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 language | English |
|---|---|
| Pages (from-to) | 89 |
| Journal | Orphanet Journal of Rare Diseases |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - May 12 2017 |
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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
Not only dominant, not only optic atrophy : expanding the clinical spectrum associated with OPA1 mutations. / Nasca, Alessia; Rizza, Teresa; Doimo, Mara; Legati, Andrea; Ciolfi, Andrea; Diodato, Daria; Calderan, Cristina; Carrara, Gianfranco; Lamantea, Eleonora; Aiello, Chiara; Di Nottia, Michela; Niceta, Marcello; Lamperti, Costanza; Ardissone, Anna; Bianchi-Marzoli, Stefania; Iarossi, Giancarlo; Bertini, Enrico; Moroni, Isabella; Tartaglia, Marco; Salviati, Leonardo; Carrozzo, Rosalba; Ghezzi, Daniele.
In: Orphanet Journal of Rare Diseases, Vol. 12, No. 1, 12.05.2017, p. 89.Research output: Contribution to journal › Article
}
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 -