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To describe the relationships between foveal structure and visual function in a cohort of individuals with foveal hypoplasia (FH) and to estimate FH grade and visual acuity using a deep learning classifier.Retrospective cohort study and experimental study.A total of 201 patients with FH were evaluated at the National Eye Institute from 2004 to 2018.Structural components of foveal OCT scans and corresponding clinical data were analyzed to assess their contributions to visual acuity. To automate FH scoring and visual acuity correlations, we evaluated the following 3 inputs for training a neural network predictor: (1) OCT scans, (2) OCT scans and metadata, and (3) real OCT scans and fake OCT scans created from a generative adversarial network.The relationships between visual acuity outcomes and determinants, such as foveal morphology, nystagmus, and refractive error.The mean subject age was 24.4 years (range, 1-73 years; standard deviation = 18.25 years) at the time of OCT imaging. The mean best-corrected visual acuity (n = 398 eyes) was equivalent to a logarithm of the minimal angle of resolution (LogMAR) value of 0.75 (Snellen 20/115). Spherical equivalent refractive error (SER) ranged from -20.25 diopters (D) to +13.63 D with a median of +0.50 D. The presence of nystagmus and a high-LogMAR value showed a statistically significant relationship (Nystagmus and foveal anatomy impact visual outcomes in patients with FH, and computational algorithms reliably estimate FH grading and visual acuity.

Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibular evoked myogenic potentials in contradiction to the classical assumption of normal vestibular function. The surprising lack of consistent genotypic to vestibular phenotypic findings as well as no clear vestibular phenotypic patterns among atypical USH cases, indicate that even rigorous vestibular phenotyping data will not reliably differentiate the three USH types.

The diagnosis of a heritable (Mendelian) eye condition can have a significant impact on patients and their families. Although a diverse group of conditions, many Mendelian eye conditions are early-onset, untreatable, progressive, and result in significant visual disability. To increase understanding of the challenges faced by this population, we review studies describing the psychosocial impacts of Mendelian eye conditions. Reduced mental health and quality of life and increased strain on relationships are common themes. We synthesize the evidence presented in this review to propose an overall model of illness factors, cultural factors, psychosocial impacts, and quality of life. Finally, we discuss implications for patient management and future research directions.

Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone-rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018. Three unrelated sporadic cases were systematically evaluated for ocular phenotype and determined to have cone-rod dystrophy with bull's eye maculopathy, photophobia, and nystagmus. All patients had amelogenesis imperfecta. Two of these patients had Guatemalan ancestry and the same novel homozygous CNNM4 variant (p.Arg236Trp c.706C > T) without evidence of consanguinity. This variant met likely pathogenic criteria by the American College of Medical Genetics guidelines. An additional patient had a homozygous deleterious variant in CNNM4 (c.279delC p.Phe93Leufs*31), which resulted from paternal uniparental isodisomy for chromosome 2p22-2q37. This individual had additional syndromic features including developmental delay and spastic diplegia, likely related to mutations at other loci. Our work highlights the genotypic variability of Jalili syndrome and expands the genotypic spectrum of this condition by describing the first series of patients seen in the United States.

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

Purpose To characterize the ocular phenotype of DICER1 syndrome. Design Prospective, single-center, case-control study. Participants One hundred three patients with an identified germline pathogenic DICER1 variant (DICER1 carriers) and 69 family control participants underwent clinical and ophthalmic examination at the National Institutes of Health between 2011 and 2016. Methods All participants were evaluated with a comprehensive ophthalmic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, and a dilated fundus examination. A subset of patients returned for a more detailed evaluation including spectral-domain OCT, color fundus photography, fundus autofluorescence imaging, visual field testing, full-field electroretinography, and genetic testing for inherited retinal degenerative diseases. Main Outcome Measures Visual acuity and examination findings. Results Most DICER1 carriers (97%) maintained a visual acuity of 20/40 or better in both eyes. Twenty-three DICER1 carriers (22%) showed ocular abnormalities compared with 4 family controls (6%; P = 0.005). These abnormalities included retinal pigment abnormalities (n = 6 [5.8%]), increased cup-to-disc ratio (n = 5 [4.9%]), optic nerve abnormalities (n = 2 [1.9%]), epiretinal membrane (n = 2 [1.9%]), and drusen (n = 2 [1.9%]). Overall, we observed a significant difference (P = 0.03) in the rate of retinal abnormalities in DICER1 carriers (n = 11 [11%]) versus controls (n = 1 [1.5%]). One patient demonstrated an unexpected diagnosis of retinitis pigmentosa with a novel variant of unknown significance in PRPF31, and 1 showed optic nerve elevation in the setting of increased intracranial pressure (ICP) of unclear cause. Three patients (3%) demonstrated DICER1-related ciliary body medulloepithelioma (CBME), 2 of which were identified during routine examination, a higher rate than that reported previously. Conclusions Ophthalmologists should be aware of the ophthalmic manifestations of DICER1 syndrome, and individuals and families should be counseled on the potential signs and symptoms. We recommend that children with a germline pathogenic variant in DICER1, especially those younger than 10 years, undergo annual dilated ophthalmic examination, looking for evidence of CBME, signs of increased ICP, and perhaps changes in the retinal pigment epithelium.

