P-14 Multiple acyl-coa dehydrogenase deficiency: a possibly treatable condition
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SUBMITTER: Rimoldi M
PROVIDER: S-EPMC3235835 | biostudies-literature | 2011 Oct
REPOSITORIES: biostudies-literature
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Project description:BackgroundMultiple acyl-CoA dehydrogenase (MADD) deficiency represents a rare fatty acid oxidation disorder where sporadic reports of pancreatitis already exist. Here, we report three cases of MADD with pancreatic involvement raising questions whether this represents an incidental finding or it is related to the pathophysiology of MADD.MethodsWe have retrospectively studied the clinical, biochemical and radiologic data of patients with MADD diagnosed in our department over the last 20 years to identify patients with pancreatic involvement.ResultsThree out of 17 patients had pancreatic involvement. All three patients were diagnosed with MADD in the neonatal period (two-third symptomatic-riboflavin nonresponsive, one-third asymptomatic via newborn screening-riboflavin responsive). Age at presentation of pancreatitis ranged from 20 months to 11 years. Presentations included a single episode of acute pancreatitis in the first patient, chronic necrotizing pancreatitis in the second patient, while the third patient was diagnosed with chronic pancreatitis (CP) incidentally through ultrasonography. All patients had inflammation features on either abdominal computed tomography or ultrasound. Pancreatic enzymes were elevated in two patients. Management of pancreatitis was done conservatively while the patient with necrotic CP required subtotal pancreatectomy.DiscussionOur data suggest that pancreatitis might be more common in patients with MADD than previously reported, requiring a high index of suspicion in patients with acute metabolic decompensation or nonspecific abdominal symptoms. We hypothesize that the underlying mechanism of pancreatitis in MADD is similar to that in mitochondrial disorders, both resulting from disordered energy metabolism and oxidative phosphorylation.
| S-EPMC7802625 | biostudies-literature
Project description:BackgroundIn infancy multiple acyl-CoA dehydrogenase deficiency (MADD) is commonly a severe inherited metabolic disease caused by genetic defects in electron transfer flavoprotein (ETF) or ETF ubiquinone oxidoreductase. Both enzymes require flavin adenine dinucleotide (FAD) as a cofactor. Riboflavin (vitamin B2) is a precursor in the synthesis of FAD. MADD can be detected by newborn screening (NBS) based on elevation of multiple acylcarnitines.MethodsWe present the results of two children whose NBS results and subsequent confirmatory testing resulted in a suspected diagnosis of MADD. In parallel in both children vitamin B12 deficiency was detected.ResultsBiochemical profiles normalized rapidly in both children under supplementation with riboflavin. After extensive work-up of both cases including molecular genetic studies there was no indication of MADD. Vitamin B12 deficiency in both children was caused by maternal vitamin B12 deficiency and was rapidly corrected by oral supplementation with vitamin B12 or (partial) formula feeding. As both vitamin B12 and riboflavin have similar food sources we postulate that in these cases positive NBS for MADD was caused by combined maternal vitamin B deficiencies.ConclusionThe differential diagnosis of maternally caused vitamin B deficiencies should be considered in children with abnormal NBS results for MADD, especially in the presence of normal molecular genetic analysis or in case of associated findings of other maternal vitamin B deficiencies like vitamin B12 or folic acid deficiency.
| S-EPMC7941148 | biostudies-literature
Project description:We investigated the in vivo skeletal muscle metabolism in patients with multiple acyl-CoA dehydrogenase deficiency (MADD) during exercise, and the effect of a glucose infusion. Two adults with MADD on riboflavin and l-carnitine treatment and 10 healthy controls performed an incremental exercise test measuring maximal oxidative capacity (VO2max) and a submaximal exercise test (≤1 hour) on a cycle ergometer. During submaximal exercise, we studied fat and carbohydrate oxidation, using stable isotope tracer methodology and indirect calorimetry. On another day, the patients repeated the submaximal exercise receiving a 10% glucose infusion. The patients had a lower VO2max than controls and stopped the submaximal exercise test at 51 and 58 minutes due to muscle pain and exhaustion. The exercise-induced increase in total fatty acid oxidation was blunted in the patients (7.1 and 1.1 vs 12 ± 4 μmol × kg-1 × min-1 in the healthy controls), but total carbohydrate oxidation was higher (67 and 63 vs 25 ± 11 μmol × kg-1 × min-1 in controls). With glucose infusion, muscle pain decreased and average heart rate during exercise dropped in both patients from 124 to 119 bpm and 138 to 119 bpm. We demonstrate that exercise intolerance in MADD-patients relates to an inability to increase fat oxidation appropriately during exercise, which is compensated partially by an increase in carbohydrate metabolism.
