Purpose: Photoreceptor neuronal degenerations are common, incurable causes of human blindness affecting 1 in 2000 patients worldwide. Only half of all patients are associated with known mutations in over 250 disease genes, prompting our research program to identify the remaining new genes. Most retinal degenerations are restricted to the retina, but photoreceptor degenerations can also be found in a wide variety of systemic diseases. We identified an X-linked family from Sri Lanka with a severe choroidal degeneration and postulated a new disease entity. Because of phenotypic overlaps with Bietti's crystalline dystrophy, which was recently found to have systemic features, we hypothesized that a systemic disease may be present in this new disease as well. Methods: For phenotyping, we performed detailed eye exams with in vivo retinal imaging by optical coherence tomography. For genotyping, we performed whole exome sequencing, followed by Sanger sequencing confirmations and cosegregation. Systemic investigations included electron microscopy studies of peripheral blood cells in patients and in normal controls and detailed fatty acid profiles (both plasma and red blood cell [RBC] membranes). Fatty acid levels were compared to normal controls, and only values two standard deviations above or below normal controls were further evaluated. Results: The family segregated a REP1 mutation, suggesting choroideremia (CHM). We then found crystals in peripheral blood lymphocytes and discovered significant plasma fatty acid abnormalities and RBC membrane abnormalities (i.e., elevated plasmalogens). To replicate our discoveries, we expanded the cohort to nine CHM patients, genotyped them for REP1 mutations, and found the same abnormalities (crystals and fatty acid abnormalities) in all patients. Conclusions: Previously, CHM was thought to be restricted to the retina. We show, to our knowledge for the first time, that CHM is a systemic condition with prominent crystals in lymphocytes and significant fatty acid abnormalities.

Retinitis pigmentosa (RP) is a chronic progressive disease with no curative treatments. Understanding the variables involved with improving patients’ quality of life is important in managing this population. The literature investigating the relationship of anxiety and depression with RP relies on the analysis of smaller subset populations of patients with RP, and no study has quantified the effect size of the potential association. This study aims to elucidate and quantify the association between RP, anxiety, and depression. A retrospective case-control study was conducted of 6 093 833 medical records within the University of North Carolina Hospital and outpatient clinic system from July 1, 2004, to August 30, 2019. Patients with a diagnosis of RP, anxiety, and depression were identified within the Carolina Data Warehouse for Health by International Classification of Diseases, Ninth and Tenth Revision codes. From the base population of 6 093 833 patients' medical records, 690 patients were diagnosed with RP, 253 065 with anxiety, and 232 541 with depression. Patients with RP have an odds ratio, adjusted for sex and age, of 4.915 (95% CI, 4.035-5.987) for having comorbid anxiety, 5.609 (95% CI, 4.622-6.807) for comorbid depression, and 4.130 (95% CI, 3.187-5.353) for comorbid anxiety and depression. Patients with RP have a higher prevalence of anxiety and depression, with increased odds of approximately 5 to 6 times for also carrying a diagnosis of anxiety or depression and about 4 times for carrying diagnoses of anxiety and depression compared with the general population.