Achilli A.,University of Perugia |
Iommarini L.,University of Bologna |
Olivieri A.,University of Pavia |
Pala M.,University of Pavia |
And 24 more authors.
PLoS ONE | Year: 2012
Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. Methodology/Principal Findings: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. Conclusions/Significance: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression. © 2012 Achilli et al.
Barboni P.,San Raffaele Scientific Institute |
Savini G.,Giovanni Battista Bietti Foundation |
Cascavilla M.L.,San Raffaele Scientific Institute |
Caporali L.,CNR Institute of Neurological Sciences |
And 22 more authors.
American Journal of Ophthalmology | Year: 2014
Purpose To assess the peripapillary retinal nerve fiber and macular retinal ganglion cell (RGC) loss in patients with dominant optic atrophy (DOA) stratified by OPA1 mutation type. Design Cross-sectional study. Methods We studied 39 patients from 28 pedigrees with DOA harboring heterozygous mutations in the OPA1 gene along with 45 age-matched healthy subjects. The retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) of patients with DOA were evaluated by optical coherence tomography (OCT) and compared to those of controls. Patients' eyes were divided into 4 groups based on increasing severity of visual loss (DOA1 to DOA4) and were stratified by OPA1 mutation type. Results The average thicknesses of the RNFL and GC-IPL were smaller in patients with DOA than in healthy controls (P < 0.0001). RNFL analysis showed a significant reduction of the average, superior and inferior quadrants thicknesses in the DOA4 group compared to the DOA1 group (P = 0.001, P = 0.002 and P = 0.001, respectively). GC-IPL analysis showed a significant thinning in the superotemporal and superior sectors in the patients with DOA2 compared to those with DOA1 (P = 0.046 and P = 0.04, respectively). Stratifying by mutation type, average, superior and nasal RNFL thinning was significantly more severe in missense mutations and had a presumed dominant-negative effect compared to mutations causing haploinsufficiency. Conclusions The present study demonstrates that in DOA, loss of macular RGCs is the earliest pathologic event, better reflected by GC-IPL measurements, whereas RNFL thickness is a measure of spared axons in late stages of the disease. Thus, mild cases (DOA2) show significant macular RGC loss as opposed to substantial maintenance of RNFL thickness, which is significantly decreased only in severe cases (DOA4). A clear genotype/phenotype correlation emerged, stratifying OCT measures by OPA1 mutation type, missense mutations being the most severe. © 2014 by Elsevier Inc. All rights reserved.
Ziccardi L.,Neurophthalmology Unit |
Parisi V.,Neurophthalmology Unit |
Giannini D.,University of Rome La Sapienza |
Sadun F.,Ospedale San Giovanni Evangelista |
And 8 more authors.
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2015
Purpose: To differentiate the bioelectrical cortical responses driven by axons from central and mid-peripheral retina in Leber’s hereditary optic neuropathy (LHON) by using multifocal visual evoked potentials (mfVEP). Methods: Seventeen genetically confirmed LHON patients (33.35 ± 8.4 years, 17 eyes) and 22 age-matched controls (C) (38.2 ± 6.0 years, 22 eyes) were studied by mfVEP and optical coherence tomography. MfVEP P1 implicit time (P1 IT, ms) and response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg2) of the second order binary kernel were measured for five concentric retinal areas between the fovea and mid-periphery: 0–20 degrees (R1 to R5). Results: Mean mfVEP P1 ITs and N1-P1 RADs at all five foveal eccentricities were significantly different (p < 0.01) in LHON when compared to controls. In both groups, mean mfVEP responses obtained from R1 to R5 showed a progressive shortening of P1 ITs (linear fitting, LHON: r = −0.95; C: r = −0.98) and decrease of N1-P1 RADs (exponential fitting, LHON: r2 = 0.94; C: r2 = 0.93). The slope of the linear fitting between mean mfVEP P1 ITs in the two groups was about three times greater in LHON than in controls (LHON: y = −13.33x +182.03; C: y = −4.528x +108.1). MfVEP P1 ITs detected in R1 and R2 (0–5 degrees) were significantly correlated (p < 0.01) with the reduction of retinal nerve fiber layer thickness of the temporal quadrant. Conclusions: MfVEP identifies abnormal neural conduction along the visual pathways in LHON, discriminating a predominant involvement of axons driving responses from the central retina when compared to those serving the mid-peripheral retina. © 2015, Springer-Verlag Berlin Heidelberg.