Abstract
Pathogenic mutations in the OPA1 gene can be associated with Autosomal Dominant Optic Atrophy (ADOA). In approximately 20 % of patients with OPA1 mutations, a more complex neurodegenerative disorder with extraocular manifestations, known as ADOA Plus, can arise. 12 members of a multigenerational family were assessed clinically and screened for a genetic mutation in OPA1. Eight family members displayed manifestations consistent with ADOA Plus and four did not. Affected members of the oldest available generation displayed the most severe phenotype, which included severe optic atrophy, deafness, ptosis, ophthalmoplegia, proximal myopathy, neuropathy and ataxia. The next generation was less severely affected but several members displayed manifestations only after the fifth decade. Genetic analysis revealed a heterozygous variant in the OPA1 gene (c.1053T>A, p.Asp351Glu) that segregated with disease. The affected family members described here exhibited visual loss later than is typical for OPA1-related disease, as well as later onset of other neurological abnormalities in the fifth or sixth decades of life that progressed to severe neurological disability by the seventh decade. These findings expand the clinical spectrum of OPA1-related disease associated with a novel OPA1 mutation.
Similar content being viewed by others
References
Amati-Bonneau P, Valentino ML, Reynier P et al (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain 131(Pt 2):338–351
Elachouri G, Vidoni S, Zanna C et al (2011) OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res 21(1):12–20
Olichon A, Baricault L, Gas N et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278(10):7743–7746
Alexander C, Votruba M, Pesch UE et al (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26(2):211–215
Delettre C, Lenaers G, Griffoin JM et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26(2):207–210
Yu-Wai-Man P, Griffiths PG, Gorman GS et al (2010) Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 133(Pt 3):771–786
Ferre M, Amati-Bonneau P, Tourmen Y, Malthiery Y, Reynier P (2005) eOPA1: an online database for OPA1 mutations. Hum Mutat 25(5):423–428
Liesa M, Palacin M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89(3):799–845
Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7):1073–1081
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362
Marks B, Stowell MH, Vallis Y et al (2001) GTPase activity of dynamin and resulting conformation change are essential for endocytosis. Nature 410(6825):231–235
Griparic L, van der Wel NN, Orozco IJ, Peters PJ, van der Bliek AM (2004) Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem 279(18):18792–18798
Patten DA, Wong J, Khacho M et al (2014) OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J 33(22):2676–2691
Lenaers G, Hamel C, Delettre C et al (2012) Dominant optic atrophy. Orphanet J Rare Dis. 7:46
Acknowledgments
The authors wish to acknowledge the clinical assistance of Dr N. Gerbis. KEA is a NHMRC postgraduate scholar (#1074763). RLD is a NHMRC early career research fellow (#1037797). CMS is a NHMRC practitioner fellow (#1008433).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare no conflicts of interest.
Ethical standards
The authors hereby declare that the research documented in the submitted manuscript has been carried out in accordance with ethical standards laid down in the 1964 declaration of Helsinki and was approved by the ethics committee of the Northern Sydney Local Health District.
Additional information
K. E. Ahmad and R. L. Davis contributed equally to this work.
Rights and permissions
About this article
Cite this article
Ahmad, K.E., Davis, R.L. & Sue, C.M. A novel OPA1 mutation causing variable age of onset autosomal dominant optic atrophy plus in an Australian family. J Neurol 262, 2323–2328 (2015). https://doi.org/10.1007/s00415-015-7849-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-015-7849-6