Documenta Ophthalmologica最新文献

Purpose: To characterize the clinical phenotype associated with a homozygous start codon-altering complex variant in the ABCA4 gene and evaluate its severity and prognosis in the context of Stargardt disease.

Methods: Patient records were retrospectively reviewed for homozygous ABCA4 start codon variants. Patients underwent ophthalmic exam, multimodal imaging, full-field electroretinography (ffERG), and inherited retinal disease panel testing. Structural and functional retinal assessments were reviewed to determine phenotype severity.

Results: Three brothers of Ashkenazi Jewish descent presented with profound early-onset vision loss beginning at age 7, with best-corrected visual acuity reduced to counting fingers or hand motion by early adulthood. Imaging revealed widespread macular atrophy, extensive intraretinal pigment migration, and near-complete foveal outer nuclear layer loss. ffERG demonstrated extinguished scotopic and photopic responses. The patients were found to be homozygous for a complex ABCA4 allele containing the start codon variant c.[1A > G;6089G > A]. These features were consistent with the rapid-onset chorioretinopathy phenotype, previously associated with null ABCA4 alleles.

Conclusions: This report characterizes the clinical findings in patients homozygous for the c.[1A > G;6089G > A] variant in ABCA4, confirming its association with a severe, rapid-onset chorioretinopathy phenotype. The data support the pathogenic nature of this complex allele and expands the genotype-phenotype correlational spectrum of ABCA4-related disease, with implications for prognosis and genetic counseling.

Purpose: We report the clinical history of two siblings, initially diagnosed with juvenile glaucoma (JG), who were subsequently found to harbor a novel pathogenic OPA1 splicing variant consistent with dominant optic atrophy (DOA).

Methods and results: The male proband presented with elevated intraocular pressure (IOP) at age 11, while his sister had normal IOP values at age 16. Both developed bilateral temporal optic nerve pallor, central visual field defects, and reduced color vision. Optical coherence tomography (OCT) confirmed thinning of the retinal nerve fiber and ganglion cell layers. Whole exome sequencing identified a novel splice-site variant in OPA1 (NM_130837.3:c.611-2A>T) in both siblings and their affected mother, classified as pathogenic according to ACMG/AMP guidelines. During treatment washout, the male proband showed elevated IOP, consistent with concomitant JG and DOA, whereas the sister exhibited DOA only.

Conclusions: This report highlights the importance of considering DOA in young patients with presumed JG, and suggests potential overlapping pathophysiology involving mitochondrial dysfunction and retinal ganglion cells vulnerability.

Purpose: To report a case of α-mannosidosis with intellectual, hearing impairment and progressive retinal degeneration, supported by ten years of ophthalmic follow-up, genetic testing, and leukocyte α-mannosidase enzymatic analysis.

Methods: The patient underwent serial ophthalmic examinations over a ten-year period, including best-corrected visual acuity (BCVA) testing, fundus photography, optical coherence tomography (OCT), and fundus autofluorescence (FAF), to monitor disease progression. Trio-based whole-exome sequencing (WES) was performed on the family. Variant confirmation was conducted via Sanger sequencing. To support the genetic findings, leukocyte α-mannosidase activity was measured using fresh peripheral blood samples.

Results: At first presentation, BCVA was 20/50 OD and 20/40 OS. Over the next decade, vision progressively declined to 20/200 in both eyes. Fundus images showed granular pigment mottling in the posterior pole, and subsequent wide-angle imaging detected bone-spicule pigmentation deposits in peripheral retina. OCT demonstrated progressive retinal thinning, with loss of the ellipsoid zone. FAF revealed expanding areas of retinal atrophy. The patient has presented with bilateral sensorineural hearing loss, delayed speech development, persistent dysarthria, mild cognitive impairment, and coarse facial features since childhood. Genetic analysis identified a novel homozygous MAN2B1 mutation: c.1316_1327delinsTGATG (p.Ala439Valfs*36), inherited from consanguineous parents with the same heterozygous genotypes. The variant was classified as pathogenic based on ACMG criteria. The patient's leukocyte α-mannosidase activity was profoundly decreased, confirming the diagnosis.

Conclusions: This case highlights the progressive nature of retinal degeneration in α-mannosidosis and underscores the diagnostic value of leukocyte enzyme testing alongside genetic and ophthalmic assessments. Early recognition of ophthalmic signs, particularly in patients with syndromic features such as hearing loss and facial dysmorphism, is essential for timely diagnosis and intervention.

Purpose: Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the retina acts as a dopaminergic extension of the central nervous system. This study aimed to evaluate the effects of dopaminergic therapy on retinal electrophysiological responses in newly diagnosed, treatment-naïve PD patients and to compare these findings with those of healthy controls.

Methods: Forty eyes from 20 PD patients underwent full-field electroretinography (ffERG). Photopic a-wave, b-wave, and photopic negative response (PhNR) wave amplitudes and implicit times were recorded before and after one month of dopaminergic therapy. For comparison, one randomly selected eye from each of 20 age- and sex-matched healthy control subjects also underwent the same ffERG protocol.