| S-EPMC6498824 | biostudies-literature
Project description:BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by variants in ETFA, ETFB, and ETFDH. Recently, riboflavin transporter genes and the mitochondrial FAD transporter gene have also been associated with MADD-like phenotype.MethodsWe present a case of MADD identified by newborn biochemical screening in a full-term infant suggestive of both medium-chain acyl-CoA dehydrogenase deficiency and MADD. Urine organic acid GC/MS analysis was also concerning for both disorders. However, panel sequencing of ETFA, ETFB, ETFDH, and ACADM was unrevealing. Ultimately, a variant in the FAD synthase gene, FLAD1 was found explaining the clinical presentation.ResultsExome sequencing identified compound heterozygous variants in FLAD1: NM_025207.4: c.[442C>T];[1588C>T], p.[Arg148*];[Arg530Cys]. The protein damaging effects were confirmed by Western blot. The patient remained asymptomatic and there was no clinical decompensation during the first year of life. Plasma acylcarnitine and urinary organic acid analyses normalized without any treatment. Riboflavin supplementation was started at 15 months.ConclusionNewborn screening, designed to screen for specific treatable congenital metabolic diseases, may also lead to the diagnosis of additional, very rare metabolic disorders such as FLAD1 deficiency. The case further illustrates that even milder forms of FLAD1 deficiency are detectable in the asymptomatic state by newborn screening.
| S-EPMC6732309 | biostudies-literature
Project description:In this report, we describe the case of an 11-year-old boy, who came to our attention for myalgia and muscle weakness, associated with inappetence and vomiting. Hypertransaminasemia was also noted, with ultrasound evidence of hepatomegaly. Biochemical investigations revealed acylcarnitine and organic acid profiles resembling those seen in MADD, that is, multiple acyl-CoA dehydrogenase deficiencies (OMIM #231680) a rare inherited disorder of fatty acids, amino acids, and choline metabolism. The patient carried a single pathogenetic variant in the ETFDH gene (c.524G>A, p.Arg175His) and no pathogenetic variant in the riboflavin (Rf) homeostasis related genes (SLC52A1, SLC52A2, SLC52A3, SLC25A32, FLAD1). Instead, compound heterozygosity was found in the ACAD8 gene (c.512C>G, p.Ser171Cys; c.822C>A, p.Asn274Lys), coding for isobutyryl-CoA dehydrogenase (IBD), whose pathogenic variants are associated to IBD deficiency (OMIM #611283), a rare autosomal recessive disorder of valine catabolism. The c.822C>A was never previously described in a patient. Subsequent further analyses of Rf homeostasis showed reduced levels of flavins in plasma and altered FAD-dependent enzymatic activities in erythrocytes, as well as a significant reduction in the level of the plasma membrane Rf transporter 2 in erythrocytes. The observed Rf/flavin scarcity in this patient, possibly associated with a decreased ETF:QO efficiency might be responsible for the observed MADD-like phenotype. The patient's clinical picture improved after supplementation of Rf, l-carnitine, Coenzyme Q10, and also 3OH-butyrate. This report demonstrates that, even in the absence of genetic defects in genes involved in Rf homeostasis, further targeted molecular analysis may reveal secondary and possibly treatable biochemical alterations in this pattern.
| S-EPMC9259400 | biostudies-literature
Project description:The human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant's metabolome reveals a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit β and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.
| S-EPMC8593149 | biostudies-literature
Project description:BACKGROUND:Multiple acyl-CoA dehydrogenase deficiency (MADD) showed great clinical heterogeneity and poses a challenge to diagnosis. Guillain-Barré syndrome (GBS) is an acute-onset autoimmune-mediated peripheral neuropathy. However, no patients of acute-onset MADD mimicking the GBS phenotype are reported previously. CASE PRESENTATION:Two patients displayed acute-onset limb weakness, areflexia, and length-dependent sensory disturbances, which clinically indicate the diagnosis of GBS, but electrophysiological and cerebrospinal fluid results threw doubtful points to the initial diagnosis. The muscle biopsy showed lipid storage disorder; and compound heterozygous mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene were found in the two patients through targeted next generation sequencing, which provided the definite diagnostic evidences of late-onset MADD. Muscle weakness was quickly improved by riboflavin supplementation, but sensory disturbances required a long-term treatment. DISCUSSION:The present two cases have demonstrated that MADD can mimic GBS. Taking into consideration the significant differences of therapeutic regimen and prognosis, MADD should be included in the differential diagnosis of GBS.
