title: Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes.
abstract: Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system. Few patients have been reported with mutations in IBA57 and with variable clinical phenotype. Herein, we describe four unrelated patients carrying novel mutations in IBA57. All patients presented with combined or isolated defect of complex I and II. Clinical features varied widely, ranging from fatal infantile onset of the disease to acute and severe psychomotor regression after the first year of life. Brain MRI was characterized by cavitating leukodystrophy. The identified mutations were never reported previously and all had a dramatic effect on IBA57 stability. Our study contributes to expand the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients.
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Alessandra
authors: A
authors: Torraco
authors: Child Neurology Unit, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Anna
authors: A
authors: Ardissone
authors: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Federica
authors: F
authors: Invernizzi
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Teresa
authors: T
authors: Rizza
authors: Laboratory of Biochemistry and Molecular Biology, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via E. Orabona 4, Bari, Italy.
authors: Giuseppe
authors: G
authors: Fiermonte
authors: Division of Genetic Disorders and Rare Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Marcello
authors: M
authors: Niceta
authors: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Nadia
authors: N
authors: Zanetti
authors: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Diego
authors: D
authors: Martinelli
authors: Laboratory of Biochemistry and Molecular Biology, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via E. Orabona 4, Bari, Italy.
authors: Angelo
authors: A
authors: Vozza
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Daniela
authors: D
authors: Verrigni
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Michela
authors: M
authors: Di Nottia
authors: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Eleonora
authors: E
authors: Lamantea
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Daria
authors: D
authors: Diodato
authors: Division of Genetic Disorders and Rare Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Marco
authors: M
authors: Tartaglia
authors: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Carlo
authors: C
authors: Dionisi-Vici
authors: Child Neurology Unit, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Isabella
authors: I
authors: Moroni
authors: Unit of Neuroradiology, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Laura
authors: L
authors: Farina
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Enrico
authors: E
authors: Bertini
authors: Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.
authors: Daniele
authors: D
authors: Ghezzi
authors: Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. rosalba.carrozzo@opbg.net.
authors: Rosalba
authors: R
authors: Carrozzo
mesh_terms: D015153:Blotting, Western; D001921:Brain / Q000000981:diagnostic imaging*; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D055550:Protein Stability
chemical_list: D002352:Carrier Proteins; C585465:IBA57 protein, human
keywords: IBA57; Leukodystrophy; MMDS; Mitochondrial disorders