Results: Following dopaminergic treatment, a-wave (- 6.6 ± 1.4 µV, p < 0.001), b-wave (20.0 ± 4.8 µV, p = 0.001), and PhNR wave amplitudes (- 7.9 ± 1.8 µV, p < 0.001) significantly increased. Pre-treatment, a-wave (- 8.9 ± 3.5 µV, p = 0.014), b-wave (38.3 ± 9.8 µV, p < 0.001), and PhNR-wave (- 17.6 ± 2.8 µV, p < 0.001) amplitudes were significantly lower in the PD group compared with controls. Post-treatment, a- and b-wave amplitudes became comparable to those of the control group (p > 0.05), while PhNR-wave amplitude remained significantly reduced (- 9.7 ± 4.1 µV, p = 0.023).

Conclusion: Dopaminergic therapy significantly improved retinal electrophysiological responses in treatment-naïve PD patients. After treatment, the a- and b-wave amplitudes approached control levels, whereas the PhNR amplitude remained significantly reduced. These findings suggest that retinal dopaminergic dysfunction in PD may be partially reversible, and ffERG parameters can serve as sensitive biomarkers for monitoring treatment response.

Purpose: To describe a case of High-altitude retinopathy (HAR) and associated imaging and multimodal assessment.

Methods: The patient was evaluated at Columbia University Irving Medical Center using a comprehensive multimodal imaging protocol that included color fundus photography, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (OCT). Functional assessments were conducted using full-field electroretinography (ERG), following the ISCEV standard protocols to ensure consistent and reproducible measurements of photoreceptor activity.

Results: A 44-year-old woman with stable RP and previously remitted cystoid macular edema presented with acute bilateral blurry and distorted vision after climbing Mt. Kilimanjaro. OCT revealed new bilateral foveal EZ loss with preserved peripheral retina. OCT-A demonstrated intact retinal and choroidal perfusion, excluding ischemic injury. Dilated fundus examination (DFE) and autofluorescence were unchanged from baseline. Methazolamide was discontinued, and N-acetylcysteine (1800 mg BID) was initiated. At 3-month follow-up, visual acuity improved, and OCT showed partial EZ recovery, consistent with a metabolic or hypoxic insult.

Conclusions: This case highlights a previously undescribed manifestation of HAR: isolated central photoreceptor damage without vascular involvement presenting as EZ line loss. The findings suggest that the high metabolic demand of foveal cones may predispose to hypoxia-induced injury, especially in patients with pre-existing retinal degeneration. Ophthalmologists should consider non-vascular mechanisms of high-altitude retinal injury, particularly in individuals with underlying retinal disease.

Purpose: To report a case of non-hereditary bilateral foveomacular and peripheral retinoschisis in a young female, with electrophysiological abnormalities in the absence of high myopia.

Methods: A 25-year-old female with recent-onset diminution of vision in the left eye (LE) underwent comprehensive ophthalmic evaluation including best-corrected visual acuity (BCVA), slit lamp biomicroscopy, indirect ophthalmoscopy, optical coherence tomography (OCT), full field electroretinography (ERG) and genetic evaluation.

Results: BCVA at presentation was 6/6, N6 in the right eye(RE) and 6/9, N8 in the LE. The patient had a prior history of laser refractive surgery for moderate myopia. Anterior segment examination was unremarkable. Fundus evaluation revealed bilateral foveoschisis and peripheral retinal schisis. OCT showed retinoschisis predominantly involving outer plexiform and outer nuclear layer, along with mild vitreoschisis. Foveal detachment was noted in the LE. ERG demonstrated rod and cone system dysfunction, severe rod bipolar cell dysfunction in both eyes, and a borderline electronegative waveform in the LE. There was no family history, and clinical exome sequencing did not reveal any pathogenic variants associated with the phenotype.

Conclusion: Electrophysiological abnormalities with bipolar cell dysfunction, similar to those seen in hereditary retinoschisis, can also occur in non-hereditary retinoschisis. Genetic evaluation is recommended to differentiate between the two, as ERG may show abnormalities in both.

Purpose: To provide a conceptual understanding of the continuous and discrete wavelet transforms (CWT, DWT) for clinical electroretinography (ERG) analysis, and how these methods uncover time-frequency features that complement traditional time-domain analysis.

Methods: A technical overview without the use of mathematical formula describing the basics of CWT and DWT and implementation considerations. We also review an example of four standard ISCEV full-field ERG (ffERG) recordings from a healthy 32-year-old male.

Results: Wavelet analysis uncovered time-frequency signatures absent in raw traces. In DA 0.01 cd s/m² DWT scalogram, energy localized in the 2-5 Hz range, with CWT scalograms corroborating these findings. In DA 3.0 cd s/m², a broader frequency response is seen across 10, 20 and 40 Hz center frequencies. A similar progression was found in the LA 3.0 cd s/m², with additional low energy indices at 80 and 160 Hz. For the LA 30 Hz flicker, all frequency and time-frequency profiles effectively replicated the 30 Hz response of the cone system.

Conclusions: CWT and DWT provide complementary and objective insight into ERG responses. Open-source MATLAB toolkit and step-by-step tutorial provided herein lower technical barriers and enable use by the broader community.

