Hiroyuki Sakuramoto

Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy.

PURPOSE To determine the clinical and genetic characteristics of Japanese patients with occult macular dystrophy (OMD) in a nationwide multicenter study. METHODS Twenty-three patients from 21 families with clinically diagnosed OMD were studied at 10 institutions throughout Japan. Ophthalmologic examinations including spectral-domain optic coherence tomography were performed. Patients were classified into two phenotype groups: a classical group having both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors, and a nonclassical group lacking at least one of these two features. Whole-exome sequencing, direct sequencing, and in silico molecular analysis were performed to detect the pathogenic RP1L1 variants. Statistical associations between the phenotype and genotypes based on the presence of pathogenic RP1L1 variants were investigated. RESULTS There were 12 families with the classical findings and 9 families with the nonclassical findings. Nine pathogenic RP1L1 missense variants were identified in 12 families (57%) including three reported variants, namely, p.R45W, p.S1199C, and p.G1200A, and six novel variants, p.G221R, p.T1194M, p.T1196I, p.G1200D, p.G1200V, and p.V1201G. The pathogenic missense variants in seven families (33%) were located between amino acid numbers 1196 and 1201. A significant association was found between the photoreceptor microstructural phenotypes and molecular genotypes. CONCLUSIONS The spectrum of the morphologic phenotypes and pathogenic RP1L1 variants was documented in a well-characterized Japanese cohort with OMD. A unique motif including six amino acids (1196-1201) downstream of the doublecortin domain could be a hot spot for RP1L1 pathogenic variants. The significant association of the morphologic phenotypes and genotypes indicates that there are two types of pathophysiology underlying the occult macular dysfunction syndrome: a hereditary OMD with the classical phenotype (Miyakes disease), and a nonhereditary OMD-like syndrome with progressive occult maculopathy.

Two siblings with late-onset cone-rod dystrophy and no visible macular degeneration.

Background We report our findings in two siblings with late-onset cone–rod dystrophy (CRD) with no visible macular degeneration. Cases and methods Case 1 was an 82-year-old man who first noticed a decrease in vision and color blindness in his early seventies. His mother and younger sister also had visual disturbances. His decimal visual acuity was 0.3 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed normal fundi, and fluorescein angiography was also normal in both eyes. The photopic single flash and flicker eletroretinograms (ERGs) were severely attenuated and the scotopic ERGs were slightly reduced in both eyes. Case 2 was the 80-year-old younger sister of Case 1. She first noticed a decline in vision and photophobia in both eyes in her early seventies. Her decimal visual acuity was 0.4 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed mottling of the retinal pigment epithelium in the midperiphery with no visible macular degeneration. The photopic single flash and flicker ERGs were severely attenuated, and the scotopic ERGs were slightly reduced in both eyes. Conclusion These siblings are the oldest reported cases of CRD with no visible macular degeneration. Thus, CRD should be considered in patients with reduced visual acuity, color blindness, and photophobia even if they are older than 70 years.

