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BACKGROUND: A Slovenian three-generation family with 3 individuals with bilateral optic neuropathy and 2 unaffected relatives with a novel homoplasmic missense variant m.13042G > T (A236S) in the ND5 gene is described. A detailed phenotype at initial diagnosis and a follow-up of bilateral optic neuropathy progression is presented for 2 affected individuals. METHODS: A detailed phenotype analysis with clinical examination in the early and chronic phase with electrophysiology and OCT segmentation is presented. Genotype analysis with full mitochondrial genome sequencing was performed. RESULTS: Two affected male individuals (maternal cousins) had a profound visual loss at an early age (11 and 20 years) with no recovery. The maternal grandmother exhibited bilateral optic atrophy with a history of visual loss at the age 58 years. The visual loss of both affected male individuals was characterized by centrocecal scotoma, abnormal color vision, abnormal PERG N95, and VEP. Later with disease progression, retinal nerve fiber layer thinning was observed on OCT. We observed no other extraocular clinical features. Mitochondrial sequencing identified a homoplasmic novel variant m.13042G > T (A236S) in the MT-ND5 gene, belonging to a haplogroup K1a. CONCLUSIONS: Novel homoplasmic variant m.13042G > T (A236S) in the ND5 gene in our family was associated with Leber hereditary optic neuropathy-like phenotype. However, predicting the pathogenicity of a novel ultra-rare missense variant in the mitochondrial ND5 gene is challenging. Genetic counseling should consider genotypic and phenotypic heterogeneity, incomplete penetrance, haplogroup type, and tissue-specific thresholds.
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Atrofia Óptica Hereditaria de Leber , Masculino , Humanos , Atrofia Óptica Hereditaria de Leber/diagnóstico , Atrofia Óptica Hereditaria de Leber/genética , ADN Mitocondrial/genética , Mitocondrias/genética , Fenotipo , Trastornos de la Visión , Ceguera , Mutación , LinajeRESUMEN
Genetic characteristics and a long-term clinical follow-up of 18 Slovenian retinitis pigmentosa GTPase regulator (RPGR) patients from 10 families with retinitis pigmentosa (RP) or cone/cone-rod dystrophy (COD/CORD) are reported. RP (eight families) was associated with two already known (p.(Ser407Ilefs*46) and p.(Glu746Argfs*23)) and five novel variants (c.1245+704_1415-2286del, p.(Glu660*), p.(Ala153Thr), c.1506+1G>T, and p.(Arg780Serfs*54)). COD (two families) was associated with p.(Ter1153Lysext*38). The median age of onset in males with RP (N = 9) was 6 years. At the first examination (median age of 32 years), the median best corrected visual acuity (BCVA) was 0.30 logMAR, and all patients had a hyperautofluorescent ring on fundus autofluorescence (FAF) encircling preserved photoreceptors. At the last follow-up (median age of 39 years), the median BCVA was 0.48 logMAR, and FAF showed ring constriction transitioning to patch in 2/9. Among females (N = 6; median age of 40 years), two had normal/near-normal FAF, one had unilateral RP (male pattern), and three had a radial and/or focal pattern of retinal degeneration. After a median of 4 years (4-21) of follow-up, 2/6 exhibited disease progression. The median age of onset in males with COD was 25 years. At first examination (median age of 35 years), the median BCVA was 1.00 logMAR, and all patients had a hyperautofluorescent FAF ring encircling foveal photoreceptor loss. At the last follow-up (median age of 42 years), the median BCVA was 1.30 logMAR, and FAF showed ring enlargement. The majority of the identified variants (75%; 6/8) had not been previously reported in other RPGR cohorts, which suggested the presence of distinct RPGR alleles in the Slovenian population.