Purpose: To describe multimodal imaging and electrophysiology features of CTNNA1-associated retinal dystrophy in a family with p.(Leu318Ser) substitution.

Methods: Three family members including a 48-year-old male proband, his 52-year-old sister, and their 67-year-old mother, were evaluated with multimodal imaging and electrophysiology. The proband, referred with suspected Best's disease, underwent a retinal dystrophy panel and two affected family members were target sequenced for the familial variant.

Results: The NM_001903.5:c.953T > C variant in CTNNA1 segregated with affected family members. They maintained a visual acuity of 20/25 or better throughout 2-4 years of follow-up. The proband exhibited butterfly-shaped pigment dystrophy whilst his sister had no macular lesions, and their mother had foveal pigmentary changes. All three displayed peripheral retinal reticular pigmentation with variable atrophy. Microperimetry demonstrated enlarging paracentral scotoma in the proband whilst Esterman binocular suprathreshold test showed reproducible peripheral loss in the proband's sister. Multifocal electroretinography (ERG) confirmed central macular dysfunction in the proband. In all three, full-field ERG showed mildly delayed dark-adapted (DA) 0.01 b-wave and DA3.0 a-wave, and a light-rise of < 1.7 in one or both eyes on electro-oculography (EOG).

Conclusions: CTNNA1-associated retinal dystrophy due to p.(Leu318Ser) has a unique peripheral retinal phenotype despite variable macular involvement. Reduced EOG light-rise and peripheral reticular pigmentation should raise suspicion of CTNNA1 in butterfly-shaped pigment dystrophy.

Purpose: The photopic negative response (PhNR) and pattern ERG, both established electrophysiological measures of retinal ganglion cell (RGC) function, are recorded under photopic conditions. The purpose of this study was to describe the mesopic negative response (MeNR), a novel marker of RGC function within the rod pathway.

Methods: Ten visually-normal controls (mean age ± SD 54.6 ± 5.6 years) and 12 patients with severe primary open-angle glaucoma (mean age ± SD 58.4 ± 4.9 years) participated. Light-adapted, full-field ERGs were elicited by a rod-isolating pulse generated on the principle of silent substitution (0.46 scot. cd/m²; 55% contrast; 40 ms) presented against a steady background (0.30 scot. cd/m²). In addition, (1) the PhNR was recorded; (2) subjects were dark-adapted for 20 min and the ISCEV DA 0.01 was recorded.

Results: The normal rod-isolated pulse response was characterized by a positive potential at 85 ms followed by a slow negative potential (MeNR) at 175 ms following the pulse. The mean (± SEM) amplitude of the positive potential was similar for the control (13.4 ± 1.2 µV) and glaucoma (11.6 ± 1.35 µV) groups (p = 0.33), and was correlated with the DA 0.01 amplitude (r = 0.71, p < 0.001). The amplitude of the MeNR was significantly (p < 0.001) attenuated for the glaucoma group (4.5 ± 0.7 µV) compared to the controls (9.7 ± 1.25 µV), and was correlated with the PhNR amplitude (r = 0.86, p < 0.001).

Conclusions: Rod-isolated ERGs can be obtained without dark-adaptation using silent-substitution. The positive potential and MeNR of the rod-isolated response appear to be generated by rod bipolar cells and RGCs, respectively. In severe glaucoma, the positive (bipolar cell) potential was not significantly affected, whereas the MeNR was significantly reduced. MeNR analysis may be useful for studying RGC function within the rod pathway.

Purpose: To report a rare case of bilateral idiopathic multifocal retinal pigment epithelial detachments (imfPEDs) and to describe the long-term morphological and functional changes observed over a 16-year follow-up period.

Methods: A 49-year-old woman was diagnosed with imfPEDs based on multimodal imaging, including optical coherence tomography (OCT), fluorescein angiography (FA), and fundus photography. Full-field electroretinograms (ffERGs) and multifocal ERGs (mfERGs) were recorded to assess retinal function. The patient voluntarily discontinued follow-up but returned 16 years later due to cataract progression. Retinal morphology and function were re-evaluated using comparable multimodal imaging and electrophysiological methods.

Results: At the initial visit, multiple bilateral pigment epithelial detachments (PEDs) were identified. OCT showed hyporeflective, dome-shaped PEDs with smooth borders, and ERG responses were within normal limits. Sixteen years later, some PEDs had resolved, others had newly developed or fused, and geographic atrophy was observed, particularly in the peripheral retina. Fundus autofluorescence (FAF), performed in place of FA, revealed hyperautofluorescent PEDs and numerous peripheral hypofluorescent spots. ffERGs remained normal, while mfERGs showed localized attenuation with relatively preserved macular function. These findings were consistent with large colloid drusen and cuticular drusen.

Conclusion: This case demonstrates the slow morphological progression and relative functional preservation in bilateral imfPEDs over 16 years. Comparable multimodal imaging and electrophysiological testing were valuable in monitoring the long-term clinical course and support the classification of this phenotype as a variant of large colloid or cuticular drusen.