Novel Mutations in Enhanced S-cone Syndrome

Dear Editor: Enhanced S-cone syndrome (ESCS) is a rare and unique retinal dystrophy with a pattern of autosomal-recessive inheritance. Patients with ESCS show night blindness and high sensitivity to short-wavelength light, because of the 2-fold increased number of short-wavelength-sensitive cones (S cones) with absence of rods in the retina. Since the first discovery of mutations in the NR2E3 gene on chromosome 15q23 in patients with ESCS, 40 mutations have been reported as causes of ESCS and allied diseases (Fig 1, available online at http://aaojournal.org). In this letter, we report novel mutations in the NR2E3 gene that were discovered in 2 cases with ESCS. Cases are 2 Japanese patients who were reported previously. Case 1 was a 31-year-old man whose parents were consanguineous. His vision was 0.7 in the right eye and 0.3 in the left eye. Funduscopy revealed retinal degeneration surrounding the vascular arcade with cystic changes in both maculae (Fig 2, available online at http://aaojournal.org). Perimetry showed ring-shaped scotoma and electrophysiology showed unique responses corresponding to ESCS (Figs 3–6, available online at http://aaojournal.org). During 23-year clinical follow-up, clumped pigmentation has appeared in the retinal degeneration and the cystic changes in the foveal region have become ambiguous (Fig 2). His latest vision was 0.5 in the right eye and 0.3 in the left eye at age 53. Genetic analysis revealed a novel nucleotide substitution (c.151G A) in exon 2 homozygously, resulting in a novel missense mutation (a glycine-to-arginine substitution) at amino acid position 51 (p.G51R; Fig 7; available online at http://aaojournal.org). Case 2 was a 78-year-old woman. Funduscopy showed diffuse mild retinal degeneration with no pigmentation in both eyes (Fig 8, available online at http://aaojournal.org). Optical coherence tomography showed a subtle foveal schisis in the left eye, although the structure of the retina including the outer nuclear layer in the macular area was relatively well maintained (Fig 8). After cataract surgery, her vision improved to 0.3 in the right eye and 0.2 in the left. Genetic analysis revealed compound heterozygous mutations of c.142C T (exon 2) and c.311G A (exon 3), resulting in an arginine-to-cysteine substitution at amino acid position 48 (p.R48C) and an arginine-to-glutamine substitution at amino acid position 104 (p.R104Q; Fig 7). A daughter of case 2 who was asymptomatic and had normal fundus appearance showed only the p.R48C mutation heterozygously, that indicated she was an unaffected carrier relative (Fig 7). NR2E3 protein, a photoreceptor-specific orphan nuclear receptor, plays an important role in the development and differentiation of rods and all cone classes. NR2E3 has 2 functionally important domains, namely, the DNA-binding domain (DBD) and the ligand-binding domain (Fig 1). Mutations within these domains result in serious dysfunction of NR2E3 protein leading to abnormal process of development and differentiation of multipotent progenitor cells to rods and cones. Genetic analysis revealed a homozygous mutation (p.G51R) in case 1 and compound heterozygous mutations of (p.R48C) and (p.R104Q) in case 2. Among these mutations, (p.G51R) and (p.R48C) are novel as causative mutations of ESCS. The mutation (p.G51R) found in case 1 resides in the first zinc finger of the DBD, and the compound heterozygous mutations (p.R48C and p.R104Q), which were found in case 2 reside in the first and second zinc fingers of the DBD. Because the zinc fingers are necessary for maintenance the structure of NR2E3 protein, these mutations in the zinc fingers of NR2E3 result in phenotypes as ESCS (Fig 1). Clinically, case 1 with a homozygous missense mutation (p.G51R) showed typical features as ESCS, whereas case 2 with compound heterozygous mutations (p.R48C and p.R104Q) showed mild retinal degeneration and has kept some level of vision and construction of the macula despite advanced age. In the past, the mutation (p.R104Q) has never been reported except in 1 case, which demonstrated the normal structure and function of the macula with recordable rod electrophysiology. These facts indicate the mutation (p.R104Q) may be correlated with the relatively mild clinical findings as ESCS. We identified 2 novel missense mutations (p.G51R and p.R48C) as causes of ESCS. To our knowledge, the finding of case 1 is the longest-observed clinical case ever reported, and case 2 is the oldest case among all the patients with ESCS so far reported. KAZUKI KUNIYOSHI, MD, TAKAAKI HAYASHI, MD, HIROYUKI SAKURAMOTO, MD, AKIRA NAKAO, MD, TAKASHI SATO, MD, TOMOHIRO UTSUMI, HIROSHI TSUNEOKA, MD, YOSHIKAZU SHIMOMURA, MD Department of Ophthalmology, Kinki University, Faculty of Medicine, Osaka, Japan; Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan

Intravitreal Injection of Bevacizumab for Retinopathy of Prematurity in an Infant with Peters Anomaly

Purpose: To report our findings in an infant with Peters anomaly type II whose retinopathy of prematurity (ROP) was treated with an anti-VEGF agent and surgeries. Case Report: A male infant weighing 548 g was born prematurely at 23 weeks and 1 day with corneal opacity and shallow anterior chambers in both eyes. At the postmenstrual age of 35 weeks and 3 days, the infant was tentatively diagnosed with stage 3 ROP because of a dilated tunica vasculosa lentis and ultrasonographic findings. The boy was treated with bilateral intravitreal injections of bevacizumab (IVB) because laser photocoagulation of the retina could not be performed due to the corneal opacity. The retina in the right eye detached 3 times, namely 5 days, 16 days, and 7 months after the IVB; encircling the scleral buckle and a vitrectomy with endolaser photocoagulation were therefore required. In his left eye, the retina was reattached after the initial IVB, and no additional treatment was required. ROP was not reactivated in both eyes until the last examination at the age of 2 years and 6 months. Conclusions: Our results showed that IVB is a useful treatment for ROP in patients with Peters anomaly. However, a retinal detachment can be a complication after IVB. The optimal timing of IVB for ROP in infants with hazy media needs to be determined.

Reduced rod electroretinograms in carrier parents of two Japanese siblings with autosomal recessive retinitis pigmentosa associated with PDE6B gene mutations

PurposeTo present the clinical and genetic findings in two siblings with autosomal recessive retinitis pigmentosa (RP) and their non-symptomatic parents.MethodsWe studied two siblings, a 48-year-old woman and her 44-year-old brother, and their parents. They had general ophthalmic examinations including ophthalmoscopy, perimetry, and electroretinography (ERG). Their whole exomes were analyzed by the next-generation sequence technique.ResultsThe two siblings had night blindness for a long time, and clinical examinations revealed diffuse retinal degeneration with bone spicule pigmentation, constriction of the visual field, and non-recordable ERGs. Their parents were non-symptomatic and had normal fundi; however, their rod ERGs were reduced. Genetic examination revealed compound heterozygous mutations of I535N and H557Y in the PDE6B gene in the siblings, and the parents were heterozygous carriers of the mutations.ConclusionsHeterozygous mutation in the PDE6B gene can cause a reduction in the rod function to different degrees. The retinal function of non-symptomatic carriers of autosomal recessive RP should be evaluated with care.