had already have a neurotransmitter profiling or a measure of AADC enzymatic activity
- •Patient with a clearly defined anoxo-ischemic history
- •Patient with issues in blood collection
排除标准
- 未提供
结局指标
主要结局
change of plasmatic 3-OMD level beyond 25% of reference value, by age group (0 - 30 days old, 31 - 365 days old, 1 - 10 years old, > 10 years old)
时间窗: Day 0
The prevalence of high 3-OMD level, with 95% confidence interval, will be estimated in the specific population with the frequency of patients with high plasmatic 3-OMD level, over 25% of normal levels defined by age. days old, 31 - 365 days old, 1 - 10 years old, \> 10 years old)
次要结局
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Cerebral Palsy(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Motor Development Delay(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients Movement Disorder(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Epileptic Encephalopathy(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Catatonia(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Dysautonomia(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Hypertonia/Hypotonia(Day 0)
- Comparison of the frequency of high 3-OMD LEVEL among the phenotype of symptomatology of the patients with Autism Spectrum Disorder(Day 0)
- Considering a potential diagnosis of AADC deficiency obtained in current patient care, available besides this study(Day 0)