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Distrofias de Conos y Bastones , Distrofias Retinianas , Retinitis Pigmentosa , Adulto , Niño , Femenino , Humanos , Masculino , Proteínas del Ojo/genética , Estudios de Seguimiento , Fondo de Ojo , Mutación , Distrofias Retinianas/genética , Retinitis Pigmentosa/genética , Tomografía de Coherencia Óptica , EsloveniaRESUMEN
PURPOSE: To analyze the retino-choroidal vascular characteristics of patients affected by pigmented paravenous chorio-retinal atrophy by means of optical coherence tomography (OCT) angiography. METHODS: This study was designed as an observational, cross-sectional case series. Multimodal imaging included fundus autofluorescence, structural OCT, and OCT angiography. The quantitative OCT angiography analyses included the calculation of the vessel density and choriocapillaris porosity. RESULTS: Overall, 12 patients (24 eyes) affected by pigmented paravenous chorio-retinal atrophy were recruited. Structural OCT of the areas involved by pigmented paravenous chorio-retinal atrophy as visualized on the fundus autofluorescence showed a complete ellipsoid zone and external limiting membrane absence, with thinning of ganglion cell complex, outer nuclear layer, and outer plexiform layer, but associated with the optical partial preservation of the retinal pigment epithelium. Optical coherence tomography angiography quantitative assessment of the retinal regions affected by PPRCA, as visualized by fundus autofluorescence, was characterized by normal vessel density at the level of superficial capillary plexus but significantly altered vessel density of deep capillary plexus and choriocapillaris, with higher choriocapillaris porosity. The presence of macular atrophy was significantly correlated with worse deep capillary plexus and choriocapillaris vessel density values. Furthermore, a statistically significant correlation between the fundus autofluorescence patterns and the retinal vascular status was found. CONCLUSION: Optical coherence tomography angiography quantitative analyses in pigmented paravenous chorio-retinal atrophy demonstrate a specific impairment at the level of the deep capillary plexus, which could in turn bring about a thinning of ganglion cell complex and outer nuclear layer. The alterations at the level of the choriocapillaris and the choroid, in general, could then represent a secondary effect.
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Pigmentos Retinianos , Tomografía de Coherencia Óptica , Atrofia , Estudios Transversales , Enfermedades Hereditarias del Ojo , Angiografía con Fluoresceína/métodos , Humanos , Degeneración Retiniana , Tomografía de Coherencia Óptica/métodosRESUMEN
Achromatopsia has been proposed to be a morphologically predominately stable retinopathy with rare reports of progression of structural changes in the macula. A five-grade system of optical coherence tomography (OCT) features has been used for the classification of structural macular changes. However, their association with age remains questionable. We characterized the Slovenian cohort of 12 patients with pathogenic variants in CNGA3 or CNGB3 who had been followed up with OCT for up to 9 years. Based on observed structural changes in association with age, the following four-stage classification of retinal morphological changes was proposed: (I) preserved inner segment ellipsoid band (Ise), (II) disrupted ISe, (III) ISe loss and (IV) ISe and RPE loss. Data from six previously published studies reporting OCT morphology in CNGA3 and CNGB3 patients were additionally collected, forming the largest CNGA3/CNGB3 cohort to date, comprising 126 patients aged 1-71 years. Multiple regression analysis showed a significant correlation of OCT stage with age (p < 0.001) and no correlation with gene (p > 0.05). The median ages of patients with stages I-IV were 12 years, 23 years, 27 years and 48 years, respectively, and no patient older than 50 years had continuous ISe. Our findings suggest that achromatopsia presents with slowly but steadily progressive structural changes of the macular outer retinal layers. However, whether morphological changes in time follow the proposed four-stage linear pattern needs to be confirmed in a long-term study.
