Disorder Of Mitochondrial Fatty Acid Oxidation Research Articles

Enterobacteriaceae Growth Promotion by Intestinal Acylcarnitines, a Biomarker of Dysbiosis in Inflammatory Bowel Disease

Altered plasma acylcarnitine levels are well-known biomarkers for a variety of mitochondrial fatty acid oxidation disorders and can be used as an alternative energy source for the intestinal epithelium when short-chain fatty acids are low. These membrane-permeable fatty acid intermediates are excreted into the gut lumen via bile and are increased in the feces of patients with inflammatory bowel disease (IBD). Herein, based on studies in humansubjects, animal models, and bacterial cultures, we show a strong positive correlation between fecal carnitineand acylcarnitines and the abundance of Enterobacteriaceae in IBD where they can be consumed by bacteria both invitro and invivo. Carnitine metabolism promotes the growth of Escherichia coli via anaerobic respiration dependent on the cai operon, and acetylcarnitine dietary supplementation increases fecal carnitine levels with enhanced intestinal colonization of the enteric pathogen Citrobacter rodentium. In total, these results indicate that the increased luminal concentrations of carnitine and acylcarnitines in patients with IBD may promote the expansion of pathobionts belonging to the Enterobacteriaceae family, thereby contributing to disease pathogenesis.

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges.

Since the identification of the first disorder of mitochondrial fatty acid oxidation defects (FAOD) in 1973, more than 20 defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders, which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.

Cardiologic evaluation of Turkish mitochondrial fatty acid oxidation disorders.

Mitochondrial fatty acid oxidation disorders (FAODs) cause impairment in energy metabolism and can lead to a spectrum of cardiac pathologies including cardiomyopathy and arrhythmias. The frequency of underlying cardiac pathologies and the response to recommended treatment in FAODs was investigated. Sixty-eight children (35 males, 33 females) with the diagnosis of a FAOD were included in the study. Cardiac function was evaluated with 12-lead standard electrocardiography, echocardiography, and 24 h Holter monitoring. Forty-five patients (66%) were diagnosed after disease symptoms developed and 23 patients (34%) were diagnosed in the pre-symptomatic period. Among symptomatic patients (n: 45), cardiovascular findings were detected in 18 (40%) patients, including cardiomyopathy in 14 (31.1%) and conduction abnormalities in 4 (8.8%) patients. Cardiac symptoms were more frequently detected in primary systemic carnitine deficiency (57.1%). Patients with multiple acyl-CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and mitochondrial trifunctional protein deficiencies also had an increased frequency of cardiac symptoms. Patients with medium-chain acyl-CoA dehydrogenase, very long-chain acyl-CoA dehydrogenase, and carnitine palmitoyltransferase I deficiencies had a lower prevalence of cardiac symptoms both during admission and during clinical follow up. Cardiomyopathy resolved completely in 8/14 (57%) patients and partially in 2/14 (14.3%) patients with treatment. Two patients with cardiomyopathy died in the newborn period; cardiomyopathy persisted in 1 (7.1%) patient with very long-chain acyl-CoA dehydrogenase deficiency. Early diagnosis, treatment and follow up made a significant contribution to the improvement of cardiac symptoms of patients with FAODs.

Carnitine Cycle Defect in Newborn: A Rare Case Report

Carnitine Acylcarnitine Translocase (CACT) deficiency and Carnitine Palmitoyl Transferase (CPT I and II) deficiency comes under a group of disorders called mitochondrial fatty acid oxidation disorders, due to defects in the carnitine cycle. The CPT and CACT enzymes play a pivotal role in the transfer of Long Chain Fatty Acids (LCFA) from the cytoplasm to the mitochondrial matrix, where β-oxidation take place. In the present case, a male baby presented on day 2 of life with chief complaints of respiratory distress, apnoea, lethargy and seizures. The baby had multiple episodes of hypoglycaemia and seizures after admission. Diagnosis was made with the help of extended newborn screening using Tandem Mass Spectrometry (TMS) showing accumulation of hexadecanoyl carnitine due to CACT/CPT II deficiency. Echocardiography showed features of cardiomyopathy with cardiomegaly. Liver Function Test (LFT) and Prothrombin Time-International Normalisation Ratio (PT-INR) of the child was also deranged, with hypotonia of all muscles. Early detection along with carnitine supplementation and further prevention of fasting episodes resulted in generalised improvement of the baby. So, a high degree of suspicion of Inborn Error of Metabolism (IEM) and timely diagnosis can save the baby

AFLP and LCHAD deficiency – a systematic literature review

The cause of AFLP is not identified in most of the cases. However, some literature has investigated the role of mitochondrial fatty acid oxidation (FAO) disorders as a cause, specifically long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We performed a systematic literature review to evaluate the association between AFLP and LCHAD.

