Retinal Ganglion Cell Loss in X-linked Adrenoleukodystrophy with an ABCD1 Mutation (Gly266Arg).

The authors here report a single case of a 10-year-old male patient who presented with severe vision loss associated with progressive demyelination. The patient was diagnosed with X-linked childhood cerebral adrenoleukodystrophy (ALD). Genetic analysis demonstrated a missense mutation (Gly266Arg) in exon 1 of the ABCD1 gene. His corrected visual acuity confirmed the absolute lack of light perception in both eyes. Funduscopy revealed severe pallor of the optic disc in both eyes. Spectral-domain optical coherence tomography showed thinning of the retinal ganglion cell and inner plexiform layers (GCL and IPL). Thinning of the GCL and IPL may be due to transneuronal retrograde degeneration of ganglion cells secondary to optic tract demyelination.

One-year results of reduced fluence photodynamic therapy for central serous chorioretinopathy: the outer nuclear layer thickness is associated with visual prognosis.

PURPOSE: To evaluate the efficacy of reduced-fluence photodynamic therapy (RFPDT) for central serous chorioretinopathy (CSC). METHODS: This retrospective medical record review of consecutive CSC patients treated with RFPDT (full-dose verteporfin and laser fluence of 25 J/cm(2)) examined 22 eyes of 21 patients (20 males and one female). All patients were followed-up for 1 year. Best-corrected visual acuity (BCVA), complete resolution of subretinal fluid (CR of SRF), central retinal thickness (CRT), the outer nuclear layer (ONL) thickness, and the photoreceptor inner and outer segments (IS/OS) line determined by optical coherence tomography imaging were evaluated at baseline, 1, 3, 6, 9, and 12 months after initial RFPDT. RESULTS: A single RFPDT session was performed in all cases during a 12-month period. CR of SRF was identified in all patients. BCVA significantly improved between 3 and 12 months (P < 0.05). The CRT significantly decreased between 1 and 12 months. A significantly thicker ONL was observed at 1 month, and 17 eyes (77.2 %) showed recovery of the continuous foveal IS/OS line. ONL thickness was correlated with BCVA at 12 months (P < 0.01). Stepwise analysis indicated that pre-treatment BCVA (P < 0.01) and ONL thickness (P < 0.01) were significant predictive factors for BCVA at 12 months. Neither ocular nor systemic adverse effects were observed during the follow-up period. CONCLUSION: RFPDT appears to be an effective treatment method for CSC. ONL thickness is an important visual predictive factor of RFPDT for CSC.

Autosomal dominant occult macular dystrophy with an RP1L1 mutation (R45W).

PURPOSE: To characterize clinical features in occult macular dystrophy (OMD) patients with the RP1L1 gene mutation (p.R45W), one of two previously described mutations in Japanese OMD patients. METHODS: Mutational screening of the RP1L1 gene was performed via polymerase chain reaction and direct sequencing for seven unrelated probands (one autosomal dominant and six sporadic probands) with OMD. A comprehensive ophthalmic examination was performed, including Cirrus optical coherence tomography. Full-field electroretinography (ERG), multifocal ERG, and focal macular ERG were performed. RESULTS: The heterozygous mutation (p.R45W) was found in only one female proband with autosomal dominant OMD, whose mother was also diagnosed with OMD and carried the mutation. Ophthalmoscopy showed bilateral normal fundi in the proband but subtle retinal pigment epithelium mottling in the mother. Both the proband and her mother had typical OMD findings: decreased visual acuity and markedly reduced central responses in the multifocal ERG and focal macular ERG. Although full-field ERG revealed normal rod and standard combined responses, photopic and 30-Hz flicker responses were slightly reduced in both the proband and her mother. Optical coherence tomography revealed that the external limiting membrane and inner segment-outer segment boundary were disorganized despite normal macular thickness in the proband, whereas the mother exhibited macular thinning with discontinuous reflectivity of the external limiting membrane and inner segment-outer segment boundary. CONCLUSIONS: The clinical phenotypes differed between the proband and her mother and were indistinguishable from other sporadic or RP1L1-unassociated OMD patients, suggesting that mutation-dependent clinical features may not be present.

High-Resolution Adaptive Optics Retinal Image Analysis at Early Stage Central Areolar Choroidal Dystrophy With PRPH2 Mutation.

