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Results for “Multiple Acyl Coenzyme A Dehydrogenase Deficiency”

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At least 19 recordsLinked to original sources
PubMed2004

The role of methionine in ethylmalonic encephalopathy with petechiae.

BACKGROUND: Among patients with ethylmalonic aciduria, a subgroup with encephalopathy, petechial skin lesions, and often death in infancy is distinct from those with short-chain acyl-coenzyme A dehydrogenase deficiency or multiple acyl-coenzyme A dehydrogenase deficiency. The nature of the molecular defect in this subgroup is unknown, and the source of the ethylmalonic acid has been unclear. OBJECTIVE: To determine whether the administration of candidate amino acids increased the excretion of ethylmalonic acid. DESIGN: Examination of patterns of organic acids excreted in the urine before and following loading doses of isoleucine and methionine. SETTING: General clinical research center. PATIENT: An infant with ethylmalonic aciduria, global developmental delay, acrocyanosis, and intermittent showers of petechiae. MAIN OUTCOME MEASURE: Excretion of ethylmalonic acid in the urine. RESULTS: Loading with methionine increased the excretion of ethylmalonic acid, whereas loading with isoleucine did not. Restriction of the dietary intake of methionine decreased ethylmalonic acid excretion. CONCLUSION: In ethylmalonic acid encephalopathy with petechiae, methionine is a precursor of ethylmalonic acid.

Amino Acids↗
PubMed2026

A Family Exhibiting Autosomal Dominant Inheritance of Multiple Acyl-Coenzyme A (CoA) Dehydrogenase Deficiency (MADD) Disease.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an autosomal recessive disorder; yet, recent findings suggest up to 10% of cases may result from heterozygous electron transfer flavoprotein dehydrogenase (ETFDH) variants exhibiting dominant or dominant-like effects. Here, a novel heterozygous ETFDH variant (c.1798A>C, p.Asn600His) was identified within a three-generation family. The grandfather presented with muscular weakness at age 35, and the father developed similar symptoms at 19 following a tonsillectomy. Both were diagnosed with MADD based on muscle biopsies revealing neutral lipid accumulation and acylcarnitine profiles and responded fully to riboflavin therapy (150 mg/day). The two siblings, aged 8 and 10, carry the same mutation and show increased acyl-carnitine levels but remain asymptomatic due to early riboflavin treatment. Skin fibroblasts from affected individuals were immortalized and subjected to normal and reduced riboflavin levels. Gene expression analysis demonstrated unchanged ETFDH RNA but reduced protein levels in mutant cells, particularly under low riboflavin. Structural modelling suggested the Asn600His substitution destabilizes the protein, diminishing its mitochondrial function. Proximity ligation assays indicated a decreased interaction with mitochondrial complex III, while oxygen consumption via fatty acid oxidation was impaired, especially at reduced riboflavin. The novel ETFDH variant found in this family gives a possible dominant pattern of inheritance for MADD, where a single mutant allele impairs the mitochondrial metabolism, particularly under riboflavin-deficient conditions, and highlights the importance of early riboflavin supplementation in preventing clinical symptoms.

Humans↗
PubMed1994

Symmetric hypoplasia of the temporal cerebral lobes in an infant with glutaric aciduria type II (multiple acyl-coenzyme A dehydrogenase deficiency).

Symmetric hypoplasia of the temporal cerebral lobes was demonstrated by magnetic resonance imaging of the brain in a macrocephalic male patient with glutaric aciduria type II within the first week of life. Psychomotor development was normal until the age of 11 months, when the patient died of sudden cardiac arrest. Autopsy revealed symmetric hypoplasia of the temporal cerebral lobes with loss of axons and hypomyelination in the temporal medullary layers.

Fatal Outcome↗
PubMed1999

Riboflavin therapy. Biochemical heterogeneity in two adult lipid storage myopathies.

