DEFINITION
RIBOFLAVIN-RESPONSIVE MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY (RR-MADD)
Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of oxidative metabolism with a wide range of clinical severity.
Also the link to the corresponding Mesh term has to be created
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ACYL-CoA DEHYDROGENASE DEFICIENCY
EPIDEMIOLOGY
age, sex, seasonality, etc
SYMPTOMS
DIAGNOSIS
histopathology
radiology
NMR
laboratory tests
PATHOGENESIS
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Hormonal
Genetic
Acquired
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
COMPLICATIONS
THERAPY
SYMPTOMS
The most severely affected patients have congenital anomalies (such as cystic renal dysplasia) and die in the newborn period.
Other patients present with hypoglycaemia, encephalopathy, muscle weakness or cardiomyopathy in the newborn period or later in childhood. The most mildly affected patients present with muscle weakness as adults. Some of the less severely affected patients show a dramatic response.
PATHOGENETIC MECHANISMS
In MADD, multiple dehydrogenation reactions are impaired because of defective transfer of electrons from a number of primary flavoprotein dehydrogenases to the mitochondrial respiratory chain. At least 12 flavoprotein dehydrogenase enzymes seem to be affected, all of which use flavin adenine dinucleotide (FAD) as the redox prosthetic group. Several of the dehydrogenases are involved in fatty acid oxidation and the clinical features described above resemble those seen in fatty acid oxidation disorders;other affected enzymes are involved in the oxidation of several amino acids, dimethyl glycine and sarcosine. From the FAD prosthetic group, electrons are passed to ubiquinone in the respiratory chain via two other flavoproteins-electron transfer flavoprotein (ETF) and ETF: ubiquinone oxidoreductase (ETF:QO).ETF is localized in the mitochondrial matrix as a heterodimer of α- and ß-subunits and contains one FAD prosthetic group and one adenosine 5'-monophosphate (AMP); the two subunits are encoded by ETFA and ETFB genes. ETF:QO is a monomer located in the inner mitochondrial membrane, and contains a 4Fe4S cluster as well as FAD; its gene is called ETFDH. Like the majority of mitochondrial enzymes, the ETF and ETF:QO proteins are imported from the cytosol. In the mitochondria the proteins fold into the native conformation.For most mitochondrial flavoproteins, FAD binding occurs inside mitochondria, which agrees with recent lines of evidence suggesting that mitochondria can synthesize their own FAD.Many patients with MADD have been shown to have mutations in ETFA, ETFB or ETFDH; In patients with riboflavin-responsive forms of MADD, the molecular defect is still unknown. A disorder of mitochondrial flavin metabolism or transport has been proposed, for several reasons. Low intramitochondrial concentrations of FMN and FAD were found in fibroblasts from the first riboflavin-responsive patient described in 1982 and have subsequently been found in skeletal muscles from three other unrelated patients with riboflavin-responsive MADD.Moreover, studies in a number of patients have shown decreased activity and immunoreactive protein for several mitochondrial flavin-dependent enzymes, including acyl-CoA dehydrogenases.These abnormalities resemble those found in riboflavin-deficient rats, and they cannot easily be explained by primary defects of ETF or ETF:QO.
MOLECULAR STUDIES
cDNA- and genomic DNA-based PCR amplifications and sequence analysis of the human ETFA, ETFB and ETFDH genes were carried out. All references to nucleotides or amino acids are based upon the cDNA sequence of ETFDH (NM_004453.1).Fourteen different mutations were identified. Eleven are missense mutations.
The aetiology of riboflavin-responsive MADD remains uncertain, 25 years after it was first describe. An underlying disorder of mitochondrial FAD transport or metabolism has been proposed. Moreover, in some patients, decreased ETF:QO activity is improved greater than 10-fold after riboflavin therapy . ETFDH mutations have been identified in every patient referred with riboflavin-responsive MADD suggesting, therefore, that riboflavin-responsive MADD is caused by ETFDH mutations, at least in a large proportion of cases.Riboflavin supplements likely increase the intra-mitochondrial FAD concentration and thereby promote FAD binding. This could ameliorate the effect of mutations that reduce the affinity of ETF:QO for FAD. According to the 3D structure of porcine ETF:QO , none of the mutations, associated with a riboflavin-responsive MADD phenotype, change amino acids directly involved in FAD binding, making it difficult to assign them a probable mechanism of action. Two of the mutations (p.Ser82Pro and p.Gly429Arg) are located in the FAD-binding domain of ETF:QO, but the affected amino acids do not make direct interactions with FAD.The mutations may cause long-distance conformational changes that make the FAD-binding site less accessible to FAD, or they may affect catalysis by impairing flavin-ubiquinone electron transfer. It has been shown recently that flavins may bind to the unfolded state of certain flavoproteins and chaperone their folding.In this respect raising the intra-mitochondrial FAD concentration may compensate for a decreased folding capacity of the mutant proteins.ETFDH mutations alone cannot easily explain all the findings in our patients. In particular, multiple mitochondrial enzyme deficiencies have been found in all the patients for whom such studies have been possible. Studies of patients's muscle prior to riboflavin treatment showed partial deficiencies of multiple mitochondrial flavoproteins (acyl-CoA dehydrogenases and complexes I and II of the respiratory chain) and of complex IV (which does not use a flavin cofactor); all the activities except octanoyl-CoA dehydrogenase returned to normal after treatment with riboflavin.It is possible that the primary deficiency of ETF:QO in these patients may cause secondary impairment of other mitochondrial enzymes, due to the accumulation of toxic metabolites and/or increased oxidative stress. Secondary mitochondrial dysfunction is thought to occur in a number of inborn errors of metabolism, including fatty acid oxidation disorders.Alternatively, patients with riboflavin-responsive MADD may have ETFDH mutations combined with a disturbance of mitochondrial flavin and flavoprotein homeostasis. Low mitochondrial concentrations of flavins have been found in four unrelated patients with riboflavin-responsive MADD.
Defective mitochondrial flavin and flavoprotein homeostasis could also be related to diet. Diet histories and biochemical tests suggest that subclinical riboflavin deficiency is common in adults in the UK and particularly in adolescent girls. Most of the patients described first developed severe symptoms as adolescents or young adults, and it is possible that symptoms may have been precipitated by a deterioration in their riboflavin status.Thus, it is possible that the aetiology of riboflavin-responsive MADD may be heterogeneous: some may have ETFDH mutations in addition to abnormalities of mitochondrial flavin/flavoprotein homeostasis and others may have isolated genetic defects of ETF:QO, or of proteins responsible for mitochondrial flavin homeostasis.