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Defectos de la Visión Cromática/patología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Mutación , Enfermedades de la Retina/patología , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Estudios de Cohortes , Defectos de la Visión Cromática/genética , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades de la Retina/genética , Eslovenia , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
PURPOSE: The purpose of this study was to investigate the benefits of vision training with visual evoked potentials (VEP) biofeedback in amblyopia after the critical period in 8 to 17-year (11.5 ± 3.1) old children. METHODS: Ten participants with monocular amblyopia after the critical period underwent a 10-week, 20-session vision training program with the Retimax Vision Trainer device. During each session, the participants were instructed to be as focused as possible onto the fixation point in the middle of the screen. The size of the fixation point and the pitch of the background sound were changing according to VEP parameters and thus provided the participants real-time feedback of their visual performance. RESULTS: The mean BCVA improvement across our group was 0.12 LogMAR (p < 0.01). There was also a significant increase in contrast sensitivity to the FACT chart across all spatial frequencies (all p < 0.05). Electrophysiologic data revealed higher steady-state visual evoked potentials (SS-VEP) amplitudes and correspondingly lower fixation point values in the last 2 weeks of training compared to the first 2 weeks (both p < 0.01). Due to unexplainably low VEP amplitude levels in later trainings compared to those in the beginning in two participants, we have not found a significant correlation between the increase in BCVA and the increase in SS-VEP amplitude (p = 0.88). At the follow-up at 2 and 12 months following the end of training, both BCVA and contrast sensitivity remained within the levels achieved at the end of training. In some participants, however, no improvement of BCVA was observed. CONCLUSIONS: The tested vision training approach demonstrates modest but stable improvement of psychophysical parameters as well as objective characteristics in amblyopia after the critical period. Real-time SS-VEP can be used as an objective parameter to monitor participants' attention during vision training stimulation.
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Ambliopía/fisiopatología , Potenciales Evocados Visuales/fisiología , Agudeza Visual/fisiología , Adolescente , Niño , Sensibilidad de Contraste/fisiología , Electrorretinografía , Femenino , Humanos , Masculino , Neurorretroalimentación , Estimulación Luminosa , Pruebas de Visión , Baja Visión/fisiopatologíaRESUMEN
PURPOSE: Assessment of multifocal ERG (mfERG) changes in patients treated with chloroquine and their correlation with morphological abnormalities, detected by spectral-domain optical coherence tomography in relation to cumulative dosage. METHODS: Data from 37 eyes of 20 patients were retrospectively collected, and one randomly selected eye per patient was considered for statistical analysis. Eyes were divided into three groups according to mfERG and visual acuity findings: normal, early and advanced maculopathy. Functional measures of the first three mfERG rings were compared with retinal thickness measures of the corresponding OCT ETDRS circles. Data on cumulative dose and duration of therapy were also evaluated. RESULTS: The mean mfERG values progressively decreased according to the stage of the disease. In particular in the early maculopathy group, amplitudes were significantly reduced in all the three central rings. The mean ring ratio R1/R2 was abnormal only in the early maculopathy group. OCT thickness measures were significantly lower in all the three ETDRS circles in the advanced maculopathy group, and in the paracentral circle in the early maculopathy group. Considering all the eyes, there was a statistically significant correlation between functional and morphological values (p < 0.001). High chloroquine cumulative dosages were always associated with retinal toxic effects, whereas lower cumulative dosages generated different levels of toxicity. CONCLUSIONS: This study shows a strong association between mfERG ring values and the corresponding OCT thickness measures; however, mfERG may enhance early detection of functional changes in patients treated with chloroquine, especially in ambiguous cases. At low chloroquine cumulative dosages, different subjects might have different susceptibilities to the drug.
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Antirreumáticos/efectos adversos , Cloroquina/efectos adversos , Electrorretinografía/efectos de los fármacos , Retina/efectos de los fármacos , Enfermedades de la Retina/inducido químicamente , Tomografía de Coherencia Óptica , Adulto , Anciano , Artritis/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Duración de la Terapia , Femenino , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Retina/diagnóstico por imagen , Retina/fisiopatología , Enfermedades de la Retina/diagnóstico por imagen , Enfermedades de la Retina/fisiopatología , Estudios Retrospectivos , Agudeza Visual/fisiología , Adulto JovenRESUMEN
BACKGROUND: To report clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy (LHON). METHODS: Eight patients with LHON (11-26 years; one female and seven males) were examined in acute stages and at follow-up visits by means of Snellen visual acuity, Ishihara color vision, Goldmann or Octopus G2TOP perimetry, fluorescein angiography (FAG), pattern electroretinogram (PERG), visual evoked potentials (VEP) and genetic testing. RESULTS: Patients presented with typical LHON phenotype with bilateral visual acuity loss, abnormal color vision, central scotoma and hyperemic discs with no leakage on FAG. In the acute stage, electrophysiology was performed in 7/8 patients. The PERG P50 component was normal in 14/14 eyes, while the N95 component was reduced in 7/14 eyes. VEP wave P100 was reduced and delayed in 14/14 eyes. In this stage, temporal pallor of the optic disc was visible in 4/7 eyes with reduced PERG N95. At follow-up (1-11 months after), a reduced PERG N95 component was seen in 13/14 eyes and severely affected VEP in all eyes. In the only eye with a normal PERG N95, hyperemic optic disc was seen 5 months after visual acuity loss, while it was atrophic in all the others. Known mutations (14484T>C, 3460G>A) were found in 2/8 patients, while in others high-throughput sequencing identified new potentially pathogenic mutations. CONCLUSIONS: In Leber hereditary optic neuropathy, a reduced N95 component of PERG and severely reduced VEP P100 may be present already in the acute stage of disease, before optic disc pallor appears, suggesting primary dysfunction of retinal ganglion cells.