BACKGROUND AND OBJECTIVE: To report the clinical features of Japanese patients at Stage 1 and 2 of central areolar choroidal dystrophy (CACD). PATIENTS AND METHODS: Five family members had comprehensive ophthalmic examinations including adaptive optics (AO) retinal imaging. Mutation analysis of the PRPH2 gene was performed by Sanger sequencing. The protocol conformed to the tenets of the Declaration of Helsinki and was approved by the institutional review board of The Jikei University School of Medicine. RESULTS: Four family members had a heterozygous PRPH2 mutation, p.R172Q; however, one member with a mutation did not show any ophthalmological abnormalities. Two patients had mild parafoveal retinal dystrophy and a reduction of cone density determined by AO analysis. CONCLUSION: The results indicate that the parafoveal cone photoreceptors can be affected even at the early stage of CACD. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1115-1126.].

Pedicle Internal Limiting Membrane Transposition Flap Technique for Refractory Macular Hole.

BACKGROUND AND OBJECTIVE: To determine the efficacy of the pedicle internal limiting membrane (ILM) transposition flap technique for refractory macular holes (MHs) in which the inverted ILM flap technique cannot be performed. PATIENTS AND METHODS: The pedicle ILM flap transposition technique was conducted by transconjunctival microincision vitrectomy. The authors attempted to peel the remaining ILM inferior from the MH to create an ILM flap. This ILM was still attached to the retina at the upper part of the MH and covered the MH. Finally, fluid-gas exchange was performed. After surgery, patients remained face-down for 1 week. This procedure was performed in two eyes. RESULTS: There were no adverse events, and MHs were closed successfully in both study eyes. CONCLUSION: The pedicle ILM flap transposition technique has the potential to improve functional and anatomical outcomes in patients with refractory MHs.

Trisection technique for the extraction of dislocated intraocular lenses through a small surgical incision.

UNLABELLED: We describe a trisection technique for extracting a dislocated IOL through a small surgical incision. The dislocated IOL is brought into the anterior chamber and cut into 3 equal segments, with a negligible risk for the segments falling into the vitreous cavity. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Mutation analysis of BEST1 in Japanese patients with Best's vitelliform macular dystrophy.

PURPOSE: To describe the clinical and genetic features of Japanese patients with Best's vitelliform macular dystrophy (BVMD). PATIENTS AND METHODS: This study examined 22 patients, including 16 probands from 16 families with BVMD. Comprehensive ophthalmic examinations were performed, including dilated funduscopy, full-field electroretinography (ERG) and electro-oculography (EOG). BEST1 mutation analysis was performed by Sanger sequencing. RESULTS: All 16 probands exhibited characteristic BVMD fundus appearances, abnormal EOG, and normal ERG responses with the exception of one diabetic retinopathy proband. Genetic analysis identified 12 BEST1 variants in 13 probands (81%). Of these, 10 variants (p.T2A, p.R25W, p.F80L, p.V81M, p.A195V, p.R218H, p.G222E, p.V242M, p.D304del and p.E306D) have been previously reported in BVMD, while two variants (p.S7N and p.P346H) were novel, putative disease-causing variants. Single BEST1 variants were found in 12 probands. The one proband with compound heterozygous variants (p.S7N and p.R218H) exhibited typical BVMD phenotypes (pseudohypopyon stage and vitelliruptive stage in the right and left eyes, respectively). CONCLUSIONS: Twelve different variants, two of which (p.S7N and p.P346H) were novel, were identified in the 13 Japanese families with BVMD. Compound heterozygous variants were found in one proband exhibiting a typical BVMD phenotype. Our results suggest that BEST1 variants do play a large role in Japanese patients with BVMD.

2,4,6-trinitrotoluene-induced reproductive toxicity via oxidative DNA damage by its metabolite.

Several epidemiological studies and animal experiments showed that 2,4,6-trinitrotoluene (TNT), a commonly used explosive, induced reproductive toxicity. To clarify whether the toxicity results from the interference of endocrine systems or direct damage to reproductive organs, we examined the effects of TNT on the male reproductive system in Fischer 344 rats. TNT administration induced germ cell degeneration, the disappearance of spermatozoa in seminiferous tubules, and a dramatic decrease in the sperm number in both the testis and epididymis. TNT increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in sperm whereas plasma testosterone levels did not decrease. These results suggest that TNT-induced toxicity is derived from direct damage to spermatozoa rather than testosterone-dependent mechanisms. To determine the mechanism of 8-oxodG formation in vivo, we examined DNA damage induced by TNT and its metabolic products in vitro. 4-Hydroxylamino-2,6-dinitrotoluene, a TNT metabolite, induced Cu(II)-mediated damage to 32P-labeled DNA fragments and increased 8-oxodG formation in calf thymus DNA, although TNT itself did not. DNA damage was enhanced by NADH, suggesting that NADH-mediated redox reactions involving TNT metabolites enhanced toxicity. Catalase and bathocuproine inhibited DNA damage, indicating the involvement of H2O2 and Cu(I). These findings suggest that TNT induces reproductive toxicity through oxidative DNA damage mediated by its metabolite. We propose that oxidative DNA damage in the testis plays a role in reproductive toxicity induced by TNT and other nitroaromatic compounds.

