Mitochondrial Fatty Acid Oxidation Disorders: Laboratory Diagnosis, Pathogenesis, and the Complicated Route to Treatment

Abstract

Mitochondrial fatty acid (FA) oxidation deficiencies represent a genetically heterogeneous group of diseases in humans caused by defects in mitochondrial FA beta-oxidation (mFAO). A general characteristic of all mFAO disorders is hypoketotic hypoglycemia resulting from the enhanced reliance on glucose oxidation and the inability to synthesize ketone bodies from FAs. Patients with a defect in the oxidation of long-chain FAs are at risk to develop cardiac and skeletal muscle abnormalities including cardiomyopathy and arrhythmias, which may progress into early death, as well as rhabdomyolysis and exercise intolerance. The diagnosis of mFAO-deficient patients has greatly been helped by revolutionary developments in the field of tandem mass spectrometry (MS) for the analysis of acylcarnitines in blood and/or urine of candidate patients. Indeed, acylcarnitines have turned out to be excellent biomarkers; not only do they provide information whether a certain patient is affected by a mFAO deficiency, but the acylcarnitine profile itself usually immediately points to which enzyme is likely deficient. Another important aspect of acylcarnitine analysis by tandem MS is that this technique allows high-throughput analysis, which explains why screening for mFAO deficiencies has now been introduced in many newborn screening programs worldwide. In this review, we will describe the current state of knowledge about mFAO deficiencies, with particular emphasis on recent developments in the area of pathophysiology and treatment.

Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Do not Improve with Carnitine Supplementation

“…This provided us the opportunity to investigate the effects of carnitine on cardiomyocytes derived from this patient-specific hiPSC line in detail, but further studies are needed to test the carnitine effects on other VLCADD models. In the present study, we focused on LCAC concentrations and electrophysiology in hiPSC-CMs but VLCADD has a broad clinical spectrum ( Ribas and Vargas, 2020 ; Wanders et al, 2020 ). In future studies, our VLCADD hiPSC line may also be differentiated to a liver and skeletal muscle cell fate ( van der Wall et al, 2018 ; Corbett and Duncan, 2019 ) to assesses the effects of VLCADD and potential treatment in these cell types.…”

“…Patients with a deficiency in very long-chain acyl-CoA dehydrogenase (VLCAD; EC 1.3.99.3), the enzyme catalyzing the first step of the mitochondrial beta-oxidation of long-chain fatty acids ( Houten and Wanders, 2010 ; Knottnerus et al, 2018 ), are at risk for developing liver, skeletal, and heart muscle dysfunction ( Ribas and Vargas, 2020 ; Wanders et al, 2020 ), including cardiac arrhythmias ( Bonnet et al, 1999 ). Traditionally patients with VLCAD deficiency (VLCADD; OMIM 609575) are treated with dietary restriction of long-chain triglycerides, supplementation of medium-chain triglycerides, and prevention of catabolic state ( Yamada and Taketani, 2019 ).…”

“…Carnitine is required for the transport of activated long-chain fatty acids into the mitochondrial matrix, by formation of long-chain acylcarnitines (LCAC) from acyl-CoA esters, and is therefore essential for fatty acid oxidation ( Houten and Wanders, 2010 ). In humans, carnitine is mainly derived from the diet, but can also be synthesized by the liver, kidney and brain ( Vaz and Wanders, 2002 ; Reuter and Evans, 2012 ; Wanders et al, 2020 ). Tissues like skeletal muscle and the heart acquire carnitine from the circulation.…”

Mitochondrial Fatty Acid β-Oxidation and Resveratrol Effect in Fibroblasts from Patients with Autism Spectrum Disorder

“…As mentioned above, screening of inborn mtFAO deficiencies in newborns is based on acyl-carnitines analysis in dried blood spots, which needs to be followed by confirmatory testing to define the ultimate diagnosis [19]. Importantly, patients diagnosed in this way at birth are mostly asymptomatic, and the AC pattern is not predictive of symptomatology [29].…”

“…Thus, AC enables the transport of fatty acids across mitochondrial membranes, and these conjugated fatty acids typically accumulate when β-oxidation is disturbed. This led to widespread clinical applications in the screening for inborn mtFAO disorders in newborns, implemented in many countries, which is based on the detection of specific accumulating AC in the blood of newborns [19]. In line with this, it can be hypothesized that the increase in plasma AC levels in patients with ASD points to an impairment of mtFAO.…”