Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations
Abstract 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 t...
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BMC
2017-05-01
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Series: | Orphanet Journal of Rare Diseases |
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Online Access: | http://link.springer.com/article/10.1186/s13023-017-0641-1 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alessia Nasca Teresa Rizza Mara Doimo Andrea Legati Andrea Ciolfi Daria Diodato Cristina Calderan Gianfranco Carrara Eleonora Lamantea Chiara Aiello Michela Di Nottia Marcello Niceta Costanza Lamperti Anna Ardissone Stefania Bianchi-Marzoli Giancarlo Iarossi Enrico Bertini Isabella Moroni Marco Tartaglia Leonardo Salviati Rosalba Carrozzo Daniele Ghezzi |
spellingShingle |
Alessia Nasca Teresa Rizza Mara Doimo Andrea Legati Andrea Ciolfi Daria Diodato Cristina Calderan Gianfranco Carrara Eleonora Lamantea Chiara Aiello Michela Di Nottia Marcello Niceta Costanza Lamperti Anna Ardissone Stefania Bianchi-Marzoli Giancarlo Iarossi Enrico Bertini Isabella Moroni Marco Tartaglia Leonardo Salviati Rosalba Carrozzo Daniele Ghezzi Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations Orphanet Journal of Rare Diseases OPA1 Optic atrophy Mitochondrial disorder Encephalopathy Recessive trait Targeted resequencing |
author_facet |
Alessia Nasca Teresa Rizza Mara Doimo Andrea Legati Andrea Ciolfi Daria Diodato Cristina Calderan Gianfranco Carrara Eleonora Lamantea Chiara Aiello Michela Di Nottia Marcello Niceta Costanza Lamperti Anna Ardissone Stefania Bianchi-Marzoli Giancarlo Iarossi Enrico Bertini Isabella Moroni Marco Tartaglia Leonardo Salviati Rosalba Carrozzo Daniele Ghezzi |
author_sort |
Alessia Nasca |
title |
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations |
title_short |
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations |
title_full |
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations |
title_fullStr |
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations |
title_full_unstemmed |
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations |
title_sort |
not only dominant, not only optic atrophy: expanding the clinical spectrum associated with opa1 mutations |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2017-05-01 |
description |
Abstract 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. |
topic |
OPA1 Optic atrophy Mitochondrial disorder Encephalopathy Recessive trait Targeted resequencing |
url |
http://link.springer.com/article/10.1186/s13023-017-0641-1 |
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doaj-0494d6719b26407982a6465aec056ef32020-11-24T21:33:54ZengBMCOrphanet Journal of Rare Diseases1750-11722017-05-0112111010.1186/s13023-017-0641-1Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutationsAlessia Nasca0Teresa Rizza1Mara Doimo2Andrea Legati3Andrea Ciolfi4Daria Diodato5Cristina Calderan6Gianfranco Carrara7Eleonora Lamantea8Chiara Aiello9Michela Di Nottia10Marcello Niceta11Costanza Lamperti12Anna Ardissone13Stefania Bianchi-Marzoli14Giancarlo Iarossi15Enrico Bertini16Isabella Moroni17Marco Tartaglia18Leonardo Salviati19Rosalba Carrozzo20Daniele Ghezzi21Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCSDepartment of Woman and Child Health, Clinical Genetics Unit, University of PadovaUnit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Division of Genetics and Rare Diseases, Molecular Genetics and Genomics Unit, Bambino Gesù Children’s Hospital, IRCCSUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCSDepartment of Woman and Child Health, Clinical Genetics Unit, University of PadovaUnit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCSUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCSDivision of Genetics and Rare Diseases, Molecular Genetics and Genomics Unit, Bambino Gesù Children’s Hospital, IRCCSUnit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Department of Ophthalmology, Neuro-ophthalmology Unit, IRCCS Istituto Auxologico ItalianoDepartment of Ophthalmology, Bambino Gesù IRCSS Children’s HospitalUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCSUnit of Child Neurology, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Division of Genetics and Rare Diseases, Molecular Genetics and Genomics Unit, Bambino Gesù Children’s Hospital, IRCCSDepartment of Woman and Child Health, Clinical Genetics Unit, University of PadovaUnit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCSUnit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’Abstract 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.http://link.springer.com/article/10.1186/s13023-017-0641-1OPA1Optic atrophyMitochondrial disorderEncephalopathyRecessive traitTargeted resequencing |