Mutations in RPGR and RP2 account for 15% of males with simplex retinal degenerative disease.

PURPOSE: To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2. METHODS: Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. RESULTS: We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region). CONCLUSIONS: This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration.

Residual electroretinograms in young Leber congenital amaurosis patients with mutations of AIPL1.

PURPOSE: To describe in detail the clinical phenotype and electrophysiological features of three patients with Leber congenital amaurosis caused by mutations of AIPL1. METHODS: Ophthalmologic examination, color fundus photography, detailed electrophysiological assessment, and screening of AIPL1 were undertaken in three subjects. One patient also underwent visual field testing and spectral domain-optical coherence tomography. RESULTS: All three patients, two of whom were siblings, had histories consistent with Leber congenital amaurosis (severely reduced vision, poorly responsive pupils, and nystagmus presenting within the first year of life). However, each patient had recordable and similar electroretinograms (ERGs), which demonstrated absent cone-driven responses and slow insensitive scotopic responses. The first patient was found to have a homozygous Trp278 stop mutation in AIPL1, whereas the siblings were each found to have novel heterozygous mutations in AIPL1 (Leu17Pro and Lys214Asn). CONCLUSIONS: Patients with mutations in AIPL1 may present with Leber congenital amaurosis and residual ERGs characterized by slow insensitive scotopic responses. Such responses are likely seen only in very young patients and may not be seen with the typical filter settings recommended by the ISCEV standards because of low-pass filtering. Progressive loss of residual ERG activity in young LCA patients with AIPL1 mutations suggests that gene replacement therapy will likely have to be performed early.

Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy.

OBJECTIVE: To report the detailed clinical findings of patients with retinal toxicity that developed secondary to the use of hydroxychloroquine sulfate (n = 13), chloroquine phosphate (n = 2), or a combination of the agents (n = 1). METHODS: Ophthalmologic examination, fundus photography, visual field testing, and detailed electrophysiologic assessment were undertaken in all 16 affected patients. Selected patients also had spectral domain optical coherence tomography (n = 6) and fundus autofluorescence imaging (n = 4). RESULTS: Sixteen women (mean age, 67 years; range, 44-85) were monitored for 7 years. The mean duration of hydroxychloroquine therapy was 13 years (range, 2-20). In patients in whom the daily dosage of hydroxychloroquine could be estimated (12 of 13), when using actual body weight, 8 were taking 6.5 mg/kg or less and 4 were taking greater than this recommended dosage. However, if lean body weight was used, 3 patients were taking 6.5 mg/kg or less and 9 were taking greater than this daily dosage. The most common (n = 10) presenting symptom was difficulty with reading; 4 women were asymptomatic. Two patients had preexisting retinal disease, 2 were obese, and none had renal or liver dysfunction. Fundus findings ranged from mild retinal pigment epithelial changes to bull's-eye maculopathy; 3 patients had a normal-appearing macula. Two patients had full-field electroretinograms that showed no abnormalities and 6 showed evidence of generalized retinal dysfunction with reduced rod and cone responses. All 15 patients who underwent multifocal electroretinography testing had evidence of bilateral macular cone dysfunction. Four patterns of visual field abnormality were observed in the 15 patients with abnormal visual fields, the most common (n = 10) being isolated central loss. Repeat electrophysiologic and visual field assessment provided evidence of disease progression despite cessation of medication in 6 patients, with documented progression for 7 years in 1 woman. CONCLUSIONS: Sustained visual improvement following cessation of drug therapy was not observed in any patient in this series, and our identification of 6 patients with objective evidence of progression serves to remind physicians of the potentially devastating visual consequences of antimalarial-related retinal toxicity. It is also of note that profound abnormalities detected with visual field and multifocal electroretinography testing can be observed in the presence of a normal macular appearance, and our findings suggest that lean body weight should be used for all patients when calculating daily dosage.

The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis.

PURPOSE: To describe in detail the characteristic clinical phenotype and electrophysiological features of Severe Early Childhood Onset Retinal Dystrophy (SECORD) caused by mutation of RPE65. METHODS: Ophthalmological examination, color fundus photography, visual field testing, detailed electrophysiological assessment, and screening of RPE65 were undertaken in five subjects. Selected patients also had spectral domain optical coherence tomography. RESULTS: All five patients had life-long, extremely poor night vision. Variable degrees of nystagmus were present; three cases lacked nystagmus at the time of assessment. Bilateral disc drusen were evident in three subjects. While case 1 had an undetectable electroretinogram and features supporting a diagnosis of Leber congential amaurosis (LCA) as an infant, her level of acuity and function into the second decade of life was more consistent with SECORD. In two cases, both vision and electrophysiological responses were seen to improve into the second decade of life. The objective demonstration of improved retinal function over time, with electrophysiological testing, has not been previously reported. Cases 4 and 5 had evidence of fine white retinal dots. The authors propose that these represent abnormal accumulations of retinyl esters, as has been demonstrated in animal models, and has also been observed as lipid droplets within the retinal pigment epithelium (RPE). These white dots were seen to fade with time in the patients and were replaced by RPE changes. CONCLUSIONS: The identification of patients with mutations in RPE65 has attained greater significance now that gene replacement trials have begun. The features presented in this article assist in the recognition of this form of LCA/SECORD.