title: Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease.
abstract: BACKGROUND
  Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD.
  
  
  RESULTS
  Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them.
  
  
  CONCLUSIONS
  Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.
authors.affiliation: AP-HP, Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France. Electronic address: anthony.behin@aphp.fr.
authors.forename: A
authors.initials: A
authors.lastname: Béhin
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Inserm U820, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France.
authors.forename: C
authors.initials: C
authors.lastname: Acquaviva-Bourdain
authors.affiliation: AP-HP, Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: S
authors.initials: S
authors.lastname: Souvannanorath
authors.affiliation: Service de Neuropathologie, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Université Claude Bernard Lyon I, 69500 Bron, France.
authors.forename: N
authors.initials: N
authors.lastname: Streichenberger
authors.affiliation: AP-HM, Centre de Référence des Maladies Neuromusculaires et de la SLA, CHU de La Timone, 13005 Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Attarian
authors.affiliation: AP-HP, Centre de Référence de Pathologie Neuromusculaire Paris-Ouest, CHU Henri-Mondor, Créteil, France.
authors.forename: G
authors.initials: G
authors.lastname: Bassez
authors.affiliation: AP-HP, Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Robert-Debré, 75020 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Brivet
authors.affiliation: Centre de Référence lyonnais des Maladies Héréditaires du Métabolisme, Groupement Hospitalier Est, Hôpital Femme Mère-Enfant, CHU de Lyon, 69500 Bron, France.
authors.forename: A
authors.initials: A
authors.lastname: Fouilhoux
authors.affiliation: Centre de Référence Rhône-Alpes des Maladies Neuromusculaires, CHU de Grenoble, 38000 Grenoble, France.
authors.forename: A
authors.initials: A
authors.lastname: Labarre-Villa
authors.affiliation: Service d'Anatomie et Cytologie pathologiques, CHU de Rouen, 76000 Rouen, France.
authors.forename: A
authors.initials: A
authors.lastname: Laquerrière
authors.affiliation: Service de Médecine Interne, Hôpital Édouard-Herriot, 69437 Lyon cedex 03, France.
authors.forename: L
authors.initials: L
authors.lastname: Pérard
authors.affiliation: Centre de Référence des Maladies Neuromusculaires, CHU de Nancy (Hôpitaux de Brabois), 54500 Vandœuvre-Lès-Nancy, France.
authors.forename: P
authors.initials: P
authors.lastname: Kaminsky
authors.affiliation: AP-HM, Centre de Référence des Maladies Neuromusculaires et de la SLA, CHU de La Timone, 13005 Marseille, France.
authors.forename: J
authors.initials: J
authors.lastname: Pouget
authors.affiliation: AP-HP, Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Robert-Debré, 75020 Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Rigal
authors.affiliation: Centre de Compétences Pathologies Neuromusculaires Enfants, Néonatalogie et Réanimation Pédiatrique, CHU de Rouen, 76000 Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Vanhulle
authors.affiliation: AP-HP, Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: B
authors.initials: B
authors.lastname: Eymard
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Inserm U820, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France.
authors.forename: C
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: AP-HP, Service de Biochimie, Hôpital de Bicêtre, 94270 Le Kremlin-Bicêtre, France.
authors.forename: P
authors.initials: P
authors.lastname: Laforêt
mesh_terms: D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D004576:Electromyography; D044927:Electron-Transferring Flavoproteins / Q000235:genetics; D015444:Exercise; D005260:Female; D005602:France; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000150:complications* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009468:Neuromuscular Diseases / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D010084:Oxidation-Reduction; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics; D012206:Rhabdomyolysis / Q000209:etiology; D055815:Young Adult
chemical_list: D044927:Electron-Transferring Flavoproteins; D007506:Iron-Sulfur Proteins; C116917:acylcarnitine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C023120:electron-transferring-flavoprotein dehydrogenase; D002331:Carnitine
keywords: Acylcarnitine profile; ETFDH; Exercise intolerance; Multiple acyl-CoA dehydrogenase deficiency; Muscle lipidosis; Rhabdomyolysis