Mcad Deficiency Clinical Trial
Official title:
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
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.
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.
Main study parameters/endpoints: Dynamics of both traditional clinical and biochemical
metabolic parameters and unbiased multi-omics (metabolomics, lipidomics, and proteomics)
parameters will be studied.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: The trial is considered to be a low-risk study. The clinical research team at
the UMCG has a longstanding tradition of performing supervised controlled clinical fasting
test in patients with inborn errors of metabolism, for diagnostic as well as research
purposes. No adverse effects are expected during fasting in otherwise healthy infants with
MCADD. The study holds three moderate burdens for participants: insertion of the indwelling
IV catheter, the discomfort of fasting for the subject and the parent(s) or guardian(s), and
the time consumption. However, subjects and their parents(s) may directly benefit from the
results of this study by reduction of stress concerning feeding, under normal, healthy
circumstances and the (possible) institution of a personalized feeding regimen based on the
study results by the treating pediatrician. As this project will substantiate current
management guidelines and aims to identify new (prognostic) biomarkers, it may further
improve the outcomes of future MCADD patients and their parent(s) or guardian(s), by
reduction of (unnecessary) parental stress, treatment and follow-up.
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