Piero Barboni1, Giacomo Savini2, Maria Lucia Cascavilla3, Leonardo Caporali4, Jacopo Milesi3, Enrico Borrelli3, Chiara La Morgia5, Maria Lucia Valentino5, Giacinto Triolo3, Andrea Lembo6, Arturo Carta7, Annamaria De Negri8, Federico Sadun9, Giovanni Rizzo5, Vincenzo Parisi2, Luisa Pierro3, Stefania Bianchi Marzoli10, Massimo Zeviani11, Alfredo A Sadun12, Francesco Bandello3, Valerio Carelli5. 1. Scientific Institute San Raffaele, Milan, Italy; Studio Oculistico d'Azeglio, Bologna, Italy. Electronic address: p.barboni@studiodazeglio.it. 2. Giovanni Battista Bietti Foundation, Rome, Italy. 3. Scientific Institute San Raffaele, Milan, Italy. 4. Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. 5. Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy. 6. San Giuseppe Hospital, University Eye Clinic, Milan, Italy. 7. Department of Ophthalmology, University of Parma, Italy. 8. Azienda San Camillo-Forlanini, Rome, Italy. 9. Ospedale San Giovanni Evangelista, Tivoli, Italy. 10. Neuro-ophthalmology Unit Department of Ophthalmology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milano, Italy. 11. Unit of Molecular Neurogenetics, Foundation C. Besta Neurological Institute, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Medical Research Council Mitochondrial Biology Unit, Cambridge, UK. 12. Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Abstract
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.
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.
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