Early macular retinal ganglion cell loss in dominant optic atrophy: Genotype-phenotype correlation

Piero Barboni, Giacomo Savini, Maria Lucia Cascavilla, Leonardo Caporali, Jacopo Milesi, Enrico Borrelli, Chiara La Morgia, Maria Lucia Valentino, Giacinto Triolo, Andrea Lembo, Arturo Carta, Annamaria De Negri, Federico Sadun, Giovanni Rizzo, Vincenzo Parisi, Luisa Pierro, Stefania Bianchi Marzoli, Massimo Zeviani, Alfredo A. Sadun, Francesco BandelloValerio Carelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalAmerican Journal of Ophthalmology
Volume158
Issue number3
DOIs
Publication statusPublished - 2014

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Autosomal Dominant Optic Atrophy
Retinal Ganglion Cells
Genetic Association Studies
Nerve Fibers
Ganglia
Mutation
Optical Coherence Tomography
Missense Mutation
Haploinsufficiency
Pedigree
Nose
Axons
Healthy Volunteers
Cross-Sectional Studies
Maintenance

ASJC Scopus subject areas

  • Ophthalmology

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Early macular retinal ganglion cell loss in dominant optic atrophy : Genotype-phenotype correlation. / Barboni, Piero; Savini, Giacomo; Cascavilla, Maria Lucia; Caporali, Leonardo; Milesi, Jacopo; Borrelli, Enrico; La Morgia, Chiara; Valentino, Maria Lucia; Triolo, Giacinto; Lembo, Andrea; Carta, Arturo; De Negri, Annamaria; Sadun, Federico; Rizzo, Giovanni; Parisi, Vincenzo; Pierro, Luisa; Bianchi Marzoli, Stefania; Zeviani, Massimo; Sadun, Alfredo A.; Bandello, Francesco; Carelli, Valerio.

In: American Journal of Ophthalmology, Vol. 158, No. 3, 2014.

Research output: Contribution to journalArticle

Barboni, Piero ; Savini, Giacomo ; Cascavilla, Maria Lucia ; Caporali, Leonardo ; Milesi, Jacopo ; Borrelli, Enrico ; La Morgia, Chiara ; Valentino, Maria Lucia ; Triolo, Giacinto ; Lembo, Andrea ; Carta, Arturo ; De Negri, Annamaria ; Sadun, Federico ; Rizzo, Giovanni ; Parisi, Vincenzo ; Pierro, Luisa ; Bianchi Marzoli, Stefania ; Zeviani, Massimo ; Sadun, Alfredo A. ; Bandello, Francesco ; Carelli, Valerio. / Early macular retinal ganglion cell loss in dominant optic atrophy : Genotype-phenotype correlation. In: American Journal of Ophthalmology. 2014 ; Vol. 158, No. 3.
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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.",
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T2 - Genotype-phenotype correlation

AU - Barboni, Piero

AU - Savini, Giacomo

AU - Cascavilla, Maria Lucia

AU - Caporali, Leonardo

AU - Milesi, Jacopo

AU - Borrelli, Enrico

AU - La Morgia, Chiara

AU - Valentino, Maria Lucia

AU - Triolo, Giacinto

AU - Lembo, Andrea

AU - Carta, Arturo

AU - De Negri, Annamaria

AU - Sadun, Federico

AU - Rizzo, Giovanni

AU - Parisi, Vincenzo

AU - Pierro, Luisa

AU - Bianchi Marzoli, Stefania

AU - Zeviani, Massimo

AU - Sadun, Alfredo A.

AU - Bandello, Francesco

AU - Carelli, Valerio

PY - 2014

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N2 - 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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