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Potenciales Evocados Visuales/fisiología , Atrofia Óptica Hereditaria de Leber/diagnóstico , Disco Óptico/patología , Trastornos de la Visión/diagnóstico , Adolescente , Adulto , Niño , Visión de Colores/fisiología , ADN Mitocondrial/genética , Electrorretinografía , Femenino , Angiografía con Fluoresceína , Humanos , Masculino , Persona de Mediana Edad , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/fisiopatología , Mutación Puntual/genética , Eslovenia , Trastornos de la Visión/genética , Trastornos de la Visión/fisiopatología , Agudeza Visual/fisiología , Pruebas del Campo Visual , Adulto JovenRESUMEN
Variants in WDR19 (IFT144) have been implicated as another possible cause of Stargardt disease. The purpose of this study was to compare longitudinal multimodal imaging of a WDR19-Stargardt patient, harboring p.(Ser485Ile) and a novel c.(3183+1_3184-1)_(3261+1_3262-1)del variant, with 43 ABCA4-Stargardt patients. Age at onset, visual acuity, Ishihara color vision, color fundus, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (OCT) images, microperimetry and electroretinography (ERG) were evaluated. First symptom of WDR19 patient was nyctalopia at the age of 5 years. After the age of 18 years, OCT showed hyper-reflectivity at the level of the external limiting membrane/outer nuclear layer. There was abnormal cone and rod photoreceptor function on ERG. Widespread fundus flecks appeared, followed by perifoveal photoreceptor atrophy. Fovea and peripapillary retina remained preserved until the latest exam at 25 years of age. ABCA4 patients had median age of onset at 16 (range 5-60) years and mostly displayed typical Stargardt triad. A total of 19% had foveal sparing. In comparison to ABCA4 patients, the WDR19 patient had a relatively large foveal preservation and severe rod photoreceptor impairment; however, it was still within the ABCA4 disease spectrum. Addition of WDR19 in the group of genes producing phenocopies of Stargardt disease underlines the importance of genetic testing and may help to understand its pathogenesis.
