Multiple Acyl-CoA Dehydrogenase (MCAD) Deficiency (MADD) / Glutaric Acidemia Type II

• Usually autosomal recessive - gene
• Involves deficiency of several mitochondrial dehydrogenase enzymes that utilize flavin adenine dinucleotide (FAD) as cofactor, at least nine of which are known, including the acyl-CoA dehydrogenases of fatty acid beta-oxidation and enzymes that degrade glutaric acid, isovaleric acid and sarcosine (a precursor to glycine). During these dehydrogenation reactions, reduced FAD contributes its electrons to the oxidized form of electron transfer flavoprotein (ETF) and subsequently to the respiratory chain to produce ATP. The reduced form of ETF is recycled to oxidized ETF by action of ETF-ubiquinone oxidoreductase (ETF-QO, also known as ETF dehydrogenase). Deficiency of ETF or ETF-QO therefore results in decreased activity of many FAD-dependent dehydrogenases and the combined metabolic derangements seen in MADD. Some MADD patients have had normal ETF and ETF-QO, suggesting the existence of genetic defects in other unidentified proteins.
• Clinical
  • Three clinical presentations are reported for MADD, including two newborn presentations - one with congenital anomalies, the other without.
    • With congenital anomalies - often premature, develop symptoms in the first 24–48 hours consisting of hypotonia, hepatomegaly, severe nonketotic hypoglycemia, metabolic acidosis and variable body odor of sweaty feet. Dysmorphic facial features and dysplastic, cystic kidneys are present. Plasma carnitine levels are low.
    • Without congenital anomalies have similar symptoms and metabolic abnormalities. With both neonatal presentations, most patients do not live past a few weeks, though some older survivors succumb at a few months of age from hypertrophic cardiomyopathy. Heart, liver and kidneys are infiltrated with fat.
    • Third type has a mild and/or later onset with variable symptoms including lipid storage myopathy.
• Lab findings
  • Blood spot/tandem mass spectrometry - elevated acylcarnitine (C4, C5, C8, C10, and C16).
  • Severe hypoglycemia without ketosis is a cardinal finding.
  • Urine analysis for abnormal organic acids usually reveals elevated glutaric acid, and always shows elevated 2-hydroxyglutaric acid which is pathognomonic.
  • Plasma and urine sarcosine levels are elevated in the milder patients, but not in the severe neonatal cases.
  • Cultured fibroblasts and amniocytes have been used to measure dehydrogenase substrate oxidation.
  • Prenatal diagnosis has been performed by finding elevated glutaric acid and elevated acylcarnitines in amniotic fluid.
  • Mutations have been identified in the genes for ETF and ETF-QO. Prenatal diagnosis by DNA analysis is restricted to those families in which the mutation(s) is known.
• Treatment
  • There is no effective treatment for the severe forms of MADD that present in the neonatal period.
  • Patients with later onset less severe symptoms may respond to riboflavin (a precursor to FAD) and L-carnitine supplementation.
  • Dietary restriction of fats and protein has had variable results.
  • L-carnitine - yes
• Sources - Pediatrix;

Also:

• Google - Multiple acyl-CoA dehydrogenase deficiency
• OMIM
• eMedicine
• Multiple Acyl-CoA-Dehydrogenase Deficiency (MADD): Use of Acylcarnitines and Fatty Acids to Monitor the Response to Dietary Treatment
• Multiple acyl-CoA dehydrogenase deficiency: a rare cause of acidosis with an increased anion gap

Brain. 2007 Jun 20.
ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.
Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA.
The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark, Department of Clinical Chemistry, Sheffield Children's Hospital, Sheffield, UK, Institute of Human Genetics and The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark, Department of Medicine & Therapeutics, University of Aberdeen, Aberdeen, UK, Department of Child Health, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK, Centro de Diagnóstico de Enfermedades Moleculares, Centro Biología Molecular ‘Severo Ochoa’, Universidad Autónoma, Madrid, Spain, Department of Pediatrics, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado, USA, Royal Liverpool Children's NHS Trust, Alder Hey Hospital, Department of Medical Genetics, Medical School, University of Aberdeen, Aberdeen, UK, Department of Neurology, Department of Pathology, Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Neurology, Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne and Willink Unit, Royal Manchester Children's Hospital, Manchester, UK.

