This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. The investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887).

One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

Objective We introduce The Psychological Adaptation Scale (PAS) for assessing adaptation to a chronic condition or risk and present validity data from six studies of genetic conditions. Methods Informed by theory, we identified four domains of adaptation: effective coping, self-esteem, social integration, and spiritual/existential meaning. Items were selected from the PROMIS “positive illness impact” item bank and adapted from the Rosenberg self-esteem scale to create a 20-item scale. Each domain included five items, with four sub-scale scores. Data from studies of six populations: adults affected with or at risk for genetic conditions (N=3) and caregivers of children with genetic conditions (N=3) were analyzed using confirmatory factor analyses (CFA). Results CFA suggested that all but five posited items converge on the domains as designed. Invariance of the PAS amongst the studies further suggested it is a valid and reliable tool to facilitate comparisons of adaptation across conditions. Conclusion Use of the PAS will standardize assessments of adaptation and foster understanding of the relationships among related health outcomes, such as quality of life and psychological well-being. Practice Implications Clinical interventions can be designed based on PAS data to enhance dimensions of psychological adaptation to a chronic health condition or risk.

Purpose To determine the prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome (XXY). Methods Individuals (n=310) aged 14–75 years with self-reported XXY were recruited from regional and national support networks to complete a web-based survey. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Perceived consequences (Illness Perceptions Questionnaire), perceived stigma (Perceived Social Stigmatization Scale), and coping (Ways of Coping Checklist-Revised) were also measured and evaluated as correlates of depressive symptoms. Results 68.8% of the study participants reported clinically significant levels of depressive symptoms as indicated by a CES-D score ≥16. The use of emotion-focused coping strategies (p<0.01), perceptions of stigmatization (p<0.01), perceived negative consequences of XXY (p<0.01), and the importance of having children in the future (p<0.05) were all significantly associated with depressive symptoms. Conclusions Individuals with XXY may be at increased risk for depression. Routine screening for depressive symptoms and appropriate referral and evaluation may be warranted.