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases.

Mitochondrial fatty acid β-oxidation (FAO) contributes a large proportion to the body’s energy needs in fasting and in situations of metabolic stress. Most tissues use energy from fatty acids, particularly the heart, skeletal muscle and the liver. In the brain, ketone bodies formed from FAO in the liver are used as the main source of energy. The mitochondrial fatty acid oxidation disorders (FAODs), which include the carnitine system defects, constitute a group of diseases with several types and subtypes and with variable clinical spectrum and prognosis, from paucisymptomatic cases to more severe affectations, with a 5% rate of sudden death in childhood, and with fasting hypoketotic hypoglycemia frequently occurring. The implementation of newborn screening programs has resulted in new challenges in diagnosis, with the detection of new phenotypes as well as carriers and false positive cases. In this article, a review of the biochemical markers used for the diagnosis of FAODs is presented. The analysis of acylcarnitines by MS/MS contributes to improving the biochemical diagnosis, both in affected patients and in newborn screening, but acylglycines, organic acids, and other metabolites are also reported. Moreover, this review recommends caution, and outlines the differences in the interpretation of the biomarkers depending on age, clinical situation and types of samples or techniques.

Novel mutation in carnitine palmitoyltransferase 1A detected through newborn screening for a presymptomatic case in China: a case report

BackgroundCarnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare mitochondrial fatty acid oxidation (FAO) disorder that results in hypoketotic hypoglycemia and hepatic encephalopathy. It is caused by mutation in CPT1A. To date, only two symptomatic cases of CPT1A deficiency have been reported in China.Case presentationA newborn male, without any disease-related clinical manifestations, was diagnosed with CPT1A deficiency through newborn screening. Increased free carnitine levels and a significantly increased C0/(C16 + C18) ratio were detected by tandem mass spectrometry, and subsequently, mutations in CPT1A were found by gene sequence analysis. The patient was advised a low-fat, high-protein diet and followed up regularly. During three-years of follow-up since, the patient showed normal growth velocity and developmental milestones. Whole-exome sequence identified two mutations, c.2201 T > C (p.F734S) and c.1318G > A (p.A440T), in the patient. The c.2201 T > C mutation, which has been reported previously, was inherited from his father, while the c.1318G > A, a novel mutation, was inherited from his mother. The amino acid residues encoded by original sequences are highly conserved across different species. These mutations slightly altered the three-dimensional structure of the protein, as analyzed by molecular modeling, suggesting that they may be pathogenic.ConclusionThis is the first case of CPT1A deficiency detected through newborn screening based on diagnostic levels of free carnitine, in China. Three years follow-up suggested that early diagnosis and diet management may improve the prognosis in CPT1A patient. In addition, we identified a novel mutation c.1318G > A in CPT1A,and a possible unique to Chinese lineage mutation c.2201 T > C. Our findings have expanded the gene spectrum of this rare condition and provided a basis for family genetic counseling and prenatal diagnosis.

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency

BackgroundVery long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. Patients and methodsWe conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. ResultsThe number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients’ ability to conduct everyday activities was also improved by the treatment. ConclusionOur findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.

Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1Prx1-/- mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1Prx1-/- mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.

Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience

IntroductionMitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience. Materials and methodsWe analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up. ResultsWe diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic. Discussion and conclusionsOur study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well.

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

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.

Detection of allele frequencies of common c. 511C>T and c.625G>A variants in the ACADS gene in the Turkish population.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare inborn error of mitochondrial fatty acid oxidation and protein misfolding disorder. Our aim was to detect the number of Turkish patients diagnosed with SCADD in the literature and to determine the allele frequencies of two common variants (c.511C > T and c.625G > A) in the Turkish population. Five Turkish patients with SCADD were reported in the literature from four unrelated families. We also investigated allele frequencies of common variants of c.511C > T and c.625G > A, which confer susceptibility to SCADD, which were found to be 1.7% and 20.2%, respectively. Both of these susceptibility variants were found to be high in the Turkish population as they are worldwide.

Slc22a5 haploinsufficiency does not aggravate the phenotype of the long-chain acyl-CoA dehydrogenase KO mouse.

