Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

Abstract

Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…Similar to other FAO diseases, SCAD disease can be divided into subgroups based on age of presentation, which can either be in infancy/early childhood or in late adulthood. In infants, developmental delay, hypotonia and myopathy are common [118]. In addition, ethylmalonic aciduria is a common feature of SCAD deficiency, and as such is a commonly used biomarker of the disease [116].…”

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

“…The available literature is biased by reports of symptomatic patients; consequently, genotype-phenotype correlation studies concern more severe presentations. These studies show that nonsense mutations in the encoding gene (ACADVL) result in a severe and early presentation of cardiomyopathy, [12][13][14] but the more frequent missense mutations are associated with both severe or attenuated presentations. 10 Functional tests, including determination of the residual activity of the VLCAD enzyme, 10,15 have been used to test the effects of various mutations on LC-FAO activity.…”

Fatty Acid Oxidation Disorders in a Chinese Population in Taiwan

“…Impaired transfer of electrons affects multiple dehydrogenation reactions and is thus termed multiple acylCoA dehydrogenase (MAD) deficiency. FAO disorders can present with life-threatening symptoms, such as hypoketotic hypoglycemia, Reye-like syndrome in infants (Brivet et al 1999;Baruteau et al 2009;Spiekerkoetter 2010), acute encephalopathy (Gregersen et al 2001;Spiekerkoetter 2010), cardiomyopathy (Bonnet et al 1999;Spiekerkoetter et al 2009a), myolysis (Spiekerkoetter et al 2009a;van Adel and Tarnopolsky 2009), and liver dysfunction (Clayton 2003). Currently more than 15 distinct FAO disorders have been elucidated based on enzymatic and/or molecular analyses (Gregersen et al 2008).…”