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Degeneración Macular , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Enfermedad de Stargardt , Degeneración Macular/genética , Transportadoras de Casetes de Unión a ATP/genética , Angiografía con Fluoresceína , Células Fotorreceptoras Retinianas Conos , Proteínas del Citoesqueleto , Péptidos y Proteínas de Señalización IntracelularRESUMEN
BACKGROUND: Most Leber hereditary optic neuropathy (LHON) cases are bilateral and sequential; however, there are rare unilateral examples, or those in which the delay of onset of vision loss between one and the other eye is longer. In the case of presumed childhood amblyopia in one eye, vision loss in the good eye may be the only symptom of bilateral disease, which was unnoticed in the previously amblyopic eye, or a preexisting episode of LHON in the "amblyopic" eye. The clinical decision in such cases may be difficult and suggestive of other forms of atypical optic neuropathy until confirmed by genetic testing. CASE SERIES: We present three genetically confirmed (MT-ND1:m.3700G>A, MT-ND6:m14484 T>C, and MT-ND4:m.11778G>A) patients with subacute vision loss in the previously good eye, with the other eye believed to be amblyopic from childhood and their features different from what would be expected in true amblyopia. In all, electrophysiology testing showed a bilaterally reduced amplitude of PERG with low VEP P100 wave amplitudes and prolonged peak time in both eyes, also unusual for amblyopia. During follow-up, the pallor of the optic discs progressed in all eyes. Significant thinning of the peripapillary retinal nerve fiber layer (pRNFL; retinal nerve fiber layer around the optic disc) and ganglion cell complex (GCC) in the macular region was present. All three patients had a peculiar history. The first patient was treated for presumed hyperopic amblyopia that did not improve since childhood, experienced visual loss in the good eye at the age of 17, and was negative for the three typical LHON mutations. Extended testing confirmed an atypical pathogenic variant MT-ND1:m.3700G>A in homoplasmy. The second patient with presumed strabismic amblyopia had an unusual presentation of vision loss only at the age of 61, and after the exclusion of other causes, a typical MT-ND4:m.11778G>A pathogenic variant was found in homoplasmy. The third case was peculiar as he had presumed strabismic amblyopia since childhood and had some degree of disc pallor in the amblyopic eye upon presenting with loss of vision in the good eye at the age of 21, and a typical pathogenic variant m14484 T>C, p.Met64Val was subsequently confirmed. However, one year after disease onset, he started to experience significant spontaneous functional improvement in the non-amblyopic up to 1.0 Snellen whilst improvement in the presumed amblyopic eye was modest, suggesting preexisting amblyopia. This interestingly extensive improvement was carefully followed by electrophysiology as well as visual acuity and fields. CONCLUSIONS: This report shows three different scenarios of presentation of LHON in patients with presumed uniocular amblyopia from childhood. In such cases, the diagnosis may be difficult, and detailed structural and functional evaluation of the optic nerve head is necessary to assess whether an earlier LHON episode was misdiagnosed as amblyopia or whether LHON presented bilaterally on both eyes whilst only being noticed in the previously good eye.
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Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10-26) years. The median yearly VA loss was 0.009 (range 0.002-0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002-4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes.
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Degeneración Macular , Humanos , Enfermedad de Stargardt/genética , Degeneración Macular/genética , Estudios de Seguimiento , Estudios Retrospectivos , Fondo de OjoRESUMEN
Introduction: X-linked retinoschisis (XLRS) is a potential target for gene supplementation approaches. To establish potential structural and functional endpoints for clinical trials, a comprehensive understanding of the inter-eye symmetry, relationship between structural and functional parameters, and disease progression is vital. Methods: In this retrospective multicentre study, 118 eyes of 59 XLRS patients with RS1 mutations were assessed. Information from center databases included: RS1 variant; age at presentation; best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume (MV) at presentation and at the last follow up; full-field electroretinogram (ERG) findings; presence of peripheral retinoschisis and complications (vitreous hemorrhage, retinal detachment); treatment with systemic or topical carbonic anhydrase inhibitors (CAI). Results: Inter-eye symmetry revealed strong correlation in CRT (r = 0.77; p < 0.0001) and moderate correlations in MV (r = 0.51, p < 0.0001) and BCVA (r = 0.49; p < 0.0001). Weak or no correlations were observed between BCVA and structural parameters (CRT, MV). Peripheral retinoschisis was observed in 40 (68%), retinal detachment in 9 (15%), and vitreous hemorrhage in 5 (8%) patients, respectively. Longitudinal examinations (mean, 4.3 years) showed no BCVA changes; however, a reduction of the CRT (p = 0.02), and MV (p = 0.01) was observed. Oral and/or topical CAI treatment did not significantly alter the CRT (p = 0.34). Discussion: The XLRS phenotype demonstrates a strong CRT symmetry between the eyes within individual patients and stable BCVA over several years. BCVA exhibits a weak correlation with the morphological parameters of retinal thickness (CRT MV). In our cohort, longitudinal functional changes were not significant, likely attributed to the short average follow-up period. Furthermore, CAI treatment didn't influence both morphological and functional outcomes.
