Not only dominant, not only optic atrophy

expanding the clinical spectrum associated with OPA1 mutations

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)89
JournalOrphanet Journal of Rare Diseases
Volume12
Issue number1
DOIs
Publication statusPublished - May 12 2017

Fingerprint

Optic Atrophy
Mitochondrial Diseases
Mutation
Eye Manifestations
Autosomal Dominant Optic Atrophy
Exome
Muscle Hypotonia
Muscle Spasticity
Nonsense Codon
Peripheral Nervous System Diseases
Ataxia
Mitochondrial DNA
Neurodegenerative Diseases
Nucleotides
Fibroblasts
Yeasts
Phenotype
Genes

Keywords

  • Blotting, Western
  • Brain Diseases/genetics
  • Child, Preschool
  • Electrophysiology
  • GTP Phosphohydrolases/genetics
  • Humans
  • Infant
  • Male
  • Microscopy, Fluorescence
  • Mutation
  • Optic Atrophy/genetics
  • Optic Atrophy, Autosomal Dominant/genetics
  • Tomography, Optical Coherence
  • Whole Exome Sequencing

Cite this

@article{31de0a51f64943f0b71666e5f004c3ee,
title = "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 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.",
keywords = "Blotting, Western, Brain Diseases/genetics, Child, Preschool, Electrophysiology, GTP Phosphohydrolases/genetics, Humans, Infant, Male, Microscopy, Fluorescence, Mutation, Optic Atrophy/genetics, Optic Atrophy, Autosomal Dominant/genetics, Tomography, Optical Coherence, Whole Exome Sequencing",
author = "Alessia Nasca and Teresa Rizza and Mara Doimo and Andrea Legati and Andrea Ciolfi and Daria Diodato and Cristina Calderan and Gianfranco Carrara and Eleonora Lamantea and Chiara Aiello and {Di Nottia}, Michela and Marcello Niceta and Costanza Lamperti and Anna Ardissone and Stefania Bianchi-Marzoli and Giancarlo Iarossi and Enrico Bertini and Isabella Moroni and Marco Tartaglia and Leonardo Salviati and Rosalba Carrozzo and Daniele Ghezzi",
year = "2017",
month = "5",
day = "12",
doi = "10.1186/s13023-017-0641-1",
language = "English",
volume = "12",
pages = "89",
journal = "Orphanet Journal of Rare Diseases",
issn = "1750-1172",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Not only dominant, not only optic atrophy

T2 - expanding the clinical spectrum associated with OPA1 mutations

AU - Nasca, Alessia

AU - Rizza, Teresa

AU - Doimo, Mara

AU - Legati, Andrea

AU - Ciolfi, Andrea

AU - Diodato, Daria

AU - Calderan, Cristina

AU - Carrara, Gianfranco

AU - Lamantea, Eleonora

AU - Aiello, Chiara

AU - Di Nottia, Michela

AU - Niceta, Marcello

AU - Lamperti, Costanza

AU - Ardissone, Anna

AU - Bianchi-Marzoli, Stefania

AU - Iarossi, Giancarlo

AU - Bertini, Enrico

AU - Moroni, Isabella

AU - Tartaglia, Marco

AU - Salviati, Leonardo

AU - Carrozzo, Rosalba

AU - Ghezzi, Daniele

PY - 2017/5/12

Y1 - 2017/5/12

N2 - 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.

AB - 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.

KW - Blotting, Western

KW - Brain Diseases/genetics

KW - Child, Preschool

KW - Electrophysiology

KW - GTP Phosphohydrolases/genetics

KW - Humans

KW - Infant

KW - Male

KW - Microscopy, Fluorescence

KW - Mutation

KW - Optic Atrophy/genetics

KW - Optic Atrophy, Autosomal Dominant/genetics

KW - Tomography, Optical Coherence

KW - Whole Exome Sequencing

U2 - 10.1186/s13023-017-0641-1

DO - 10.1186/s13023-017-0641-1

M3 - Article

VL - 12

SP - 89

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

SN - 1750-1172

IS - 1

ER -