Leigh-like neuroimaging features associated with new biallelic mutations in OPA1

Rubegni, Anna; Pisano, Tiziana; Bacci, Giacomo Maria; Tessa, Alessandra; Battini, Roberta; Procopio, Elena; Giglio, Sabrina; Pasquariello, Rosa; Santorelli, Filippo M.; Guerrini, Renzo; Nesti, Claudia

doi:10.1016/j.ejpn.2017.04.004

Cited by 21 publications

(8 citation statements)

References 28 publications

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“…In patients carrying OPA1 mutations and having clinical signs of autosomal dominant optic atrophy, memory functions have not been systematically reported. However, cognitive deficits have been reported for OPA1 mutations leading to Behr syndrome and Parkinson-like symptoms ( Carelli et al , 2015 ; Kleffner et al , 2015 ; Rubegni et al 2017 ).…”

Section: Discussionmentioning

confidence: 99%

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory

Bevan

Williams

Waters

et al. 2020

Brain Communications

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A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6;C3-Opa1Q285STOP; Opa1+/-). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesise that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.

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Section: Discussionmentioning

confidence: 99%

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory

Bevan

Williams

Waters

et al. 2020

Brain Communications

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“…The Behr syndrome is characterized by early-onset optic atrophy, ataxia, pyramidal signs, peripheral neuropathy, mental retardation, and developmental delay [8,16]. Bonneau et al [8] reported four unrelated children with a phenotype consistent with Behr syndrome.…”

Section: Discussionmentioning

confidence: 99%

Concurrent OPA1 mutation and chromosome 3q deletion leading to Behr syndrome: a case report

et al. 2020

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Background: Optic atrophy 1 (OPA1) gene mutations are associated with dominantly inherited optic neuropathy resulting in a progressive loss of visual acuity. Compound heterozygous or homozygous variants that lead to severe phenotypes, including Behr syndrome, have been reported rarely. Case presentation: Here, we present a 14-month-old boy with early onset optic atrophy, congenital cataracts, neuromuscular disorders, mental retardation, and developmental delay. Combined genetic testing, including whole exome sequencing (WES) and chromosomal microarray analysis, revealed a concurrent OPA1 variant (c.2189 T > C p.Leu730Ser) and de novo chromosome 3q deletion as pathogenic variants leading to the severe phenotype. Conclusions: Our case is the first reporting a novel missense OPA1 variant co-occurring with a chromosomal microdeletion leading to a severe phenotype reminiscent of Behr syndrome. This expands the mutation spectrum of OPA1 and inheritance patterns of this disease.

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“…The increasing use of next-generation sequencing (NGS) approaches such as targeted gene panels or whole-exome has enabled discovering new genes or mutations involved in mitochondrial oxidative phosphorylation (OXPHOS) dysfunction, including those causing LS [12][13][14][15]. In the present study, using an OXPHOS-targeted panel, we identified two biallelic novel variants in the NDUFA13 gene in a child with features of LS and mitochondrial CI deficiency.…”

Section: Introductionmentioning

confidence: 88%

Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report

González-Quintana

García‐Consuegra

Bélanger-Quintana

et al. 2020

Genes

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Leigh syndrome (LS) usually presents as an early onset mitochondrial encephalopathy characterized by bilateral symmetric lesions in the basal ganglia and cerebral stem. More than 75 genes have been associated with this condition, including genes involved in the biogenesis of mitochondrial complex I (CI). In this study, we used a next-generation sequencing (NGS) panel to identify two novel biallelic variants in the NADH:ubiquinone oxidoreductase subunit A13 (NDUFA13) gene in a patient with isolated CI deficiency in skeletal muscle. Our patient, who represents the second family report with mutations in the CI NDUFA13 subunit, presented with LS lesions in brain magnetic resonance imaging, mild hypertrophic cardiomyopathy, and progressive spastic tetraparesis. This phenotype manifestation is different from that previously described in the first NDUFA13 family, which was predominantly characterized by neurosensorial symptoms. Both in silico pathogenicity predictions and oxidative phosphorylation (OXPHOS) functional findings in patient’s skin fibroblasts (delayed cell growth, isolated CI enzyme defect, decreased basal and maximal oxygen consumption and as well as ATP production, together with markedly diminished levels of the NDUFA13 protein, CI, and respirasomes) suggest that these novel variants in the NDUFA13 gene are the underlying cause of the CI defect, expanding the genetic heterogeneity of LS.

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Leigh-like neuroimaging features associated with new biallelic mutations in OPA1

Cited by 21 publications

References 28 publications

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory

Concurrent OPA1 mutation and chromosome 3q deletion leading to Behr syndrome: a case report

Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report

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