Secondary carnitine deficiency is commonly observed in inherited metabolic diseases characterised by the accumulation of acylcarnitines such as mitochondrial fatty acid oxidation (FAO) disorders. It is currently unclear if carnitine deficiency and/or acylcarnitine accumulation play a role in the pathophysiology of FAO disorders. The long-chain acyl-CoA dehydrogenase (LCAD) KO mouse is a model for long-chain FAO disorders and is characterised by decreased levels of tissue and plasma free carnitine. Tissue levels of carnitine are controlled by SLC22A5, the plasmalemmal carnitine transporter. Here, we have further decreased carnitine availability in the LCAD KO mouse through a genetic intervention by introducing one defective Slc22a5 allele (jvs). Slc22a5 haploinsufficiency decreased free carnitine levels in liver, kidney, and heart of LCAD KO animals. The resulting decrease in the tissue long-chain acylcarnitines levels had a similar magnitude as the decrease in free carnitine. Levels of cardiac deoxycarnitine, a carnitine biosynthesis intermediate, were elevated due to Slc22a5 haploinsufficiency in LCAD KO mice. A similar increase in heart and muscle deoxycarnitine was observed in an independent experiment using Slc22a5jvs/jvs mice. Cardiac hypertrophy, fasting-induced hypoglycemia and increased liver weight, the major phenotypes of the LCAD KO mouse, were not affected by Slc22a5 haploinsufficiency. This may suggest that secondary carnitine deficiency does not play a major role in the pathophysiology of these phenotypes. Similarly, our data do not support a major role for toxicity of long-chain acylcarnitines in the phenotype of the LCAD KO mouse.

Medium- and Short-Chain L-3-Hydroxyl-Acetyl-Coenzyme A Deficiency: A New Identified Mutation in Four Cases

Abstract Medium- and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD, SCHAD) deficiency is a mitochondrial fatty acid oxidation disorder (FAOD). This enzyme catalyzes the penultimate step in fatty acid oxidation, the NAD+ dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA for medium- and short-chain acyl-CoA intermediates (C4-C12). The clinical presentations of most patients are recurrent hypoglycemia associated with hyperinsulinism. We presented four infants with C4 acyl-carnitine elevation identified by newborn screening that also showed an unusual phenotype of congenital hypotonia and gross developmental delay. Enzymatic studies confirmed the disease. Sequencing analysis of all the HADH coding exons on the four patients revealed a homozygous variant of a novel change (c.908G>T, p.Gly303Val). Western blot analysis subsequently confirmed the lack of the SCHAD protein. In addition, there is another previously reported benign variant (c.257T>C) identified in three infants. Therefore, we postulate that the HADH variant (c.908G>T) is indeed pathogenic and associated with a severe phenotype as evidenced by the cases described herein. Population screening for the c.908G>T mutation suggests this mutation to be common among Puerto Ricans. We recommend that SCHAD deficiency is included as part of the differential diagnosis of all infants with congenital hypotonia.

Carnitine palmitoyltransferase II deficiency with a focus on newborn screening.

Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder. Its clinical phenotypes are classified into the muscle, severe infantile, and lethal neonatal forms. Among Caucasians, the muscle form predominates, and the c.338C > T (p.S113L) variant is detected in most cases, whereas among the Japanese, c.1148T > A (p.F383Y) is the variant allele occurring with the highest frequency and can apparently cause symptoms of the severe infantile form. Newborn screening (NBS) for this potentially fatal disease has not been established. We encountered an infantile case of CPT II deficiency not detected in NBS using C16 and C18:1 concentrations as indices, and therefore we adopted the (C16 + C18:1)/C2 ratio as an alternative primary index. As a result, the disease was diagnosed in nine of 31 NBS-positive subjects. The values for (C16 + C18:1)/C2 in the affected newborns partly overlapped with those in unaffected ones. Among several other indices proposed previously, C14/C3 has emerged as a more promising index. Based on these findings, nationwide NBS for CPT II deficiency using both (C16 + C18:1)/C2 and C14/C3 as indices was officially approved and started in April 2018. We diagnosed the disease in four young children presenting with symptoms of the muscle form, whose values for the new indices were not elevated. Although it is still difficult to detect all cases of the muscle form of CPT II deficiency in NBS, our system is expected to save many affected children in Japan with the severe infantile form predominating.

Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency.

Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in β-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine-acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required.

Mitochondrial Fatty Acid Oxidation Disorders Associated with Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency.