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.

Brain. 2007 Apr 5.
The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.
Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH, Palmafy B, Kale G, Tokatli A, Quinzii C, Hirano M, Naini A, Dimauro S, Prokisch H, Lochmuller H, Horvath R.
Metabolic Disease Center Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics; etc.

Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with heterogenous phenotypic manifestations and genetic background. We describe seven patients from five independent families with an isolated myopathic phenotype of CoQ10 deficiency. The clinical, histological and biochemical presentation of our patients was very homogenous. All patients presented with exercise intolerance, fatigue, proximal myopathy and high serum CK. Muscle histology showed lipid accumulation and subtle signs of mitochondrial myopathy. Biochemical measurement of muscle homogenates showed severely decreased activities of respiratory chain complexes I and II + III, while complex IV (COX) was moderately decreased. CoQ10 was significantly decreased in the skeletal muscle of all patients. Tandem mass spectrometry detected multiple acyl-CoA deficiency, leading to the analysis of the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII). All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. Our results indicate that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Since this condition is treatable, correct diagnosis is of the utmost importance and should be considered both in children and in adults. We suggest to give patients both CoQ10 and riboflavin supplementation, especially for long-term treatment.

Clin Chim Acta. 1996 Aug 30.
Acylcarnitine removal in a patient with acyl-CoA beta-oxidation deficiency disorder: effect of L-carnitine therapy and starvation.
Fontaine M, Briand G, Vallee L, Ricart G, Degand P, Divry P, Vianey-Saban C, Vamecq J.
Laboratoire de Biochimie, Hopital Huriez, Centre Hospitalo-Universitaire de Lille, France.

Carnitine levels and acylcarnitine profiles in a patient with mild multiple acyl-CoA dehydrogenase deficient beta-oxidation were compared with control results. Whereas blood and urine total carnitine levels were moderately decreased, blood esterified carnitine levels in the patient were about 2-fold higher than in controls. Urinary acylcarnitine profiles presented with a larger variety of carnitine esters than in controls and included propionylcarnitine, butyrylcarnitine, 2-methylbutyrylcarnitine, hexanoylcarnitine and octanolycarnitine. Total carnitine levels in body fluids were similarly affected by chronic oral L-carnitine administration in patient and controls. By contrast, esterified carnitine level increase was 2-fold more important in controls than in patient. Whereas no qualitative changes in urinary acylcarnitine profiles were induced by L-carnitine therapy in controls, several alterations of these profiles were observed in the patient. The effect of starvation on metabolites was also studied, especially beta-oxidation rates assessed by free fatty acids to 3-hydroxybutyric acid ratios in blood from the patient in the untreated and L-carnitine treated states. In the L-carnitine-supplemented patient, the effect of starvation on the time course of carnitine levels and acylcarnitine profiles could also be documented. The ability of chronic oral L-carnitine administration to remove relatively less important amounts of acylcarnitines in the patient than in controls is further discussed, as well as qualitative alterations of acylcarnitine profiles induced by this therapy in the pathological condition.

J Inherit Metab Dis. 1994.
Production and disposal of medium-chain fatty acids in children with medium-chain acyl-CoA dehydrogenase deficiency.
Heales SJ, Thompson GN, Massoud AF, Rahman S, Halliday D, Leonard JV.
Institute of Child Health, London, UK.

The effect of fasting on plasma concentrations of fatty acids has been determined in four children with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In addition, the in vivo rate of octanoate oxidation was measured, using [1-13C]octanoate. In the three older children (1.5-11.2 years), fasting for up to 18 h stimulated lipolysis, as reflected by the increasing concentration of free fatty acids, but with little rise in concentrations of medium-chain fatty acids, octanoate, decanoate and cis-4-decenoate. In an infant (0.5 year), lipolysis was greater and was accompanied by rising concentrations of medium-chain fatty acids. After 13.5 h there was a rapid increase in the concentration of decanoate and cis-4-decenoate. The calculated in vivo rate of octanoate oxidation was substantial in all patients studied (6.4-13.1 mumol/kg per h) despite very low MCAD activity in vitro. It is concluded that under basal conditions the in vivo oxidation rate of medium-chain fatty acids is near normal in the four children studied with MCAD deficiency.

