Mitochondrial Fatty Acid Oxidation Defects Research Articles

Clinical Spectrum, Diagnosis, and Management of TANGO2 Deficiency Disorder: A Comprehensive Review

TANGO2 deficiency disorder is an autosomal recessive disease caused by biallelic pathogenic variants in the TANGO2 gene. First described in 2016, the disorder is characterized by acute metabolic crises, neurological dysfunctions, developmental delays, and intellectual disabilities. Laboratory findings indicate a mitochondrial fatty acid oxidation defect, with metabolic crises often triggered by stressors such as illness or fasting. The TANGO2 protein, implicated in lipid metabolism, membrane trafficking, and cellular homeostasis, is critical for maintaining lipid droplets, regulating phospholipid levels, and facilitating protein and lipid transport between cellular compartments. Symptoms of TANGO2 deficiency are diverse, including psychomotor delays, intellectual impairments, seizures, ataxia, and episodic neurological symptoms known as TANGO2 spells. Diagnosis involves genetic testing, with several pathogenic variants identified. During metabolic crises, patients may experience severe cardiac and metabolic disturbances. No curative treatment exists; management includes B-vitamin supplementation, antiepileptic drugs, and interventions for spasticity, dystonia, thyroid dysfunction, and arrhythmias. TANGO2 deficiency disorder can co-occur with DiGeorge syndrome, complicating diagnosis due to overlapping symptoms. Improved awareness and diagnostic strategies are crucial for effective management of this underrecognized condition.

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.

Recognizing Mitochondrial Hepatopathy in Acute Fatty Liver of Pregnancy

Acute fatty liver of pregnancy (AFLP) is a rare cause of catastrophic liver dysfunction and failure in late pregnancy. Defective mitochondrial fatty acid oxidation (FAO) seems to be the underlying pathogenic mechanism. Stressors of both late pregnancy (increased maternal dependence on fats as energy source) and fetus with homozygous defect in mitochondrial FAO, precipitate AFLP in a woman who was previously asymptomatic. Mitochondrial disorders exhibit significant clinical heterogeneity, but many of these primary and secondary disorders have liver as the primary organ affected. The liver injury pattern in these patients also has a varied spectrum and course. Unlike other primary mitochondrial disorders affecting the liver, AFLP represents a potentially completely reversible form of liver injury. Thus, AFLP behaves as a secondary mitochondrial disorder precipitated by inciting factors from fetus and placenta. In this review, we attempt to highlight the varied aspects of mitochondrial dysfunction in AFLP. Mitochondrial injury is the mainstay of pathogenesis and can be recognized in typical clinical features and histopathological findings in patients with AFLP. We also present the consequent impact of recognizing underlying mitochondrial injury on clinical diagnosis and management strategies employed in AFLP.

Pkd1 Mutation Has No Apparent Effects on Peroxisome Structure or Lipid Metabolism.

Multiple studies of tissue and cell samples from patients and preclinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities, and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Using control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis, and morphology by immunoblotting, immunofluorescence, and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl;Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C terminus or full-length polycystin-1 colocalize with peroxisome markers by imaging studies. Peroxisome abundance, morphology, and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very-long-chain fatty acids in kidneys of mutant mice. Reanalysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, and provide further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full-length polycystin-1 or its C terminus, a fragment previously shown to go to the mitochondria, showed minimal colocalization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites. Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.

Selective Screening of Fatty Acids Oxidation Defects and Organic Acidemias by Liquid Chromatography/tandem Mass Spectrometry Acylcarnitine Analysis in Brazilian Patients

Inborn errors of metabolism (IEM) are diseases which can lead to accumulation of toxic metabolites in the organism. To investigate, by selective screening, mitochondrial fatty acid oxidation defects (FAOD) and organic acidemias in Brazilian individuals with clinical suspicion of IEM. A total of 7,268 individuals, from different regions of Brazil, had whole blood samples impregnated on filter paper which were submitted to the acylcarnitines analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS) at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre, Brazil, during July 2008-July2016. Our results showed that 68 patients (0.93%) were diagnosed with FAOD (19 cases) and organic acidemias (49 cases). The most prevalent FAOD was multiple acyl CoA dehydrogenase deficiency (MADD), whereas glutaric type I and 3-OH-3-methylglutaric acidemias were the most frequent disorders of organic acid metabolism. Neurologic symptoms and metabolic acidosis were the most common clinical and laboratory features, whereas the average age of the patients at diagnosis was 2.3years. Results demonstrated a high incidence of glutaric acidemia type I and 3-OH-3- methylglutaric acidemia in Brazil and an unexpectedly low incidence of FAOD, particularly medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

