To describe multimodal imaging and electrophysiology features of CTNNA1-associated retinal dystrophy in a family with p.(Leu318Ser) substitution. 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. 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). 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. Retinal pattern dystrophies are a slowly progressive heterogeneous group of primarily autosomal dominantly inherited macular diseases whose unifying element involves the deposition of pigment in the retinal pigment epithelium (RPE) of the macula.  Although findings are classically and most often centered in the macula, pigment deposition may also occur in the periphery. Depending on the distribution pattern, these pattern dystrophies can be separated into major categories or types. These include reticular dystrophy, fundus pulverulentus, butterfly-shaped pigment dystrophy, adult-onset foveomacular vitelliform dystrophy, and multifocal pattern dystrophy simulating Stargardt disease. Interestingly, within a patient, a given pattern may transform into another pattern. Each eye may have distinct patterns, and the same familial mutation can correspond to different phenotypic patterns.  Visual prognosis is typically good in these patients, but due to the location of the pigment deposition in the macula and its slowly progressive nature, there is always the possibility of central vision loss and secondary complications such as choroidal neovascularization and macular holes. Patients typically remain asymptomatic until the fourth to fifth decade of life, when they may start to notice changes in central vision. The appearance of pattern dystrophies may lead to misdiagnosis as age-related macular degeneration (AMD), especially given that later stages of pattern dystrophies may resemble AMD and pigment deposits can resemble drusen. Distinguishing pattern dystrophies from AMD requires further workup and follow-up.

Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA). Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available. Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCD patients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA. This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA.

Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here we report the identification of heterozygous missense mutations in the CTNNA1 gene (encoding α-catenin 1) in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice demonstrated increased cell shedding and the presence of large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, indicates that CTNNA1 is involved in maintaining RPE integrity and suggests that other components that participate in intercellular adhesion may be implicated in macular disease.