J Pediatr. 1993 May.
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.
Schmidt-Sommerfeld E, Penn D, Duran M, Bennett MJ, Santer R, Stanley CA.
Department of Pediatrics, University of Chicago, Illinois.

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.

Pediatr Res. 1985 Jul.
Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes.
Coates PM, Hale DE, Stanley CA, Corkey BE, Cortner JA.

Medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency was demonstrated in fibroblasts and/or mononuclear leukocytes from 14 patients, most of whom initially presented early in childhood with a Reye-like syndrome associated with hypoketotic hypoglycemia, dicarboxylic aciduria, and low levels of plasma carnitine. Parents of these patients had intermediate levels of medium-chain acyl CoA dehydrogenase activity, consistent with their being heterozygous for an autosomal recessive trait. All patients had normal levels of long-chain acyl CoA dehydrogenase activity, but had reduced short-chain acyl CoA dehydrogenase activity. Fatty acid oxidation was examined in cultured fibroblasts from five of the patients, using a series of 14C-labeled fatty acids of different chain length (palmitic, octanoic, and butyric). Oxidation of [1-14C]-octanoic acid was less than 20% of control levels: [1-14C], [6-14C]-, [16(14)C]-, and [14C(U)]-palmitic acid oxidation rates were 88, 51, 13, and 42% of control rates, respectively. [1-14C]-butyric acid was oxidized normally. These data extend our previous findings of medium-chain acyl CoA dehydrogenase deficiency in liver tissue from three of these patients. They demonstrate the value of cultured fibroblasts and leukocytes in the diagnosis and evaluation of inherited disorders of fatty acid oxidation.

Pediatr Res. 1983 Nov.
Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels.
Stanley CA, Hale DE, Coates PM, Hall CL, Corkey BE, Yang W, Kelley RI, Gonzales EL, Williamson JR, Baker L.

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.

Pediatr Res. 1982 Oct.
C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects.
Gregersen N, Wintzensen H, Christensen SK, Christensen MF, Brandt NJ, Rasmussen K.

The abnormal metabolites - adipic, suberic, and sebacic acids - were detected in large amounts in the urine of a boy during a Reye's syndrome-like crisis. Substantial amounts of 5-OH-caproic acid, caproylglycine, glutaric acid, and 3-OH-butyric acid and moderately elevated amounts of ethylmalonic acid, methylsuccinic acid, 3-OH-isovaleric acid, and isovalerylglycine were also found. These metabolites were consistently present in urine samples collected in the boy's habitual condition after the attack. 1-[14C]-Palmitic acid was oxidized at a normal rate, whereas U-[14C]-Palmitic acid was oxidized at a reduced rate in cultured skin fibroblasts from the patient, thus indicating a defect at the level of medium- and/or short-chain fatty acid oxidation. Riboflavin medication (100 mg three times a day) significantly reduced the excreted amounts of pathologic metabolites, suggesting a flavineadeninedinucleotide-related acyl-CoA dehydrogenation defect as the cause of the disease. Carnitine in plasma was low in the patient (6 mumole/liter, controls 26-74 mumole/liter), suggesting carnitine deficiency as a secondary effect of the acyl-CoA dehydrogenation deficiency. The present patient, who presented with a Reye's syndrome-like attack, suffers from impaired dehydrogenation of acyl-CoA resulting in accumulation of acyl-CoA in the cells. Attacks with similar symptoms are seen in other acyl-CoA dehydrogenation deficiencies, such as glutaric aciduria types I and II, other types of C6-C10-dicarboxylic acidurias and isovaleric acidemia. Reduced flow through the acyl-CoA dehydrogenation steps may therefore be an ethiologic factor in Reye's syndrome. Several of the accumulated acyl-CoA's are toxic and may be responsible for some of the symptoms. The low carnitine level in plasma and the elevated esterified carnitine excretion in the present patient indicate that acyl-CoA accumulation may cause a functional carnitine deficiency by sequestration of carnitine as acyl-carnitines. As the inborn defect, systemic carnitine deficiency may exhibit symptoms like those of Reye's syndrome, it may be speculated whether functional carnitine deficiency in patients with accumulated acyl-CoA is another causal factor in the development of the symptoms during attacks.