Pathogenic variants in DNA-damage regulated autophagy modulator 2 gene (DRAM2) cause a rare autosomal recessive retinal dystrophy and its disease course is not well understood. We present two Slovenian patients harboring a novel DRAM2 variant and a detailed review of all 23 other patients described to date. Whole exome and whole genome sequencing were performed in the two patients, and both underwent ophthalmological examination with a 2-year follow-up. PubMed was searched for papers with clinical descriptions of DRAM2 retinopathy. Patient 1 was homozygous for a novel variant, p.Met1?, and presented with the acute onset of photopsia and retina-wide retinopathy at the age of 35 years. The patient was first thought to have an autoimmune retinopathy and was treated with mycophenolate mofetil, which provided some symptomatic relief. Patient 2 was compound heterozygous for p.Met1? and p.Leu246Pro and presented with late-onset maculopathy at the age of 59 years. On review, patients with DRAM2 retinopathy usually present in the third decade with central visual loss, outer retinal layer loss on optical coherence tomography and a hyperautofluorescent ring on fundus autofluorescence. Either cone–rod or rod–cone dystrophy phenotype is observed on electroretinography, reflecting the importance of DRAM2 in both photoreceptor types. Non-null variants can result in milder disease.

BackgroundWe 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 presentationTwo 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.ConclusionsPresented 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.

Our study evaluated visual function changes after subthreshold micropulse laser (SML) treatment in persistent central serous chorioretinopathy (CSC) and SML safety profile. We conducted a prospective study including 31 fovea-involving CSC patients. The natural course was observed for the first 3 months, SML was performed at 3 months, and SML effectiveness was observed at 6 months. At all three clinical visits, optical coherence tomography (OCT), best corrected visual acuity (BCVA), contrast sensitivity (CS) in five spatial frequencies (1.5, 3.0, 6.0, 12.0, and 18.0 cycles per degree (cpd)), microperimetry (MP), and multifocal electroretinography (mfERG) were performed. The SML safety profile was evaluated with functional and morphological parameters. In the cohort of all CSC patients treated with SML, the statistically significant average improvement was observed in BCVA (p = 0.007), CS-1.5 (p = 0.020), CS-3.0 (p = 0.050), CS-12.0 (p < 0.001), CS-18.0 (p = 0.002), CS (CS-A) (p < 0.001), MP in the central ring (MP-C) (p = 0.020), peripheral ring (MP-P) (p = 0.042), and average retinal sensitivity (MP-A) (p = 0.010). After the SML treatment, mean changes in mfERG amplitudes and implicit times in our cohort were not statistically significant. No morphological or functional adverse effects of SML treatment were observed. SML treatment in persistent CSC episodes leads to significant functional improvement and has an excellent safety profile.

The striking similarity of disc edema without leakage on fluorescein angiography, which is pathognomonic of Leber hereditary optic neuropathy (LHON), was present in a patient with cystic fibrosis with antibiotic toxic optic neuropathy. This similarity suggested the common effect of oxidative stress on retinal ganglion cells in inherited mitochondrial and antibiotic optic neuropathies. We present the case of a patient with advanced cystic fibrosis on chronic antibiotic treatment who experienced a rapid painless bilateral visual decline over a course of a few weeks. At examination, his corrected visual acuity was reduced to 0.3 in both eyes, with dyschromatopsia and central scotoma. The appearance of the fundus resembled the typical clinical features of acute LHON with hyperemic optic discs and tortuous vessels with no dye leakage from the optic discs on fluorescein angiography. Ganglion cell layer loss was seen on optic coherence tomography, with all findings pointing to LHON. Genetic testing did not reveal any LHON-specific mutations. After extended genetic testing, a heterozygous variant c.209C>T in the OPA3 gene on chromosome 19, g.46032648G>A, classified as a variant of unknown significance, was also found. After discontinuing antibiotics and general improvements in his health, surprisingly, his visual function completely improved. Later, he also received a bilateral lung transplant that further improved his general condition, and his vision remained normal. Excluding LHON, the transient optic neuropathy in our patient could be mainly due to antibiotic toxicity of linezolid and ciprofloxacin, which have been linked to mitochondrial dysfunction and advanced cystic fibrosis with hypoxic status. We suggest the possibility that patients with cystic fibrosis may be more prone to developing mitochondrial optic neuropathy, especially with additional risk factors such as chronic antibiotic therapy, which affect mitochondrial function, and can perhaps serve as a model for LHON.

(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.