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(1) Background: The purpose of this study was to evaluate the thickness of retinal layers in Leber hereditary optic neuropathy (LHON) in the atrophic stage compared with presumably inherited bilateral optic neuropathy of unknown cause with the aim of seeing if any LHON-specific patterns exist. (2) Methods: 14 patients (24 eyes) with genetically confirmed LHON (LHON group) were compared with 13 patients (23 eyes) with negative genetic testing results (mtDNA + WES) and without identified etiology of bilateral optic atrophy (nonLHON group). Segmentation analysis of retinal layers in the macula and peripapillary RNFL (pRNFL) measurements was performed using Heidelberg Engineering Spectralis SD-OCT. (3) Results: In the LHON group, the thickness of ganglion cell complex (GCC) (retinal nerve fiber layer (RNFL)ganglion cell layer (GCL)inner plexiform layer (IPL)) in the central ETDRS (Early Treatment Diabetic Retinopathy Study) circle was significantly higher than in the nonLHON group (p < 0.001). In all other ETDRS fields, GCC was thinner in the LHON group. The peripapillary RNFL (pRNFL) was significantly thinner in the LHON group in the temporal superior region (p = 0.001). Longitudinal analysis of our cohort during the follow-up time showed a tendency of thickening of the RNFL, GCL, and IPL in the LHON group in the central circle, as well as a small recovery of the pRNFL in the temporal region, which corresponds to the observed central macular thickening. (4) Conclusions: In LHON, the retinal ganglion cell complex thickness (RNFL-GCL-IPL) appears to be relatively preserved in the central ETDRS circle compared to nonLHON optic neuropathies in the chronic phase. Our findings may represent novel biomarkers as well as a structural basis for possible recovery in some patients with LHON.
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Background: We present the disease course and long-term follow-up of two patients who were phenotypically diagnosed with atypical Leber Hereditary Optic Neuropathy (LHON) 14 and 12 years ago, respectively, whereby whole exome sequencing revealed recently described recessive DNAJC30:c.152G>A 152 A>G (p.Tyr51Cys) homozygous pathogenic variant with significant spontaneous visual acuity recovery in one. Case presentation: Two presented unrelated males with atypical LHON with sequential visual acuity (VA) loss were followed for many years. Both patients had negative family history. At the presentation at ages 17 (Case 1) and 18 years (Case 2), both had reduced visual acuity (Snellen): (Case 1) right eye (RE):CF 3m, left eye (LE):0.6, (Case 2) RE:0.2, LE:0.15; and color vision (Ishihara): (Case 1) 1/15 and 13/15; (Case 2) 2/15 and 3/15. Both had hyperemic optic disks (PNO) and central scotoma in their visual fields. Electrophysiology in the acute phase showed reduced and delayed visually evoked potentials (VEP) P100 in both patients, with reduced N95 amplitude in Case 2, and initially normal N95 amplitude in Case 1. Fluorescein angiography showed no early leakage with some late pooling at optic disks. Extensive clinical workout, including brain magnetic resonance imaging (MRI), aquaporin 4 (Aq4), and anti-myelin oligodendrocyte protein (anti-MOG) antibodies, was negative. Intravenous corticosteroids did not improve vision. Both experienced further deterioration several months after the onset accompanied by thinning of the peripapillary retinal nerve fiber layer (RNFL). Genetic testing for typical LHON pathogenic variants and whole mitochondrial DNA (mtDNA) sequencing was negative. 1 year after the onset, modest VA improvement began in Case 2 and continued over the next 3 years. VA improved bilaterally to 0.7, color vision 15/15, and islands of vision appeared within the visual field scotoma. VEP P100 peak time shortened, and amplitude increased, despite further RNFL thinning on optical coherent tomography (OCT). The patient's visual function remained stable during the entire 12-year follow-up period. Case 1 experienced modest VA improvement to 0.1 with some improvement in the visual field seven years after the disease onset, remaining stable during the entire 14-year follow-up period. VEP P100 wave remained undetectable. Conclusions: Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases with the same DNAJC30:c.152G>A pathogenic variant and different degrees of spontaneous visual recovery despite progressive RNFL thinning during a long-term follow-up. This mutation should be screened in every atypical LHON patient.