Two unrelated adult males, aged 36 (patient 1) and 25 (patient 2) years, presented with subacute carnitine-deficient lipid storage myopathy that was totally and partly responsive to riboflavin supplementation in the two patients, respectively. Plasma acyl-carnitine and urinary organic acid profiles indicated multiple acyl coenzyme A dehydrogenase deficiency, which was mild in patient 1 and severe in patient 2. The activities of short-chain and medium-chain acyl coenzyme A dehydrogenases in mitochondrial fractions were decreased, especially in patient 2. This was in agreement with Western blotting results. Flavin-dependent complexes I and II were studied by immunoblotting and densitometric quantification of two-dimensional electrophoresis with comparable results. Complex I was present in normal amounts in both patients, whereas complex II was decreased only in the pretherapy muscle of patient 2. Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) concentrations in muscle and isolated mitochondria, and the activity of mitochondrial FAD pyrophosphatase, showed that patient 1 had low levels of FAD (46%) and FMN (49%) in mitochondria, with a significant increase (P < 0.01) in mitochondrial FAD pyrophosphatase (273%) compared with controls. Patient 2 had similar low levels of FAD and FMN in both total muscle (FAD and FMN 22% of controls) and mitochondria (FAD 26%; FMN 16%) and normal activity of mitochondrial FAD pyrophosphatase. All of these biochemical parameters were either totally or partly corrected after riboflavin therapy.

Adult↗
PubMed1994

Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency.

We studied the effect of riboflavin treatment on the clinical status and on the activities of beta-oxidation and respiratory chain enzymes in a 69-year-old patient with late-onset myopathy. Before treatment, she was very weak and wasted in the limbs and trunk muscles; also, she could not walk or attend to daily activities. Marked lipid storage was present in the muscle biopsy. The activities of short-chain acyl coenzyme A (acyl-CoA) dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) in isolated muscle mitochondria were reduced to less than 10% of control values. This defect in fatty acid oxidation was associated with a marked deficiency of two flavin-dependent respiratory chain complexes: complex I activity was 20% and complex II activity was 25% of control values. By contrast, the activities of the nonflavin-dependent complex III and complex IV were normal. Western blot analysis of the patient's muscle mitochondrial extracts with antibodies raised against purified SCAD, MCAD, and the alpha- and beta-subunits of the electron transfer flavoprotein (ETF) showed absence of SCAD cross-reacting material (CRM), markedly decreased MCAD-CRM, and normal amounts of both alpha- and beta-ETF-CRM. After riboflavin treatment, the patient's clinical status dramatically improved and morphologic changes in muscle disappeared. SCAD activity increased to 55% of control values, whereas MCAD, LCAD, and complex I and complex II activities normalized. SCAD and MCAD immunoreactivity was restored to normal. On the basis of our experience and the data in the literature, we concluded that some lipid storage myopathies can show dramatic response to riboflavin.

Acyl-CoA Dehydrogenase↗
PubMed1991

Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency: functional evaluation of recovery after high dose vitamin supplementation.

The effect of riboflavin supplementation on muscle performance and exercise metabolism was investigated in four patients with multiple acyl-coenzyme A dehydrogenase deficiency (MAD). Maximum oxygen consumption and endurance measurements were performed to assess the patients' aerobic capacity and energy metabolism during exercise. They were tested before and after treatment with pharmacological doses of riboflavin. The initially low maximum oxygen consumption and high levels of blood lactate during submaximal exercise suggest that the oxidation of both fatty acids and carbohydrates was severely impaired. All four patients experienced a dramatic improvement in aerobic performance under riboflavin supplementation.

Acyl-CoA Dehydrogenases↗
PubMed1993

Detection of inborn errors of fatty acid oxidation from acylcarnitine analysis of plasma and blood spots with the radioisotopic exchange-high-performance liquid chromatographic method.

Sixty-one plasma samples from patients with inborn errors of fatty acid oxidation and from control subjects were analyzed in a blinded fashion for acylcarnitines by the radioisotopic exchange-high-performance liquid chromatographic method. All samples from patients with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency (n = 30), some of which had been stored in a frozen state for several years, showed a prominent octanoylcarnitine peak. In all blood spots from 11 patients with MCAD deficiency, octanoylcarnitine was also detected. Control plasma specimens and blood spots contained small amounts of octanoylcarnitine; however, the octanoylcarnitine/acetylcarnitine ratio differentiated patients with MCAD deficiency. Longer-chain acylcarnitines were found in plasma of all three patients with defects in long-chain fatty acid oxidation. Plasma and blood spots from a patient with multiple acyl-coenzyme A dehydrogenase deficiency contained C4-acylcarnitine, hexanoylcarnitine, octanoylcarnitine, and decanoylcarnitine. The results suggest that the method may be highly sensitive in detecting MCAD deficiency and other defects in fatty acid oxidation from plasma or blood spots.