Three-year visual outcome of photodynamic therapy plus intravitreal bevacizumab with or without subtenon triamcinolone acetonide injections for polypoidal choroidal vasculopathy.

PURPOSE: To compare the 3-year visual outcome after double therapy of photodynamic therapy (PDT) with intravitreal bevacizumab (IVB) and triple therapy of PDT combined with IVB and subtenon triamcinolone acetonide (STTA) injections for polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective, comparative, interventional case series. METHODS: Medical records for 36 eyes in 36 patients (33 men, 3 women; mean age 73.5 years old; range 63-82 years old) with treatment-naive subfoveal PCV were reviewed retrospectively. Of the 36 eyes, 17 were treated with double therapy and 19 with triple therapy. RESULTS: The change in visual acuity after triple therapy was significantly better than that after double therapy (p<0.05). At 36 months, improvement in visual acuity was seen in 5 eyes (29.4%) in the double therapy group and 10 eyes (52.6%) in the triple therapy group. Retreatment using the initial treatment was performed for six eyes (35.3%) in the double therapy group and five eyes (26.3%) in the triple therapy group, and treatment-free period was significantly longer in the triple therapy group (p<0.05). The mean number of additional antivascular endothelial growth factor therapy was higher in the double therapy group. Post-treatment vitreous haemorrhage or retinal pigment epithelium tear occurred only in the double therapy group, in one eye (5.9%) and one eye (5.9%), respectively. CONCLUSIONS: Initial therapy consisting of a single session of PDT combined with IVB and STTA improves vision in treatment-naive subfoveal PCV. Compared with double therapy, this triple therapy may be more effective for PCV.

Retinal angiomatous proliferation associated with risk alleles of ARMS2/HTRA1 gene polymorphisms in Japanese patients.

BACKGROUND: The purpose of this study was to investigate the association between ARMS2/HTRA1, CFH, and C3 gene polymorphisms and retinal angiomatous proliferation (RAP), an infrequent and severe form of exudative age-related macular degeneration, which is characterized by intraretinal neovascularization. METHODS: Diagnosis of RAP was based on fundus photographs, images of fluorescein and indocyanine green angiographies, and optical coherence tomography findings. Six single nucleotide polymorphisms (SNPs), A69S (rs10490924) in ARMS2, rs11200638 in HTRA1, I62V (rs800292) in CFH, Y402H (rs1061170) in CFH, R80G (rs2230199) in C3, and rs2241394 in C3, were genotyped in eight Japanese patients with RAP. RESULTS: The two SNPs in the ARMS2/HTRA1 were in complete linkage disequilibrium. The frequency of the risk T allele in ARMS2 (the risk A allele in HTRA1) was 93.8% in the RAP patients. The frequency of homozygosity for the risk genotype TT of ARMS2 (the risk genotype AA of HTRA1) was 87.5%. The frequency of the non-risk allele (A) of I62V was 100%. The frequencies of risk alleles of Y402H, R80G, and rs2241394 were 12.5%, 0%, and 18.8%, respectively. CONCLUSION: Our results suggest that the risk alleles of the ARMS2/HTRA1 SNPs may be associated with development of RAP and play a major role in the pathogenesis of intraretinal angiogenesis.

Efficacy of reduced-fluence photodynamic therapy for serous retinal pigment epithelial detachment with choroidal hyperpermeability.

BACKGROUND: Very few reports have addressed methods of treatment for idiopathic serous (IS) pigment epithelial detachment (PED). OBJECTIVE: The purpose of this report was to describe clinical courses of two patients with ISPED in whom reduced-fluence photodynamic therapy (RFPDT) was performed. CASE REPORTS: Two patients (a 38-year-old woman and a 42-year-old man) were diagnosed with ISPED. In both patients, indocyanine green angiography revealed an area of choroidal vascular hyperpermeability including hyperfluorescent PED, which was evident at the subfoveal area. Both patients underwent RFPDT at an energy of 25 J/cm(2). The PED was seen to have resolved 1 month after the treatment and visual acuity was maintained or improved. There was no posttreatment recurrence of PED after 6 months to 1 year, and no treatment-related adverse events were observed. CONCLUSION: RFPDT may be an effective and safe method of treatment for ISPED with choroidal vascular hyperpermeability.