| S-EPMC6306005 | biostudies-literature
Project description:BACKGROUND: Multiple Acyl-CoA-Dehydrogenase deficiency (MADD) is an inherited metabolic disorder characterized by impaired oxidation of fatty acids and some amino acids. METHODS: We were interested whether children with MADD could tolerate a prolonged low-intensity exercise test and if this test could have any additional diagnostic value. Therefore, we performed a maximal exercise test and a low-intensity prolonged exercise test in 2 patients with MADD and in 5 control subjects. During a prolonged exercise test the subjects exercised on a cycle ergometer at a constant workload of 30% of their maximum for 90 minutes and heart rate, oxygen uptake, fuel utilization and changes in relevant blood and urinary parameters were monitored. RESULTS: The tests were tolerated well. During the prolonged exercise test the fatty acid oxidation (FAO) was quite low compared to 5 control subjects, while characteristic metabolites of MADD appeared in plasma and urine. CONCLUSION: We suggest that the prolonged exercise test could be of diagnostic importance and might replace the fasting test as a diagnostic procedure in some cases, particularly in patients with anamnestic signs of intolerance for prolonged exercise.
| S-EPMC1159171 | biostudies-literature
Project description:Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing SCAD gene mutations and/or variants. SCAD gene variants are present in homozygous form in approximately 6% of the general population and considered to confer susceptibility to development of clinical disease. Clinically, SCADD generally appears to present early in life and to be most frequently associated with developmental delay, hypotonia, epilepsy, behavioral disorders, and hypoglycemia. However, these symptoms often ameliorate and even disappear spontaneously during follow-up and were found to be unrelated to the SCAD genotype. In addition, in some cases, symptoms initially attributed to SCADD could later be explained by other causes. Finally, SCADD relatives of SCADD patients as well as almost all SCADD individuals diagnosed by neonatal screening remained asymptomatic during follow-up. This potential lack of clinical consequences of SCADD has several implications. First, the diagnosis of SCADD should never preclude extension of the diagnostic workup for other potential causes of the observed symptoms. Second, patients and parents should be clearly informed about the potential lack of relevance of the disorder to avoid unfounded anxiety. Furthermore, to date, SCADD is not an optimal candidate for inclusion in newborn screening programs. More studies are needed to fully establish the relevance of SCADD and solve the question as to whether SCADD is involved in a multifactorial disease or represents a nondisease.
| S-EPMC2946545 | biostudies-literature
Project description:Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a severe mitochondrial disorder featuring multi-organ dysfunction. Mutations in either the ETFA, ETFB, and ETFDH genes can cause MADD but very little is known about disease specific mechanisms due to a paucity of animal models. We report a novel zebrafish mutant dark xavier (dxa(vu463) ) that has an inactivating mutation in the etfa gene. dxa(vu463) recapitulates numerous pathological and biochemical features seen in patients with MADD including brain, liver, and kidney disease. Similar to children with MADD, homozygote mutant dxa(vu463) zebrafish have a spectrum of phenotypes ranging from moderate to severe. Interestingly, excessive maternal feeding significantly exacerbated the phenotype. Homozygous mutant dxa(vu463) zebrafish have swollen and hyperplastic neural progenitor cells, hepatocytes and kidney tubule cells as well as elevations in triacylglycerol, cerebroside sulfate and cholesterol levels. Their mitochondria were also greatly enlarged, lacked normal cristae, and were dysfunctional. We also found increased signaling of the mechanistic target of rapamycin complex 1 (mTORC1) with enlarged cell size and proliferation. Treatment with rapamycin partially reversed these abnormalities. Our results indicate that etfa gene function is remarkably conserved in zebrafish as compared to humans with highly similar pathological, biochemical abnormalities to those reported in children with MADD. Altered mTORC1 signaling and maternal nutritional status may play critical roles in MADD disease progression and suggest novel treatment approaches that may ameliorate disease severity.
| S-EPMC3681725 | biostudies-literature