title: Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy; Studio Oculistico d'Azeglio, Bologna, Italy. Electronic address: p.barboni@studiodazeglio.it.
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.affiliation: Giovanni Battista Bietti Foundation, Rome, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Savini
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Cascavilla
authors.affiliation: Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Milesi
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Borrelli
authors.affiliation: 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.
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.affiliation: 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.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Giacinto
authors.initials: G
authors.lastname: Triolo
authors.affiliation: San Giuseppe Hospital, University Eye Clinic, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lembo
authors.affiliation: Department of Ophthalmology, University of Parma, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Carta
authors.affiliation: Azienda San Camillo-Forlanini, Rome, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Negri
authors.affiliation: Ospedale San Giovanni Evangelista, Tivoli, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Sadun
authors.affiliation: 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.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.affiliation: Giovanni Battista Bietti Foundation, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Parisi
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pierro
authors.affiliation: Neuro-ophthalmology Unit Department of Ophthalmology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Auxologico Italiano, Milano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bianchi Marzoli
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Sadun
authors.affiliation: Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bandello
authors.affiliation: 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.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002452:Cell Count; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence / Q000379:methods*; D014792:Visual Acuity; D055815:Young Adult
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human