Mitochondrial fatty acid β-oxidation (FAO) is the primary pathway for fatty acid metabolism in humans, performing a key role in liver, heart and skeletal muscle energy homeostasis. FAO is particularly important during times of fasting when glucose supply is limited, providing energy for many organs and tissues, including the heart, liver and brain. Deficiencies in FAO can cause life-threatening metabolic disorders in early childhood that present with liver dysfunction, hypoglycemia, dilated hypertrophic cardiomyopathy and Reye-like Syndrome. Alternatively, FAO defects can also cause ‘milder’ adult-onset disease with exercise-induced myopathy and rhabdomyolysis. Short-chain enoyl-CoA hydratase (ECHS1) is a key FAO enzyme involved in the metabolism of fatty acyl-CoA esters. ECHS1 deficiency (ECHS1D) also causes human disease; however, the clinical manifestation is unlike most other FAO disorders. ECHS1D patients commonly present with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy traditionally associated with defects in oxidative phosphorylation (OXPHOS). In this article, we review the clinical, biochemical and genetic features of the ESHS1D patients described to date, and discuss the significance of the secondary OXPHOS defects associated with ECHS1D and their contribution to overall disease pathogenesis.

Fluxomic assay-assisted diagnosis orientation in a cohort of 11 patients with myopathic form of CPT2 deficiency

Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation. In these patients, CPT2 gene studies was prompted by prior fluxomic explorations of mitochondrial β-oxidation on intact whole blood cells incubated with pentadeuterated ([16-2H3, 15-2H2])-palmitate. Clinical indication for fluxomic explorations was at least one acute rhabdomyolysis episode complicated, in 5 of 11 patients, by acute renal failure. Major trigger of rhabdomyolysis was febrile infection. In all patients, fluxomic data indicated deficient CPT2 function showing normal deuterated palmitoylcarnitine (C16-Cn) formation rates associated with increased ratios between generated C16-Cn and downstream deuterated metabolites (Σ deuterated C2-Cn to C14-Cn). Subsequent gene studies showed in all patients pathogenic gene variants in either homozygous or compound heterozygous forms. Consistent with literature data, allelic frequency of the c.338C > T[p.Ser113Leu] mutation amounted to 68.2% in our cohort. Other missense mutations included c.149C > A[p.Pro50His] (9%), c.200C > G[p.Ala200Gly] (4.5%) and previously unreported c.1171A > G[p.ser391Gly] (4.5%) and c.1420G > C[p.Ala474Pro] (4.5%) mutations. Frameshift c.1666-1667delTT[p.Leu556val*16] mutation (9%) was observed in two patients unknown to be related.

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders.

This review focuses on advances made in the past three years with regards to understanding the mitochondrial fatty acid oxidation (FAO) pathway, the pathophysiological ramifications of genetic lesions in FAO enzymes, and emerging therapies for FAO disorders. FAO has now been recognized to play a key energetic role in pulmonary surfactant synthesis, T-cell differentiation and memory, and the response of the proximal tubule to kidney injury. Patients with FAO disorders may face defects in these cellular systems as they age. Aspirin, statins, and nutritional supplements modulate the rate of FAO under normal conditions and could be risk factors for triggering symptoms in patients with FAO disorders. Patients have been identified with mutations in the ACAD9 and ECHS1 genes, which may represent new FAO disorders. New interventions for long-chain FAODs are in clinical trials. Finally, post-translational modifications that regulate fatty acid oxidation protein activities have been characterized that represent important new therapeutic targets. Recent research has led to a deeper understanding of FAO. New therapeutic avenues are being pursued that may ultimately cause a paradigm shift for patient care.

Mitochondrial Fatty Acid Oxidation Disorders Associated with Cardiac Disease

To elucidate the role metabolic pathways have on pathophysiological mechanisms involving the heart, it is essential to understand how biochemical pathways influence pathophysiology, clinical findings, and treatment. In this review, we focus on fatty acid oxidation disorders that affect the heart. We enumerate the defects that arise from each step of fatty acid oxidation leading to cardiomyopathy, conduction defects, arrhythmias, and sudden death. With the advent of newborn screening, careful interpretation of diagnostic findings and early treatment, morbidity, and mortality associated with these conditions have significantly decreased. However, treatment of the energy defect alone is not enough. New potential therapies and pathobiological mechanisms will be mentioned. Mitochondrial fatty acid oxidation disorders associated with energy defects leading to cardiac disease are reviewed (clinical, biochemical findings and treatment); while highlighting the biochemical pathways involved in the pathophysiology of these disorders.