title: Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2.
abstract: Dihydrolipoamide dehydrogenase (DLD, E3) is a flavoprotein common to pyruvate, α-ketoglutarate and branched-chain α-keto acid dehydrogenases. We found two novel DLD mutations (p.I40Lfs*4; p.G461E) in a 19 year-old patient with lactic acidosis and a complex amino- and organic aciduria consistent with DLD deficiency, manifesting progressive exertional fatigue. Muscle biopsy showed mitochondrial proliferation and lack of DLD cross-reacting material. Riboflavin supplementation determined the complete resolution of exercise intolerance with the partial restoration of the DLD protein and disappearance of mitochondrial proliferation in the muscle. Morphological and functional studies support the riboflavin chaperon-like role in stabilizing DLD protein with rescue of its expression in the muscle.
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: rosalba.carrozzo@opbg.net.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, Via E. Orabona 4, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Di Nottia
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, Via E. Orabona 4, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vozza
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, Via E. Orabona 4, Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parisi
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Maiorana
authors.affiliation: Department of Laboratory Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rizzo
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, Via E. Orabona 4, Bari, Italy.
authors.forename: Ciro Leonardo
authors.initials: CL
authors.lastname: Pierri
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, Via E. Orabona 4, Bari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zucano
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: carlo.dionisivici@opbg.net.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
mesh_terms: D000140:Acidosis, Lactic / Q000150:complications* / Q000628:therapy*; D001706:Biopsy; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D008375:Maple Syrup Urine Disease / Q000150:complications* / Q000628:therapy*; D017240:Mitochondrial Myopathies / Q000473:pathology* / Q000628:therapy*; D009132:Muscles / Q000473:pathology; D010641:Phenotype; D055550:Protein Stability / Q000187:drug effects; D012256:Riboflavin / Q000008:administration & dosage*; D014803:Vitamin B Complex / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D014803:Vitamin B Complex; D012256:Riboflavin
keywords: Branched-chain amino acids; Chaperon; Dihydrolipoamide dehydrogenase deficiency; Mitochondrial myopathy; Riboflavin; α-Keto acids