Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies

Mereis, Michelle; Wanders, Ronald J. A.; Schoonen, Maryke; Dercksen, Marli; Smuts, Izelle; Westhuizen, Francois H. van der

doi:10.1016/j.biocel.2020.105899

Cited by 27 publications

(38 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Defects in riboflavin intake or transport and FAD synthesis or transport can resemble a MAD deficiency [ 14 , 17 ]. The identification of these disorders could be included in the value of acylcarnitines analysis, since FAD acts as a cofactor in MAD, and the resulting acylcarnitine profiles in serum are very similar [ 104 ].…”

Section: Study Of Metabolites In the Diagnosis Of Fatty Acid Oxidation Defectsmentioning

confidence: 99%

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Ruíz-Sala

Quintana

2021

JCM

View full text Add to dashboard Cite

Mitochondrial fatty acid β-oxidation (FAO) contributes a large proportion to the body’s energy needs in fasting and in situations of metabolic stress. Most tissues use energy from fatty acids, particularly the heart, skeletal muscle and the liver. In the brain, ketone bodies formed from FAO in the liver are used as the main source of energy. The mitochondrial fatty acid oxidation disorders (FAODs), which include the carnitine system defects, constitute a group of diseases with several types and subtypes and with variable clinical spectrum and prognosis, from paucisymptomatic cases to more severe affectations, with a 5% rate of sudden death in childhood, and with fasting hypoketotic hypoglycemia frequently occurring. The implementation of newborn screening programs has resulted in new challenges in diagnosis, with the detection of new phenotypes as well as carriers and false positive cases. In this article, a review of the biochemical markers used for the diagnosis of FAODs is presented. The analysis of acylcarnitines by MS/MS contributes to improving the biochemical diagnosis, both in affected patients and in newborn screening, but acylglycines, organic acids, and other metabolites are also reported. Moreover, this review recommends caution, and outlines the differences in the interpretation of the biomarkers depending on age, clinical situation and types of samples or techniques.

show abstract

Section: Study Of Metabolites In the Diagnosis Of Fatty Acid Oxidation Defectsmentioning

confidence: 99%

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Ruíz-Sala

Quintana

2021

JCM

View full text Add to dashboard Cite

show abstract

“…Also, like prior studies [2] , [19] , elevation of 2-methylbutyrylglycine, isovalerylgylcine and 2-hydroxyglutaric acid was observed, arising from inhibition of the amino acid catabolism. As the energy supply from fatty acids oxidation decreases in diseased horses, energy needs are replaced by glycolysis and lactate and pyruvate increase [11] . As previously described and in contrast to humans, glutaric acid is not a good biomarker for the disease, as glutaric acid was not found to be elevated in all affected horses [3] .…”

Section: Discussionmentioning

confidence: 99%

“…The acquired disease observed in horses and humans due to hypoglycin A ingestion mimics the autosomal recessive disease multiple acyl-CoA dehydrogenase deficiency (MADD) observed in human, in which genetic mutations lead to electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase deficiency [11] . The disease leads to disruption in mitochondria metabolism (fatty acid beta-oxidation, catabolism of branched-chain amino acids and lysine) by affecting many acyl-CoA-dehydrogenases and other dehydrogenases due to disturbance in electron transfer and inability to re-oxidize the cofactor FADH2 of the flavoproteins [12] .…”

Section: Introductionmentioning

confidence: 99%

“…MADD diagnosis in human proceeds usually by the analysis of acylcarnitines in blood and organic acids in urine, in which increase of short and medium chain acylcarnitines and dicarboxylic acids, respectively, are the hallmark [11] . Similarly, the diagnosis in horses showing compatible clinical signs for acMADD can be made by determination of those same metabolites or by the presence of MCPA conjugates and hypoglycin A in blood and urine [13] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diagnosis of atypical myopathy based on organic acid and acylcarnitine profiles and evolution of biomarkers in surviving horses

