Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

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 SalviatiRosalba Carrozzo, Daniele Ghezzi

Research output: Contribution to journalArticlepeer-review


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
Issue number1
Publication statusPublished - May 12 2017


  • 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

Fingerprint Dive into the research topics of 'Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations'. Together they form a unique fingerprint.

Cite this