Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo <i>OPA3</i> mutation

Bourne, Stephanie C.; Townsend, Katelin N.; Shyr, Casper; Matthews, Allison; Lear, Scott A.; Attariwala, Raj; Lehman, Anna; Wasserman, Wyeth W.; Sinclair, Graham; Vallance, Hilary; Gibson, William T.

doi:10.1101/mcs.a001156

Cited by 12 publications

(10 citation statements)

References 19 publications

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“…Here, we describe the members from 3 families in which a novel missense variant (c.23T>C, p.Met8Thr) and a known mutation (c.313C>G, p.Gln105Glu) in OPA3 were the most likely underlying cause of a complex phenotype consisting of OA, cataracts, gastrointestinal dysmotility, axonal neuropathy, and possibly autonomic dysfunction and hearing loss. This observation, together with 2 former reports of similar phenotypes associated with the missense substitutions p.Leu79Val and p.Gln105Glu, 15,18 demonstrates that the dominant OPA3 mutations can cause syndromic forms of ADOAC (ADOAC “plus”).…”

Section: Discussionsupporting

confidence: 63%

“…6–13 Dominant mutations, in contrast, lead to OA that typically presents within the first 2 decades of life and is often associated with cataracts with variable age at onset (autosomal dominant OA and cataract; ADOAC [MIM 165300]). 14–18 Additional features such as hearing loss, cerebellar and extrapyramidal signs, and dysautonomic or gastrointestinal symptoms have been reported less consistently in patients with ADOAC (table e-2). Symptoms or signs suggestive of peripheral neuropathy (PN) have been described to date in 4 individuals with dominant OPA3 mutations, 14,15,18 although it was confirmed by nerve conduction studies (NCSs) in only one of them.…”

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confidence: 99%

“…14–18 Additional features such as hearing loss, cerebellar and extrapyramidal signs, and dysautonomic or gastrointestinal symptoms have been reported less consistently in patients with ADOAC (table e-2). Symptoms or signs suggestive of peripheral neuropathy (PN) have been described to date in 4 individuals with dominant OPA3 mutations, 14,15,18 although it was confirmed by nerve conduction studies (NCSs) in only one of them. 18…”

mentioning

confidence: 99%

“…Symptoms or signs suggestive of peripheral neuropathy (PN) have been described to date in 4 individuals with dominant OPA3 mutations, 14,15,18 although it was confirmed by nerve conduction studies (NCSs) in only one of them. 18…”

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confidence: 99%

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Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Horga

Bugiardini²,

Manole³

et al. 2019

Neurol Genet

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ObjectiveTo characterize the phenotype in individuals with OPA3-related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN).MethodsTwo probands with multiple affected relatives and one sporadic case were referred for evaluation of a PN. Their phenotype was determined by clinical ± neurophysiological assessment. Neuropathologic examination of sural nerve and skeletal muscle, and ultrastructural analysis of mitochondria in fibroblasts were performed in one case. Exome sequencing was performed in the probands.ResultsThe main clinical features in one family (n = 7 affected individuals) and one sporadic case were early-onset cataracts (n = 7), symptoms of gastrointestinal dysmotility (n = 8), and possible/confirmed PN (n = 7). Impaired vision was an early-onset feature in another family (n = 4 affected individuals), in which 3 members had symptoms of gastrointestinal dysmotility and 2 developed PN and cataracts. The less common features among all individuals included symptoms/signs of autonomic dysfunction (n = 3), hearing loss (n = 3), and recurrent pancreatitis (n = 1). In 5 individuals, the neuropathy was axonal and clinically asymptomatic (n = 1), sensory-predominant (n = 2), or motor and sensory (n = 2). In one patient, nerve biopsy revealed a loss of large and small myelinated fibers. In fibroblasts, mitochondria were frequently enlarged with slightly fragmented cristae. The exome sequencing identified OPA3 variants in all probands: a novel variant (c.23T>C) and the known mutation (c.313C>G) in OPA3.ConclusionsA syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy.

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Section: Discussionsupporting

confidence: 63%

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confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Horga

Bugiardini²,

Manole³

et al. 2019

Neurol Genet

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“…The optic neuropathy is similar to that caused by OPA1 mutations characterized by primary involvement of the papillomacular bundle (147). The phenotypic spectrum of autosomal dominant mutations in OPA3 was further expanded recently with the identification of a de novo mutation in exon 2 encoding OPA3 Leu79Val, which leads to an unusually severe phenotype including optic atrophy, cataracts, ataxia, and peripheral and autonomic neuropathy (154).…”

Section: Afg3l2 Heterozygous Missense Mutations In the Afg3l2mentioning

confidence: 89%

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Bagli

Zikou

Agnantis

et al. 2017

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Abstract. Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and nonsyndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical -even in asymptomatic patients -for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.Mitochondria represent a tubular and branched membrane system playing a fundamental role in several cellular processes required for the development and maintenance of an organism, such as metabolism, apoptosis, ion buffering and autophagy (1-3). They reveal a high degree of interconnectivity and plasticity, mainly dictated by metabolic status and developmental stage (4) and, therefore, a constant state of mitochondrial network flux is fundamental. This dynamic state is achieved through mitochondrial dynamics, a complex machinery of highly conserved mechanisms, including mitochondrial fusion, fission, transport, interorganellar communication and mitochondrial quality control (i.e. mitophagy), tuned to a variety of signals and stimuli (5-7), and well-orchestrated by specific intracellular proteins.The morphology and intracellular distribution of mitochondria vary significantly between tissues and cell types, being enriched in areas of increased metabolic demand, such as neurons, especially the presynaptic and postsynaptic terminals (8). Accordingly, it is not surprising that the pathogenic mechanism of various neurodegenerative diseases is established through an underlying deficiency of mitochondrial energy metabolism (9). However, in recent years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10,11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel neuroprotective strategies (12).Mitochondrial membrane dynamics, and more specifically fission and fusion, are indispensable for mitochondrial distribution and hom...

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Phenotypic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities

2018

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Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation

Cited by 12 publications

References 19 publications

Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies

Phenotypic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities

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