fasting tolerance in mcadd-infants

Conditions: Mcad Deficiency

Summary: 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.

Eligibility criteria:
inclusion criteria: * 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. exclusion criteria: * any other chronic and/or genetic condition that is deemed an exclusion criterion based on the judgement of the treating metabolic paediatrician.

Keywords: mcad deficiency phenotypic variation biomarkers diet therapy