Despite their seemingly monogenetic nature, many inborn errors of metabolism, such as fatty acid oxidation disorders, have a remarkably heterogeneous clinical presentation making the disease course and severity difficult to predict. In fact, we propose that there is no clear distinction between simple Mendelian disorders and complex diseases, but rather a spectrum of disease phenotypes representing a continuum of diminishing effects from a single gene defect influenced by modifier genes to increasingly shared influence by variants in multiple genes. This realization highlights the need for an unbiased approach to finding candidate modifier genes for seemingly ‘monogenetic’ diseases and reveals the possibility of applying experimental model systems ‘designed’ for complex diseases to inborn errors of metabolism. Our research demonstrates that by employing this method, we can advance our understanding of inborn errors of metabolism by revealing the molecular networks underlying inborn error disease biology.

Mitochondrial fatty acid beta-oxidation (FAO) plays a crucial role in energy homeostasis of organs such as liver, heart and skeletal muscle. During fasting when glucose supply becomes limited, FAO is a vital energy source. For most FAO enzymes, a recessively inherited defect is known, leading to an overall high cumulative incidence (~1 in 10,000). Typical clinical features of these FAO defects are fasting-induced hypoketotic hypoglycemia, and cardiac and skeletal myopathy. Many countries have included FAO defects in their expanded neonatal screening programs. The main reason for screening is the life-threatening hypoglycemia that can lead to coma or sudden death, but can be prevented by avoidance of fasting. The treatment opportunities for (cardio)myopathy are suboptimal and new developments are hampered by a lack of fundamental insight into the consequences of a FAO defect. The goal of this research line is to define the pathogenetic mechanisms that underlie the various symptoms of FAO defects and to design rational therapeutic strategies for patients affected with FAO defects.

Glutaric aciduria type 1 (GA1) is an autosomal recessive inborn error of lysine degradation. Patients can present with brain atrophy and macrocephaly and may develop dystonia after acute encephalopathic crises that lead to striatal degeneration. These crises typically occur in the first year of life and are often triggered by a catabolic state such as those that occur during childhood illnesses. GA1 is caused by a defect of glutaryl-CoA dehydrogenase (GCDH) leading to the accumulation of glutaryl-CoA, glutaric acid and 3-hydroxyglutaric acid, which is thought to be neurotoxic. GA1 is rare (~1 in 100,000), but occurs frequently in some communities and ethnic groups such as the Amish, Ojibwe and Lumbee Indigenous peoples, and black South Africans. GA1 patients benefit from early intervention and the disorder is therefore included in newborn screening programs in many countries including the US. The goal of this research line is to improve current treatment by developing substrate reduction therapy.