Mathis

Sass

Graubner

et al. 2021

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Background Atypical myopathy (AM), an acquired multiple acyl-CoA dehydrogenase deficiency (MADD) in horses, induce changes in mitochondrial metabolism. Only few veterinary laboratories offer diagnostic testing for this disease. Inborn and acquired MADD exist in humans, therefore determination of organic acids (OA) in urine and acylcarnitines (AC) in blood by assays available in medical laboratories can serve as AM diagnostics. The evolution of OA and AC profiles in surviving horses is unreported. Methods AC profiles using electrospray ionization tandem mass spectrometry (ESI-MS/MS) and OA in urine using gas chromatography mass spectrometry (GC–MS) were determined in dried blot spots (DBS, n = 7) and urine samples ( n = 5) of horses with AM ( n = 7) at disease presentation and in longitudinal samples from 3/4 survivors and compared to DBS ( n = 16) and urine samples (n = 7) from control horses using the Wilcoxon test. Results All short- (C2-C5) and medium-chain (C6-C12) AC in blood differed significantly ( p < 0.008) between horses with AM and controls, except for C5:1 ( p = 0.45) and C5OH + C4DC ( p = 0.06). In AM survivors the AC concentrations decreased over time but were still partially elevated after 7 days. 14/62 (23%) of OA differed significantly between horses with AM and control horses. Concentrations of ethylmalonic acid, 2-hydroxyglutaric acid and the acylglycines (butyryl-, valeryl-, and hexanoylglycine) were highly elevated in the urine of all horses with AM at the day of disease presentation. In AM survivors, concentrations of those metabolites were initially lower and decreased during remission to approach normalization after 7 days. Conclusion OA and AC profiling by specialized human medical laboratories was used to diagnose AM in horses. Elevation of specific metabolites were still evident several days after disease presentation, allowing diagnosis via analysis of samples from convalescent animals.

show abstract

“…166 Also, the homologues of this transporter, SLC52A1 and SLC52A2, with 86% sequence identity between them and about 42% with SLC52A3, may contribute to intestinal absorption, enterocyte export, blood cell import/export and cellular uptake of riboflavin (Figure 4). 167,168 In blood riboflavin is transported bound to albumin or in erythrocytes and leukocytes.…”

Section: Fad Biosynthesis and Distributionmentioning

confidence: 99%

Mitochondrial transport and metabolism of the vitamin B‐derived cofactors thiamine pyrophosphate, coenzyme A,FADandNAD⁺, and related diseases: A review

et al. 2022

View full text Add to dashboard Cite

Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD + , which are all structurally similar to nucleotides and derived from different B-vitamins. These mitochondrial cofactors bind more or less tightly to their enzymes and, after having been involved in a specific reaction step, are regenerated, spontaneously or by other enzymes, to return to their active form, ready for the next catalysis round. Disease-causing mutations in the mitochondrial cofactor carrier genes compromise not only the transport reaction but also the activity of all mitochondrial enzymes using that particular cofactor and the metabolic pathways in which the cofactordependent enzymes are involved. The mitochondrial transport, metabolism

show abstract

Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies

Cited by 27 publications

References 75 publications

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Diagnosis of atypical myopathy based on organic acid and acylcarnitine profiles and evolution of biomarkers in surviving horses

Mitochondrial transport and metabolism of the vitamin B‐derived cofactors thiamine pyrophosphate, coenzyme A,FADandNAD⁺, and related diseases: A review

Contact Info

Product

Resources

About

Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies

Cited by 27 publications

References 75 publications

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Diagnosis of atypical myopathy based on organic acid and acylcarnitine profiles and evolution of biomarkers in surviving horses

Mitochondrial transport and metabolism of the vitamin B‐derived cofactors thiamine pyrophosphate, coenzyme A,FADandNAD+, and related diseases: A review

Contact Info

Product

Resources

About

Mitochondrial transport and metabolism of the vitamin B‐derived cofactors thiamine pyrophosphate, coenzyme A,FADandNAD⁺, and related diseases: A review