A rare case of Mitochondrial Fatty Acid Oxidation Defect- Systemic Primary Carnitine Deficiency

Systemic primary carnitine deficiency (SPCD) also known as, carnitine transporter deficiency (CTD) is an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane, leading to a variety of symptoms such as chronic muscle weakness, cardiomyopathy and hypoglycaemia and liver dysfunction. The first suspicion of SPCD in a patient with a non-specific presentation is an extremely low plasma carnitine level, confirmed by demonstrating reduced carnitine transport in skin fibroblasts from the patient. Treatment for SPCD involves high dose carnitine supplementation, which must be continued for life. We report a case of Systemic primary carnitine deficiency with classical clinical & laboratory characteristics.

Antenatal manifestations of inborn errors of metabolism: biological diagnosis.

Inborn errors of metabolism (IEMs) that present with abnormal imaging findings in the second half of pregnancy are mainly lysosomal storage disorders (LSDs), cholesterol synthesis disorders (CSDs), glycogen storage disorder type IV (GSD IV), peroxisomal disorders, mitochondrial fatty acid oxidation defects (FAODs), organic acidurias, aminoacidopathies, congenital disorders of glycosylation (CDGs), and transaldolase deficiency. Their biological investigation requires fetal material. The supernatant of amniotic fluid (AF) is useful for the analysis of mucopolysaccharides, oligosaccharides, sialic acid, lysosphingolipids and some enzyme activities for LSDs, 7- and 8-dehydrocholesterol, desmosterol and lathosterol for CSDs, acylcarnitines for FAODs, organic acids for organic acidurias, and polyols for transaldolase deficiency. Cultured AF or fetal cells allow the measurement of enzyme activities for most IEMs, whole-cell assays, or metabolite measurements. The cultured cells or tissue samples taken after fetal death can be used for metabolic profiling, enzyme activities, and DNA extraction. Fetal blood can also be helpful. The identification of vacuolated cells orients toward an LSD, and plasma is useful for diagnosing peroxisomal disorders, FAODs, CSDs, some LSDs, and possibly CDGs and aminoacidopathies. We investigated AF of 1700 pregnancies after exclusion of frequent etiologies of nonimmune hydrops fetalis and identified 108 fetuses affected with LSDs (6.3%), 29 of them with mucopolysaccharidosis type VII (MPS VII), and six with GSD IV (0.3%). In the AF of 873 pregnancies, investigated because of intrauterine growth restriction and/or abnormal genitalia, we diagnosed 32 fetuses affected with Smith-Lemli-Opitz syndrome (3.7%).

Stilbenes and resveratrol metabolites improve mitochondrial fatty acid oxidation defects in human fibroblasts

BackgroundInborn enzyme defects of mitochondrial fatty acid beta-oxidation (FAO) form a large group of genetic disorders associated to variable clinical presentations ranging from life-threatening pediatric manifestations up to milder late onset phenotypes, including myopathy. Very few candidate drugs have been identified in this group of disorders. Resveratrol (RSV) is a natural polyphenol with anti-oxidant and anti-inflammatory effects, recently shown to have beneficial metabolic properties in mice models. Our study explores its possible effects on FAO and mitochondrial energy metabolism in human cells, which are still very little documented.MethodsUsing cells from controls and from patients with Carnitine Palmitoyl Transferase 2 (CPT2) or Very Long Chain AcylCoA Dehydrogenase (VLCAD) deficiency we characterized the metabolic effects of RSV, RSV metabolites, and other stilbenes. We also focused on analysis of RSV uptake, and on the effects of low RSV concentrations, considering the limited bioavailability of RSV in vivo.ResultsTime course of RSV accumulation in fibroblasts over 48 h of treatment were consistent with the resulting stimulation or correction of FAO capacities. At 48 h, half maximal and maximal FAO stimulations were respectively achieved for 37,5 microM (EC50) and 75 microM RSV, but we found that serum content of culture medium negatively modulated RSV uptake and FAO induction. Indeed, decreasing serum from 12% to 3% led to shift EC50 from 37,5 to 13 microM, and a 2.6-3.6-fold FAO stimulation was reached with 20 microM RSV at 3% serum, that was absent at 12% serum. Two other stilbenes often found associated with RSV, i.e. cis- RSV and piceid, also triggered significant FAO up-regulation. Resveratrol glucuro- or sulfo- conjugates had modest or no effects. In contrast, dihydro-RSV, one of the most abundant circulating RSV metabolites in human significantly stimulated FAO (1.3-2.3-fold).ConclusionsThis study provides the first compared data on mitochondrial effects of resveratrol, its metabolites, and other natural compounds of the stilbene family in human cells. The results clearly indicate that several of these compounds can improve mitochondrial FAO capacities in human FAO-deficient cells.

