Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations
| Autor: | Giancarlo Iarossi, Enrico Bertini, Andrea Ciolfi, Isabella Moroni, Daniele Ghezzi, Daria Diodato, Costanza Lamperti, Teresa Rizza, Rosalba Carrozzo, Cristina Calderan, Eleonora Lamantea, Stefania Bianchi-Marzoli, Andrea Legati, Michela Di Nottia, Marco Tartaglia, Alessia Nasca, Marcello Niceta, Gianfranco Carrara, Chiara Aiello, Anna Ardissone, Mara Doimo, Leonardo Salviati |
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| Přispěvatelé: | Nasca, A, Rizza, T, Doimo, M, Legati, A, Ciolfi, A, Diodato, D, Calderan, C, Carrara, G, Lamantea, E, Aiello, C, Di Nottia, M, Niceta, M, Lamperti, C, Ardissone, A, Bianchi-Marzoli, S, Iarossi, G, Bertini, E, Moroni, I, Tartaglia, M, Salviati, L, Carrozzo, R, Ghezzi, D |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Encephalopathy Mitochondrial disorder OPA1 Optic atrophy Recessive trait Targeted resequencing WES Blotting Western Brain Diseases Child Preschool Electrophysiology GTP Phosphohydrolases Humans Infant Microscopy Fluorescence Mutation Optic Atrophy Optic Atrophy Autosomal Dominant Tomography Optical Coherence Whole Exome Sequencing lcsh:Medicine Compound heterozygosity GTP Phosphohydrolase Missense mutation Pharmacology (medical) Child Tomography Exome sequencing Genetics (clinical) Genetics Microscopy Blotting Brain Disease General Medicine Hypotonia Autosomal Dominant medicine.symptom Western Human Ataxia Mitochondrial disease Biology Fluorescence Frameshift mutation 03 medical and health sciences Atrophy Exome Sequencing medicine Preschool Research lcsh:R medicine.disease eye diseases 030104 developmental biology Optical Coherence |
| Zdroj: | Orphanet Journal of Rare Diseases Orphanet Journal of Rare Diseases, Vol 12, Iss 1, Pp 1-10 (2017) |
| Popis: | Background Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients’ biological samples, and a clearly fragmented mitochondrial network was observed in patients’ fibroblasts. Conclusions This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0641-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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