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PURPOSE: To describe results of intravitreal bevacizumab treatment of the secondary choroidal neovascularisation in Best vitelliform macular dystrophy in an adult and paediatric patient, and present the management of three asymptomatic patients with confirmed BEST1 gene mutation. CASE SERIES DESCRIPTION: Five patients from the same family with the Best vitelliform macular dystrophy are presented. In two patients (aged 63 and 4 years) secondary choroidal neovascularisation caused a rapid decline in visual acuity. In the adult patient with advanced Best vitelliform macular dystrophy, visual acuity did not improve despite eight intravitreal bevacizumab injections to the right eye. The formation of a central scar and rapid reoccurrence of choroidal neovascularisation three months after completing the initial treatment affected the outcome. As for the paediatric patient with bilateral choroidal neovascularisation in the vitelliform stage of Best vitelliform macular dystrophy, a complete recovery of visual acuity was observed after two (left eye) and three (right eye) bevacizumab injections, with adjunctive amblyopia treatment. The other three patients with an abnormal electrooculogram reported no visual problems during more than 10 years of follow-up. Minimal changes were seen on optical coherence tomography in the youngest patient. CONCLUSIONS: Intravitreal bevacizumab seems to be an effective treatment for exudative choroidal neovascularisation in the vitelliform stage of Best vitelliform macular dystrophy; however, it may not be beneficial in the advanced stages of Best vitelliform macular dystrophy. It is important to regularly screen all family members with an abnormal electrooculogram and confirmed mutation for vitelliform changes and choroidal neovascularisation from an early age. The decision for anti-vascular endothelial growth factor treatment should be made on a case-to-case basis as complications may arise.
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Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T>A (Ter1153Lysext*38), which results in a C-terminal extension. Three male patients from two families were recruited, aged 31, 35, and 38 years. Genetic testing was performed by whole exome sequencing. Filtered variants were analysed according to the population frequency, ClinVar database, the variant's putative impact, and predicted pathogenicity; and were classified according to the ACMG guidelines. Examination included visual acuity (Snellen), colour vision (Ishihara), visual field, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrophysiology. All patients were myopic, and had central scotoma and reduced colour vision. Visual acuities on better eyes were counting fingers, 0.3 and 0.05. Electrophysiology showed severely reduced cone-specific responses and macular dysfunction, while the rod-specific response was normal. FAF showed hyperautofluorescent ring centred at the fovea encompassing an area of photoreceptor loss approximately two optic discs in diameter (3462-6342 µm). Follow up after 2-11 years showed enlargement of the diameter (avg. 100 µm/year). The novel c.3457T>A (Ter1153Lysext*38) mutation in the terminal RPGRORF15 codon is associated with cone dystrophy, which corresponds to the previously described phenotypes associated with mutations in the distal end of the RPGRORF15. Minimal progression during follow-up years suggests a relatively stable disease after the initial loss of the central cones.
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Codón , Distrofia del Cono/patología , Proteínas del Ojo/genética , Mutación , Fenotipo , Adulto , Distrofia del Cono/genética , Femenino , Humanos , Masculino , LinajeRESUMEN
PURPOSE: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. METHODS: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. RESULTS: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. CONCLUSIONS: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele.
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Codón sin Sentido , Proteínas de la Matriz Extracelular/genética , Haplotipos , Homocigoto , Ceguera Nocturna , Adolescente , Adulto , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Ceguera Nocturna/genética , Ceguera Nocturna/metabolismo , Ceguera Nocturna/mortalidad , Ceguera Nocturna/patología , Eslovenia/epidemiología , Tasa de SupervivenciaRESUMEN
USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of double hyperautofluorescent rings was performed. Twenty-four patients with typical single hyperautofluorescent rings were used for comparison of the ages of onset, visual fields, optical coherence tomography, electrophysiology, and audiograms. Double rings delineated the area of pericentral retinal degeneration in all cases. Two patients exhibited rod-cone dystrophy, whereas the third had a cone-rod dystrophy type of dysfunction on electrophysiology. There was minimal progression on follow-up in all three. Patients with double rings had significantly better visual acuity, cone function, and auditory performance than the single ring group. Double rings were associated with combinations of null and missense mutations, none of the latter found in the single ring patients. According to these findings, the double hyperautofluorescent rings indicate a mild subtype of USH2A disease, characterized by pericentral retinal degeneration, mild to moderate hearing loss, and either a rod-cone or cone-rod pattern on electrophysiology, the latter expanding the known clinical spectrum of USH2A-retinopathy.