Clinical, biochemical and genetic analysis of the mitochondrial disorders presenting with cardiac damage

Mitochondrial disease is a group of energy metabolic disorders, characterized by involvement of multisystem with high energy requirements. Encephalomyopathies are common clinical findings of the mitochondrial diseases. However, mitochondrial cardiac damage is not rare. In this study, the clinical, biological, and genetic analyses were performed in three patients with mitochondrial cardiac damage, in order to understand the characteristics of mitochondrial diseases. Three girls presented with arrhythmia and cardiac enlargement from the age of 3, 4 and 8 years respectively. They were admitted into the Peking University First Hospital. Infection, autoimmune diseases, aminoacidopathies, organic acidurias, mitochondrial-fatty acid oxidation defects, and lysosomal storage disease were excluded by routine laboratory examinations and metabolic analysis for blood amino acids, acylcarnitines, urinary organic acids, and lysosome activity assay. Peripheral leukocytes mitochondrial respiratory chain enzyme I to V activities were measured by spectrophotometry. The entire sequence of the mitochondrial DNA was analyzed. In two patients (case 1 and case 3), hypertrophic cardiomyopathy and grade I to grade II of cardiac function were found. One patient (case 2) was diagnosed with arrhythmia and grade I of cardiac function. Increased creatine phosphokinase and creatine kinase isoenzyme MB were observed. Mitochondrial respiratory chain complex deficiencies were indentified in the three patients. Patient 1 had combined deficiencies of complex III and V. The activity of complex I+III was 18.7 nmol/(min·mg mitochondrial protein) (control 84.4 ± 28.5). The activity of complex V was 20.4 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). In her mitochondrial gene, A14693G on tRNA(Glu) and T16519C on D-loop were found. Patient 2 had an isolated complex I deficiency. The activity was 22.0 nmol/(min·mg mitochondrial protein) (control 44.0 ± 5.4). A16183C, T16189C and G15043A mutations on D-loop were found. Patient 3 had a combined deficiency of complex IV and V. The activity of complex IV was 21.0 nmol/(min·mg mitochondrial protein) (control 54.1 ± 12.3). The activity of complex V was 23.2 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). C253T and C16187T mutations on D-loop were detected. Haplotype analysis showed that three patients belong to H2a2a. Improvement was observed after the treatment with L-carnitine, coenzyme Q10, vitamin C and E. At present, the patients are 7, 5 and 8 years old. Although excise intolerance still persists, they had a good general condition with normal school life. The mitochondrial diseases with cardiac damage show cardiomyopathy, arrhythmia and exercise intolerance. Many kinds of mitochondrial respiratory chain deficiency were observed. A14693G in mitochondrial tRNA(Glu) gene is probably one of the causes in China.

Metabolomics Reveals the role of hypoxia‐inducible factors in hypoxia‐induced liver metabolic shift

Hypoxia‐inducible factor (HIF) is critical in the cellular adaptation to low cellular oxygen. A sustained increase in HIF signaling leads to spontaneous steatosis, inflammation and liver tumorigenesis. However, the metabolic responses and signaling networks regulated by HIFs in the liver are unclear. In the current study, serum from liver‐specific Von Hippel‐Lindau (Vhl)‐deficient mice overexpressing HIF was analyzed by metabolomics using LC‐MS. A dramatic decrease in metabolites involved in fatty acid β‐oxidation, which was correlated with the suppression of genes responsible for β‐oxidation, indicating a mitochondrial fatty acid oxidation defect. GC‐MS data revealed a sustained enrichment of lactate and alanine in serum of Vhl‐deficient mice. However, glutamine, an important energy substrate was robustly increased with these mice. These metabolomics data demonstrate that HIF is responsible for a metabolic shift from oxidative phosphorylation to glycolysis under hypoxia. In addition, many bile acids were found dramatically accumulated in Vhl‐deficient mice, indicating a disruption of liver bile acid metabolism. Taken together, these data reveal a central role for HIF in hepatic and systemic metabolic reprogramming under hypoxia and provide potential biomarkers for liver diseases. This study was funded by National Cancer Institute Intramural Program.