Acyl-CoA Dehydrogenase↗
PubMed1993

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of fatty acid catabolism, with autosomal recessive inheritance. The disease is characterized by episodic illness associated with potentially fatal hypoglycemia and has a relatively high frequency. A rapid and reliable method for the diagnosis of MCAD deficiency is highly desirable. Analysis of specific acylcarnitines was performed by isotope-dilution tandem mass spectrometry on plasma or whole blood samples from 62 patients with MCAD deficiency. Acylcarnitines were also analyzed in 42 unaffected relatives of patients with MCAD deficiency and in other groups of patients having elevated plasma C8 acylcarnitine, consisting of 32 receiving valproic acid, 9 receiving medium-chain triglyceride supplement, 4 having multiple acyl-coenzyme A dehydrogenase deficiency, and 8 others with various etiologies. Criteria for the unequivocal diagnosis of MCAD deficiency by acylcarnitine analysis are an elevated C8-acylcarnitine concentration (> 0.3 microM), a ratio of C8/C10 acylcarnitines of > 5, and lack of elevated species of chain length > C10. These criteria were not influenced by clinical state, carnitine treatment, or underlying genetic mutation, and no false-positive or false-negative results were obtained. The same criteria were also successfully applied to profiles from neonatal blood spots retrieved from the original Guthrie cards of eight patients. Diagnosis of MCAD deficiency can therefore be made reliably through the analysis of acylcarnitines in blood, including presymptomatic neonatal recognition. Tandem mass spectrometry is a convenient method for fast and accurate determination of all relevant acylcarnitine species.

Acyl-CoA Dehydrogenase↗
PubMed2000

Quantitative analysis of urinary acylglycines for the diagnosis of beta-oxidation defects using GC-NCI-MS.

The analysis of acylglycines is an important biochemical tool for the diagnosis of inherited disorders of mitochondrial fatty acid beta-oxidation. A stable isotope dilution gas chromatography negative chemical ionisation mass spectrometry method for the quantitative analysis of short- and medium-chain acylglycines as their bis(trifluoromethyl)benzyl (BTFMB) ester derivatives is described. The diagnostic usefulness of the method was demonstrated in nine patients with medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency, and seven patients with multiple acyl-CoA dehydrogenation defect (MAD). The urinary acylglycine profiles in these patients were compared to those in controls (n = 19), children on a medium-chain triglyceride (MCT) supplemented diet (n = 4), and patients with various other diseases (n = 5).

Acyl Coenzyme A↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed1994

A riboflavin-responsive lipid storage myopathy due to multiple acyl-CoA dehydrogenase deficiency: an adult case.

A 62-year-old man was admitted to our hospital because of easy fatigability of the lower limbs during walking. The biopsied muscle specimen showed excessive lipid accumulation. The carnitine concentration in the muscle was at the lower level of the normal range. Organic acid urinalysis was consistent with the diagnosis of multiple acyl-CoA dehydrogenase deficiency or glutaric acidemia type II. In cultured lymphoblastoid cells from this patient there was impaired beta-oxidation, but the activities of acyl-CoA dehydrogenases were normal. Riboflavin therapy resulted in a dramatic improvement in both clinical and biochemical aspects. In this patient, the defect in coenzyme binding to electron transfer flavoprotein (ETF) or ETF-dehydrogenase was suspected. In the adult case of lipid storage myopathy, multiple acyl-CoA dehydrogenase deficiency should be suspected as one of its pathogenesis and riboflavin therapy should be considered.

Acyl-CoA Dehydrogenases↗
PubMed1980

Glutaric aciduria type II: in vitro studies on substrate oxidation, acyl-CoA dehydrogenases, and electron-transferring flavoprotein in cultured skin fibroblasts.