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Síndromes de Usher/diagnóstico por imagen , Adulto , Electrorretinografía , Proteínas de la Matriz Extracelular/genética , Ojo/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Imagen Óptica , Fenotipo , Síndromes de Usher/genética , Síndromes de Usher/fisiopatologíaRESUMEN
PURPOSE: To determine the spectrum of BEST1 mutations and to study the phenotype in Slovenian families with Best vitelliform macular dystrophy (BVMD) to identify genotype-phenotype correlations. METHODS: Twenty patients from five families underwent the ophthalmological examination including electrooculogram (EOG; N = 17), fundus autofluorescence imaging (N = 16) and optical coherence tomography (N = 14). Mutational screening was performed by direct DNA sequencing of the BEST1 gene. RESULTS: Mutation c.43G>C (p.Gly15Arg) was detected in three patients from family M presenting with different clinical stages of Best disease. Mutation c.313G>C (p.Arg105Gly) was found in families K, ST, S, B and was associated with incomplete clinical penetrance and variable retinal changes, including extramacular and multifocal lesions. In three patients from family K, an atypical form of BVMD was observed; there were additional peripheral lesions outside of the vascular arcades in addition to the typical macular lesions. Multiple alterations between the vitelliruptive and pseudohypopyon stages over a period of 11 years were seen in one patient. CONCLUSION: Two previously unreported disease-associated variants in the BEST1 gene (p.Gly15Arg and p.Arg105Gly) were found in Slovenian patients with Best disease. Our data expand the mutation spectrum of the BEST1 gene and further support the broad phenotypic variability observed clinically and with optical coherence tomography (OCT) and AF imaging.
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Canales de Cloruro/genética , Proteínas del Ojo/genética , Mutación Missense , Distrofia Macular Viteliforme/genética , Adolescente , Adulto , Bestrofinas , Niño , Preescolar , Análisis Mutacional de ADN , Electrooculografía , Exones/genética , Femenino , Estudios de Asociación Genética , Heterogeneidad Genética , Humanos , Masculino , Imagen Óptica , Linaje , Eslovenia , Tomografía de Coherencia Óptica , Distrofia Macular Viteliforme/diagnóstico por imagenRESUMEN
Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
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Pruebas Genéticas/métodos , Mutación , Síndromes de Usher/genética , Alelos , Hibridación Genómica Comparativa/métodos , Europa (Continente) , Exoma , Proteínas de la Matriz Extracelular/genética , Genes Modificadores , Humanos , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodos , Síndromes de Usher/diagnósticoRESUMEN
Purpose of this study was to characterize retinal disease in Usher syndrome using fundus autofluorescence and optical coherence tomography. Study included 54 patients (26 male, 28 female) aged 7-70 years. There were 18 (33%) USH1 and 36 (67%) USH2 patients. 49/52 (94%) patients were found to carry at least one mutation in Usher genes. Ophthalmological examination included assessment of Snellen visual acuity, color vision with Ishihara tables, Goldmann visual fields (targets II/1-4 and V/4), microperimetry, fundus autofluorescence imaging and optical coherence tomography. Average age at disease onset (nyctalopia) was significantly lower in USH1 than USH2 patients (average 9 vs. 17 years, respectively; p<0.01); however no significant differences were found regarding type of autofluorescence patterns, frequency of foveal lesions and CME, rate of disease progression and age at legal blindness. All representative eyes had abnormal fundus autofluorescence of either hyperautofluorescent ring (55%), hyperautofluorescent foveal patch (35%) or foveal atrophy (10%). Disease duration of more than 30 years was associated with a high incidence of abnormal central fundus autofluorescence (patch or atrophy) and visual acuity loss.