Data mining methods for classification of Medium-Chain Acyl-CoA dehydrogenase deficiency (MCADD) using non-derivatized tandem MS neonatal screening data

Newborn screening programs for severe metabolic disorders using tandem mass spectrometry are widely used. Medium-Chain Acyl-CoA dehydrogenase deficiency (MCADD) is the most prevalent mitochondrial fatty acid oxidation defect (1:15,000 newborns) and it has been proven that early detection of this metabolic disease decreases mortality and improves the outcome. In previous studies, data mining methods on derivatized tandem MS datasets have shown high classification accuracies. However, no machine learning methods currently have been applied to datasets based on non-derivatized screening methods.A dataset with 44,159 blood samples was collected using a non-derivatized screening method as part of a systematic newborn screening by the PCMA screening center (Belgium). Twelve MCADD cases were present in this partially MCADD-enriched dataset. We extended three data mining methods, namely C4.5 decision trees, logistic regression and ridge logistic regression, with a parameter and threshold optimization method and evaluated their applicability as a diagnostic support tool. Within a stratified cross-validation setting, a grid search was performed for each model for a wide range of model parameters, included variables and classification thresholds.The best performing model used ridge logistic regression and achieved a sensitivity of 100%, a specificity of 99.987% and a positive predictive value of 32% (recalibrated for a real population), obtained in a stratified cross-validation setting. These results were further validated on an independent test set. Using a method that combines ridge logistic regression with variable selection and threshold optimization, a significantly improved performance was achieved compared to the current state-of-the-art for derivatized data, while retaining more interpretability and requiring less variables. The results indicate the potential value of data mining methods as a diagnostic support tool.

PONM13 Fatty acid oxidation disorders in adults: a potentially treatable cause of muscle disease

BackgroundThe metabolic myopathies are a heterogeneous group of muscle diseases. The three primary categories include the mitochondrial myopathies, glycogen storage diseases (GSD), and fatty acid oxidation (FAO) defects. Mitochondrial FAO...

Deuterated palmitate-driven acylcarnitine formation by whole-blood samples for a rapid diagnostic exploration of mitochondrial fatty acid oxidation disorders

Background The biochemical diagnosis of mitochondrial fatty acid oxidation defects (FAOD) currently rests on enzyme assays. A dynamic ex vivo exploration consisting of incubations of whole-blood samples with stable-labeled palmitate and determining leukocyte capacities to produce deuterated acylcarnitines was developed on healthy controls ( n = 52) and patients with very-long- (VLCADD) ( n = 2), medium- (MCADD) ( n = 6), or short- (SCADD) ( n = 1) chain acyl-CoA dehydrogenase deficiencies. Methods Incubations were optimized with l-carnitine and [16- 2H 3, 15- 2H 2]-palmitate at 37 °C for various time periods on MCADD and control whole-blood samples. Labeled acylcarnitines were quantified by electrospray-ionization tandem mass spectrometry after thawing, extraction and derivatization to their butyl esters and the method was applied to patients with defects mentioned above. Results The production of acylcarnitines was linear until 6 h of incubation and optimal on 50 to 200 nmol deuterated substrate. A good discrimination between MCADD patient and control data was found, with median C8/C4 acylcarnitine production rate ratios of 81.0 (5th–95th percentile range: 16.6–209.9) and 0.21 (5th–95th percentile range: 0.06–0.79), respectively. The method also discriminated from controls the VLCADD and SCADD patients. Preliminary studies on a healthy control indicated that the storage at 4 °C does little or not alter capacities of whole-blood samples to generate labeled acylcarnitines over a period of 48 h. Conclusion The rapid management afforded by the method, its abilities to characterize patients and to work on whole-blood samples after a stay of 24–48 h at 4 °C make it promising for the diagnostic exploration of FAOD.

