Abstract
BackgroundHeterozygous 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.ResultsWe 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.ConclusionsThis 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.
Highlights
Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations
Pathogenic mutations in the OPA1 gene have largely been associated with autosomal dominant optic atrophy (ADOA; OMIM#165500), a visual disorder associated with degeneration of retinal ganglion cells
Compound heterozygous mutations in OPA1 have been associated with Behr syndrome (OMIM#210000), a disease characterized by the association of early-onset optic atrophy with spinocerebellar degeneration [6, 7]
Summary
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. Pathogenic mutations in the OPA1 gene have largely been associated with autosomal dominant optic atrophy (ADOA; OMIM#165500), a visual disorder associated with degeneration of retinal ganglion cells. Up to 20% of OPA1-mutated patients develop additional more complex neurodegenerative disorder with extra-ocular manifestations, including. Compound heterozygous mutations in OPA1 have been associated with Behr syndrome (OMIM#210000), a disease characterized by the association of early-onset optic atrophy with spinocerebellar degeneration [6, 7]. The clinical spectrum of these emerging double-mutant OPA1-related disorders remains to be fully characterized
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