The previous biochemical evidence had suggested that glutaric aciduria type II (GA II) is due to deficient dehydrogenation of multiple short-chain acyl coenzyme A's (CoA's), bu the precise biochemical mechanism underlying this disease was unknown. We investigated substrate oxidation and in vitro activities of isovaleryl CoA- and butyryl CoA dehydrogenases as well as that of electron-transferring flavoprotein (ETF) in cultured skin fibroblasts from a patient with GA II. GA II cells have a markedly decreased ability to oxidize [1-14C]butyrate, [2-14C]lysine, and [2,14C]leucine (3, 9, and 9% of control values, respectively). Mitochondrial isovaleryl CoA- and butyryl CoA dehydrogenase activities in GA II cells were determined using a tritium release assay with [2,3-3H] acyl-CoA's as substrate. When an artificial electron acceptor, phenazine methosulfate (PMS) was not added in the assay media, these activities were 108 and 113% of controls, respectively. This represents the normal abilities of the dehydrogenases in GA II cells to bind the substrate and to catalyze tritium exchange between the bound substrate and solvent. When PMS was added to the assay mixture, these activities were 88 and 70% of control values, respectively, indicating that these enzymes can both dehydrogenate their substrates normally and then transfer electrons to an acceptor (PMS). ETF activity in mitochondrial sonic supernatants from GA II cells, as assessed by a newly devised method, was 159% of control values. These observations suggest that the acyl CoA dehydrogenases themselves and ETF are not defective in GA II. Therefore, the deficiency of another common gene product necessary for the function of all the affected acyl CoA dehydrogenases must be sought to explain the etiology of GA II.

Acyl Coenzyme A↗
PubMed1987

Complementation analysis of fatty acid oxidation disorders.

We assayed [9,10(n)-3H]palmitate oxidation by fibroblast monolayers from patients with fatty acid oxidation disorders. Activities in the different disorders were (percent control): short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (115%), medium chain acyl-CoA dehydrogenase deficiency (18%), long-chain acyl-CoA dehydrogenase deficiency (28%), multiple acyl-CoA dehydrogenation disorder, mild and severe variants (49% and 7%), and palmityl-carnitine transferase deficiency (4%). Multiple acyl-CoA dehydrogenation disorder, medium chain acyl-CoA dehydrogenase-deficient lines, and long-chain acyl-CoA dehydrogenase-deficient lines all complemented one another after polyethylene glycol fusion, with average activity increases of 31-83%. We detected two complementation groups in the severe multiple acyl-CoA dehydrogenation disorder lines, consistent with deficiencies of either electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase. The metabolic block in the latter cell lines is threefold more severe than in the former (P less than 0.001). No intragenic complementation was observed within either group. We assigned two patients with previously unreported severe multiple acyl-CoA dehydrogenation disorder to the electron transfer flavoprotein:ubiquinone oxido-reductase-deficient group.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1985

Riboflavin-responsive defects of beta-oxidation.

The key reaction in the beta-oxidation of fatty acids is the acyl-CoA dehydrogenation, catalyzed by short chain, medium chain, and long chain acyl-CoA dehydrogenases. Acyl-CoA dehydrogenation reactions are also involved in the metabolism of the branched chain amino acids, where isovaleryl-CoA and 2-methylbutyryl-CoA dehydrogenases are involved and in the metabolism of lysine, 5-hydroxylysine and tryptophan, where glutaryl-CoA dehydrogenase functions. In all of these dehydrogenation systems reducing equivalents are transported to the main respiratory chain by electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETFDH), which are common to all the dehydrogenation systems. The acyl-CoA dehydrogenation enzymes are dependent on flavin adenine dinucleotide (FAD) as coenzyme, for which riboflavin is the precursor. Patients with multiple acyl-CoA dehydrogenation deficiencies have been found in whom the defect has been located to ETF and/or ETFDH. A few patients with multiple acyl-CoA dehydrogenation deficiencies have been described, in whom no defects in acyl-CoA dehydrogenases, ETF or ETFDH have been found but who respond clinically and biochemically to pharmacological doses of riboflavin. This indicates a defect related to the metabolism of FAD. An uptake defect of riboflavin or a synthesis defect of FAD from riboflavin have been excluded by in vivo and in vitro studies. A mitochondrial transport defect of FAD or a defect in the binding FAD to ETF and/or ETFDH remains possible.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1987

Chemical diagnosis of inherited defects of fatty acid metabolism and ketogenesis.

Urinary organic acid profiles in patients with inherited defects of fatty acid metabolism and ketogenesis are described. Medium-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, multiple acyl-CoA dehydrogenase, and 3-hydroxy-3-methyl-glutaryl-CoA lyase deficiencies can be recognized at the metabolite level. Data on long-chain acyl-CoA dehydrogenase and systemic carnitine deficiencies are scarce. In the latter disorders, dicarboxylic aciduria is rather nonspecific and points to a modest omega-oxidation of long chain fatty acids.

Acyl Coenzyme A↗