Mitochondrial ß-oxidation disorders : from screening to diagnosis, fasting metabolism and optimized treatment

Abstract

Mitochondrial beta-oxidation disorders are a group of recessive diseases characterized by fasting intolerance and symptoms ranging from intermittent myalgia and rhabdomyolysis to cardiomyopathy and severe hypoketotic hypoglycemia. The studies in this thesis have focused on some of the unresolved issues regarding the pathogenesis of these disorders and how to best care for patients: phenotype prediction (study I), mitochondrial function (study II) and fasting metabolism (study III and IV).

In study I, the phenotype, biochemical data and clinical outcome of 22 Swedish pediatric patients with VLCADD were related to newborn screening data and VLCAD residual enzyme activity. Patients had a wide phenotypic spectrum, varying from asymptomatic to severely affected cases. The identified correlation between newborn screening results, residual enzyme activity analysis, and clinical outcome could significantly aid in treatment decisions and disease severity prediction.

In study II, mitochondrial respiration and glycolysis in peripheral blood mononuclear cells (PBMCs) from 21 patients with VLCADD, MCADD or CUD were determined using an XFe flux analyzer. PMBCs were suitable for analysis within a 6-hour sampling window, and VLCADD and MCADD cells consistently showed lower mitochondrial respiration rates than CUD cells.

Study III investigated fasting metabolism during a 9-hour night fast in 12 children with VLCADD or MCADD using subcutaneous microdialysis. The VLCADD group showed an earlier fasting-induced initiation of lipolysis compared to the MCADD group, and all patients maintained euglycemia during the fast. Patients with VLCADD with lower residual enzyme activity had an earlier initiation of lipolysis than those with higher enzyme activity.

Study IV investigated the fasting and postprandial hormonal and incretin response after a 4-hour daytime fast and after the intake of a standardized meal in 15 children with LCHADD, VLCADD or MCADD compared to 12 age-matched healthy controls. All participants showed a normal glycemic response, and most fasting hormone fluctuations were similar to those observed in controls. Findings of possible increased risk for insulin resistance in patients with LCHADD and a blunted postprandial incretin response in patients compared to controls warrant further investigation.