Hypoketotic Hypoglycemia with Myolysis and Hypoparathyroidism: An Unusual Association in Medium Chain Acyl-CoA Desydrogenase Deficiency (MCADD)

Medium-chain acyl-CoA deshydrogenase deficiency (MCADD) is the most frequent disorder of mitochondrial fatty acid oxidation (MFAO). We report a 3 year-old girl with enterovirus viremia who was referred after 36 hours of fasting with hypoketotic hypoglycemic coma and myolysis. Evolution was complicated by acute renal failure, increased serum levels of transaminases and hypoparathyroidism. Diagnosis of MCADD was supported by typical plasma acylcarnitine and urinary organic acid profiles, and confirmed by homozygosity for the common missense A985G mutation. Whereas myolysis is frequent in MFAO defects, it is rarely reported as a major accompanying sign in MCADD. Hypoparathyroidism has been previously reported in some MFAO deficiencies but has never been mentioned in association with MCADD. We review the possible mechanisms of hypoparathyroidism in MFAO deficiencies. Parathyroid glands and pancreas dysfunction should be screened in MFAO defects as these organs could be implicated in the clinical spectrum of the frequent A985G MCADD disease-causing mutation.

Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals

A reduction in fatty acid (FA) oxidation has been associated with lipid accumulation and insulin resistance in skeletal muscle of obese individuals. Numerous reports suggest that the reduction in FA oxidation may result from intrinsic mitochondrial defects, although little direct evidence has been offered to support this conclusion. This brief review summarizes recent work from our laboratory that reexamined whether this decrease in skeletal muscle FA oxidation with obesity was attributable to a dysfunction in FA oxidation within mitochondria or simply to a reduction in muscle mitochondrial content. Whole-muscle mitochondrial content and FA oxidation was reduced in the obese, but there was no decrease in the ability of isolated mitochondria to oxidize FA. The mitochondrial content of the transport protein, FA translocase (FAT/CD36), did not differ between lean and obese women but was correlated with mitochondrial FA oxidation. It was concluded that the reduced FA oxidation in obesity is attributable to decreased muscle mitochondrial content and not intrinsic defects in mitochondrial FA oxidation, and that mitochondrial FAT/CD36 is involved in regulating FA oxidation in human skeletal muscle. The reduced skeletal muscle mitochondrial content with obesity may result from impaired mitochondrial biogenesis. However, this did not result from decreased protein contents of various transcription factors, because peroxisome proliferater-activated receptor γ coactivator 1α (PGC1α), PGC1β, peroxisome proliferator-activated receptor α (PPARα), and mitochondrial transcription factor A (TFAM) were not reduced with obesity. In contrast, it appears that obesity is associated with altered regulation of cofactors (PGC1α and PGC1β) and their downstream transcription factors (PPARα, PPARδ/β, and TFAM), because relations among these variables were present in muscle from lean individuals but not from obese individuals. These findings imply that obese individuals would benefit from interventions that increase the skeletal muscle mitochondrial content and the potential for oxidizing FAs.

Carnitine‐palmitoyltransferase 2 deficiency: Novel mutations and relevance of newborn screening

We report on a newborn male, born at term after an uneventful pregnancy presenting with a pathological acylcarnitine profile in routine newborn screening on the third day of life. The profile showed characteristic elevations of C14:0-, C16:0-, C16:1- and C18:1-acylcarnitines, while the ratio of (C16 + C18:1)/C2 was increased, suggesting CPT2- or carnitine-acylcarnitine-translocase- deficiency. The acylcarnitine profile in blood taken on day 9 was normal with breast milk feeding. No dicarboxylic aciduria was found. In fibroblasts, the activity of CPT2 was decreased to 25%, overall oxidation of the long-chain fatty acids was reduced to 10% of control values. Sequence analysis of the CPT2 gene showed heterozygosity for two previously undescribed mutations in exon 4: c.748-749delAA (truncating), and c.1436A > G (p.Tyr479Cys; missense) mutations. The asymptomatic parents were found to be heterozygous, the mother carries the c.748-749delAA and the father the c.1436A > G mutation. The boy is now 2.5 years old; no clinical symptoms associated with the marked impairment of long-chain fatty acid oxidation have occurred. Confirmation of mitochondrial fatty acid oxidation defects from an initial abnormal newborn-screening by tandem mass spectrometry should include enzyme and, if possible, molecular genetic analysis despite a normal 2nd screening. Biochemical testing of urine (organic acids) may be unrevealing.

Mitochondrial fatty acid oxidation defects—remaining challenges

Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3-4 'new' disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the 'old' defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only approximately 50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q(10). With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.

Mice heterozygous for mitochondrial fatty acid oxidation defect are insulin resistant and susceptible for nonalcoholic fatty liver disease

Mice heterozygous for mitochondrial fatty acid oxidation defect are insulin resistant and susceptible for nonalcoholic fatty liver disease

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

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. Hum Mutat 18:169–189, 2001. © 2001 Wiley-Liss, Inc.

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

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.