Genotype–phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal‐dominant optic atrophy

Rönnbäck, Cecilia; Nissen, Claus; Almind, Gitte Juul; Grønskov, Karen; Miléa, Dan; Larsen, Michael

doi:10.1111/aos.12835

Cited by 7 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Firstly, the macular GCL-IPL thickness in DOA patients was less than 50% of normative values and with a similar rate of decline with increasing age compared with healthy controls. Similar findings have been reported in other DOA cohorts, 9 – 11 and taken together, the evidence indicates that a major proportion of the RGC loss has already occurred in early childhood, and probably starting in utero. If the remaining 50% of the GCL-IPL thickness is liberally converted to RGC density, that is, 50% of the foveolar maximum, this corresponds approximately to the RGC density found at a foveolar eccentricity of 7° in normal retina.…”

Section: Discussionsupporting

confidence: 89%

“… 1 – 3 Affected individuals usually become symptomatic in childhood, and several optical coherence tomography studies have confirmed the early loss of RGCs. 7 – 11 However, there is a marked inter- and intrafamilial variation in the severity and rate of progression of the disease, and the exact pattern and chronology of RGC loss are not fully understood. 2 , 10 , 11 …”

mentioning

confidence: 99%

“…7 – 11 However, there is a marked inter- and intrafamilial variation in the severity and rate of progression of the disease, and the exact pattern and chronology of RGC loss are not fully understood. 2 , 10 , 11 …”

mentioning

confidence: 99%

See 2 more Smart Citations

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

Majander

João

Rider

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PurposeProgressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes.MethodsWe recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength–sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency.ResultsSpatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log10 unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline.ConclusionsLosses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone–related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.

show abstract

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

See 1 more Smart Citation

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

Majander

João

Rider

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…This disease affects retinal ganglion cells with no evidence of functional or structural abnormalities in the preceding neural stages in the outer retina (Cohn et al, 2008;Johnston et al, 1979;Kjer, 1959;Kjer et al, 1983;Votruba et al, 1998;Yagasaki et al, 1986a;Yu-Wai-Man et al, 2010). Patients usually become symptomatic in childhood exhibiting moderate losses in spatial acuity, central field defects, and colour vision defects; moreover, optical coherence tomography studies show a loss of retinal ganglion cells (Barboni et al, 2014;Cohn et al, 2008;Kjer, 1959;Milea et al, 2010;Ronnback et al, 2013;Ronnback et al, 2015;Votruba et al, 1998).…”

Section: Autosomal Dominant Optic Atrophymentioning

confidence: 99%

Clinical vision and molecular loss: Integrating visual psychophysics with molecular genetics reveals key details of normal and abnormal visual processing

Stockman¹,

Henning²,

Rider³

2021

Progress in Retinal and Eye Research

View full text Add to dashboard Cite

“…The c.2708_2711del/p. (V903Gfs � 3) variant has been described repeatedly in the literature, including studies performed in Italy, France, Denmark, UK, China and the USA [17,68,71,[97][98][99][100][101][102][103][104]. This suggests a mutation hotspot rather than a founder effect.…”

Section: Plos Onementioning

confidence: 99%

Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

et al. 2021

View full text Add to dashboard Cite

Autosomal dominant optic atrophy is one of the most common inherited optic neuropathies. This disease is genetically heterogeneous, but most cases are due to pathogenic variants in the OPA1 gene: depending on the population studied, 32–90% of cases harbor pathogenic variants in this gene. The aim of this study was to provide a comprehensive overview of the entire spectrum of likely pathogenic variants in the OPA1 gene in a large cohort of patients. Over a period of 20 years, 755 unrelated probands with a diagnosis of bilateral optic atrophy were referred to our laboratory for molecular genetic investigation. Genetic testing of the OPA1 gene was initially performed by a combined analysis using either single-strand conformation polymorphism or denaturing high performance liquid chromatography followed by Sanger sequencing to validate aberrant bands or melting profiles. The presence of copy number variations was assessed using multiplex ligation-dependent probe amplification. Since 2012, genetic testing was based on next-generation sequencing platforms. Genetic screening of the OPA1 gene revealed putatively pathogenic variants in 278 unrelated probands which represent 36.8% of the entire cohort. A total of 156 unique variants were identified, 78% of which can be considered null alleles. Variant c.2708_2711del/p.(V903Gfs*3) was found to constitute 14% of all disease-causing alleles. Special emphasis was placed on the validation of splice variants either by analyzing cDNA derived from patients´ blood samples or by heterologous splice assays using minigenes. Splicing analysis revealed different aberrant splicing events, including exon skipping, activation of exonic or intronic cryptic splice sites, and the inclusion of pseudoexons. Forty-eight variants that we identified were novel. Nine of them were classified as pathogenic, 34 as likely pathogenic and five as variant of uncertain significance. Our study adds a significant number of novel variants to the mutation spectrum of the OPA1 gene and will thereby facilitate genetic diagnostics of patients with suspected dominant optic atrophy.

show abstract

Genotype–phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal‐dominant optic atrophy

Cited by 7 publications

References 21 publications

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

Clinical vision and molecular loss: Integrating visual psychophysics with molecular genetics reveals key details of normal and abnormal visual processing

Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

Contact Info

Product

Resources

About