Fasting Tolerance in Patients With Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCADD) in the First Six Months of Life: an Investigator-initiated Human Pilot-study
试验速览
- 阶段
- 不适用
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Change in Respiratory rate
研究概览
简要总结
MCAD deficiency (MCADD; #OMIM 201450) is the most common inherited disorder of mitochondrial fatty acid oxidation. Already before the introduction of population newborn bloodspot screening (NBS), large phenotypic heterogeneity was observed between MCADD-patients, ranging between deceased patients and asymptomatic subjects. Most clinically ascertained patients were homozygous for the common c.985A>G ACADM mutation. After NBS, newborns with novel ACADM-genotypes have been identified and subjects can be classified as either severe/classical or mild/variant MCADD-patients.
Dietary management guidelines are based on expert opinion, limited experimental data summarized in one retrospective study on fasting tolerance in 35 MCADD patients. Interestingly, data are absent from fasting tolerance in MCADD patients between 0-6 months of age. These guidelines cause parental stress, especially for young patients. Moreover, the guidelines do not take into account the heterogeneity between patients, including the classification between severe versus mild MCADD-patients. The investigators question whether at least a subset of the MCADD-patients is overtreated with these guidelines.
Therefore, the investigators propose this pilot-study on fasting tolerance in 10 subjects with severe MCADD and 10 subjects with mild MCADD at the ages of two and six months. Differences between subsets of MCADD-patients will be studied longitudinally by both traditional metabolic parameters and unbiassed metabolomics, lipidomics and proteomics approach. This project will substantiate current management guidelines and aims to identify new (prognostic) biomarkers.
详细描述
Rationale: MCAD deficiency (MCADD; #OMIM 201450) is the most common inborn error of mitochondrial fatty acid oxidation. Already before the introduction of population newborn bloodspot screening (NBS), large phenotypic heterogeneity was observed between MCADD patients, ranging between deceased patients and asymptomatic subjects. Most clinically ascertained patients were homozygous for the common c.985A>G ACADM mutation. After the introduction of the disorder to the NBS, newborns with novel ACADM-genotypes have been identified. Subjects can be classified as either severe/classical or mild/variant MCADD patients. Dietary management guidelines are based on expert opinion and limited experimental data summarized in one retrospective study on fasting tolerance in 35 MCADD-patients. Interestingly, data are absent from the fasting tolerance of MCADD patients between 0-6 months of age. These guidelines cause parental stress, especially regarding young patients (0-6 months). Moreover, the guidelines do not take into account the heterogeneity between patients, including the classification between severe versus mild MCADD patients. The investigators question whether at least a subset of the MCADD patients is overtreated with these guidelines.
Objective: The main objective of the study is to explore the fasting tolerance in MCADD-patients of two and six months of life. Second, it is aimed to compare fasting tolerance and biochemical dynamics between subsets of MCADD patients. Third, it is aimed to identify novel diagnostic and/or prognostic biomarkers. The last objective is to elucidate the (fundamental) origin of phenotypical differences between MCADD patients.
Study design: Longitudinal, prospective investigator-initiated human pilot-study.
Study population: Otherwise healthy infants with severe MCADD and mild MCADD at the ages of two and six months of life.
Intervention: During two visits, the included infants will be fasted according to local standardized procedures at the University Medical Centre Groningen (UMCG). Fasting will take place under continuous blood glucose monitoring and bedside supervision by an experienced, dedicated pediatric nurse in collaboration with a metabolic pediatrician, who will be available to attend the patient instantly. During visit 1, at two months of life, fasting will be continued for maximally eight hours. During visit 2, at six months of life, fasting will be continued for maximally twelve hours. Fasting will be ended prematurely if; (a) the blood glucose concentration drops < 3.6 mmol/L, (b) the fasting subject shows symptoms/signs of a low blood glucose concentration, and/or (c) subject's parent(s) or guardian(s) request the end of fast.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 2 Months 至 6 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A child must be at least younger than 6 months of life at inclusion. In case of prematurity, the child will be included and treated according to the adjusted age.
- •Established MCADD diagnosis. The diagnosis should be confirmed by a combination of (a) NBS outcome (b) MCAD enzyme activity measured with phenylpropionyl-CoA as a substrate, ideally in lymphocytes (considered to be the golden standard) and (c) ACADM gene mutation-analysis.
排除标准
- •Any other chronic and/or genetic condition that is deemed an exclusion criterion based on the judgement of the treating metabolic paediatrician.
研究组 & 干预措施
Severe/classical MCADD
Severe MCADD will be defined by ACADM mutations associated with clinical ascertainment or residual MCAD enzyme activity < 10 %, as defined previously (Touw et al., 2012).
Interventions include fasting challenges at two and six months of age.
干预措施: Fasting test (Other)
Mild MCADD
Mild MCADD will be defined by the remaining ACADM genotype variants and residual MCAD enzyme activity ≥ 10%.
Interventions include fasting challenges at two and six months of age.
干预措施: Fasting test (Other)
结局指标
主要结局
Change in Respiratory rate
时间窗: Up to 8 frequencies will be noted during the maximally 8 hour fast (session 1), up to 12 frequencies will be noted during the maximally 12 hour fast (session 2).
Respiratory rate per minute will be noted at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.
Change in plasma free fatty acid (FFA) concentrations
时间窗: Up to 8 samples will be taken during the maximally 8 hour fast (session 1), up to 12 samples will be taken during the maximally 12 hour fast (session 2).
Sample #1 will be collected at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.
Change in Heart rate
时间窗: Up to 8 frequencies will be noted during the maximally 8 hour fast (session 1), up to 12 frequencies will be noted during the maximally 12 hour fast (session 2)
Heart rate per minute will be noted at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.
Change in blood glucose concentrations
时间窗: Up to 8 samples will be taken during the maximally 8 hour fast (session 1), up to 12 samples will be taken during the maximally 12 hour fast (session 2).
Sample #1 will be collected at baseline (8:00 AM) and hereafter hourly during the fast of session 1 and session 2.
(Change in) presence of lethargy
时间窗: Up to 8 physical examinations will be performed during the maximally 8 hour fast (session 1), up to 12 physical examinations will be performed during the maximally 12 hour fast (session 2). Physical examinations will take 5 minutes.
Physical examination will be performed hourly by a nurse during the fast of session 1 and session 2. Yes/no; if yes, #hours, minutes.
(Change in) presence of trembling
时间窗: Up to 8 physical examinations will be performed during the maximally 8 hour fast (session 1), up to 12 physical examinations will be performed during the maximally 12 hour fast (session 2). Physical examinations will take 5 minutes.
Physical examination will be performed hourly by a nurse during the fast of session 1 and session 2. Yes/no; if yes, #hours, minutes.
次要结局
- Continuous glucose monitoring (CGM) data(Blood glucose concentrations will be sensored every 5 minutes, during the maximally 8 hour fast (session 1). Blood glucose concentrations will be sensored every 5 minutes, during the 12 hour fast (session 2).)
- Plasma ketones concentrations (β-hydroxybutyrate, acetoacetate)(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Plasma bicarbonate concentrations(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Lipidomics(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Blood pH(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Base excess(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Plasma amino acid concentrations(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Blood oxygen partial pressure(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Plasma acylcarnitines concentrations(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Blood carbon dioxide partial pressure(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Blood oxygen saturation(3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2).)
- (Untargeted) Metabolomics(3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
- Proteomics(3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2).)
- Urine organic acids concentrations(2 samples will be collected during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).)
研究者
Terry G.J. Derks, MD, PhD
Principal Investigator
University Medical Center Groningen