IMPORTANCE: Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix. OBJECTIVE: To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence. DESIGN, SETTING, AND PARTICIPANTS: This case series of 2 families with early-onset diffuse maculopathy was conducted at the National Eye Institute, National Institutes of Health Clinical Center. Data were collected and analyzed from October 2009 to December 2021. MAIN OUTCOMES AND MEASURES: Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were assessed for cleavage defects after transfection. RESULTS: Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed. Cosegregation with phenotype was confirmed in additional family members. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition. CONCLUSIONS AND RELEVANCE: This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition into the extracellular matrix, implicating a novel macular dystrophy disease.

Dark cone photoreceptors, defined as those with diminished or absent reflectivity when observed with adaptive optics (AO) ophthalmoscopy, are increasingly reported in retinal disorders. However, their structural and functional impact remain unclear. Here, we report a 3-year longitudinal study on a patient with oligocone trichromacy (OT) who presented with persistent, widespread dark cones within and near the macula. Diminished electroretinogram (ERG) cone but normal ERG rod responses together with normal color vision confirmed the OT diagnosis. In addition, the patient had normal to near normal visual acuity and retinal sensitivity. Occasional dark gaps in the photoreceptor layer were observed on optical coherence tomography, in agreement with reflectance AO scanning light ophthalmoscopy, which revealed that over 50% of the cones in the fovea were dark, increasing to 74% at 10° eccentricity. In addition, the cone density was 78% lower than normal histologic value at the fovea, and 20–40% lower at eccentricities of 5–15°. Interestingly, color vision testing was near normal at locations where cones were predominantly dark. These findings illustrate how a retina with predominant dark cones that persist over at least 3 years can support near normal central retinal function. Furthermore, this study adds to the growing evidence that cones can continue to survive under non-ideal conditions.

Background/Aims. Optic disc drusen (ODD) are calcified deposits of proteinaceous material in the optic disc, and their burden in ocular conditions is unknown. As ODD can be associated with visual field defects further compromising already degenerating visual function in patients with retinal degenerations, it is important to further our knowledge of ODD in inherited eye disease. The present study aims to evaluate prevalence, demographic features, and optic disc parameters of eyes with superficial ODD in inherited eye conditions. Materials and Methods. Electronic medical records of patients evaluated in the Ophthalmic Genetics clinic at the National Eye Institute (NEI) between 2008 and 2018 were searched for a superficial ODD diagnosis. Color fundus and autofluorescence images were reviewed to confirm ODD, supplemented with optical coherence tomography (OCT) in uncertain cases when available. Demographic information, examination, and genetic testing were reviewed. Disc areas and disc-to-macula distance to disc diameter ratios (DM : DD) were calculated. Results. Fifty six of 6207 patients had photographically confirmed ODD (0.9%). Drusen were predominantly bilateral (66%), with a female (62%) and Caucasian (73%) predilection. ODD prevalence in our cohort of patients with inherited retinal degenerations was 2.5%, and ODD were more prevalent in the rod-cone dystrophy subgroup at 2.95% (OR = 3.3 [2.1–5.3], P < 0.001 ) compared to the ophthalmic genetics cohort. Usher patients were more likely to have ODD (10/132, 7.6%, OR = 9.0 [4.3–17.7], P < 0.001 ) and had significantly smaller discs compared to the rest of our ODD cohort (disc area: P = 0.001 , DM : DD: P = 0.03 ). Discussion. While an association between ODD and retinitis pigmentosa has been reported, this study surveys a large cohort of patients with inherited eye conditions and finds the prevalence of superficial ODD is lower than that in the literature. Some subpopulations, such as rod-cone dystrophy and Usher syndrome, had a higher prevalence than the cohort as a whole.

Usher syndrome has classically been described as a combination of hearing loss and rod-cone dystrophy; vestibular dysfunction is present in many patients. Three distinct clinical subtypes were documented in the late 1970s. Genotyping efforts have led to the identification of several genes associated with the disease. Recent literature has seen multiple publications referring to "atypical" Usher syndrome presentations. This manuscript reviews the molecular etiology of Usher syndrome, highlighting rare presentations and molecular causes. Reports of "atypical" disease are summarized noting the wide discrepancy in the spectrum of phenotypic deviations from the classical presentation. Guidelines for establishing a clear nomenclature system are suggested.

Purpose To explore the experiences of parents of sons with X-linked retinoschisis (XLRS). Design Mixed methods—qualitative interviews with quantitative survey. Methods Parents of sons with XLRS who were evaluated at the National Eye Institute between December 2017 and January 2019 were eligible for this study. Participation involved engaging in a semistructured interview and completing a survey assessing optimism, anxiety, personality traits, and sociodemographics using valid and reliable scales. Interview transcripts were coded and analyzed thematically, and scales were scored and used descriptively. Results Eleven mothers and 8 fathers from 13 families participated. Optimism, anxiety, and personality traits fell into the normative ranges for the scales. Parents described a process of continuous adaptation to their son's condition. The initial diagnosis was characterized by shock, grief, and “devastation” for most parents. Maternal guilt was common, but usually lessened over time. As parents adjusted to life postdiagnosis, they attempted to achieve a state of normalcy while balancing a desire to protect their sons. Significant sources of stress included decisions around sports participation and driving. Among all parents, the fear of retinal detachment was an ongoing concern. Most parents did identify perceived benefits from their experiences, such as feelings of gratitude or family cohesion. Conclusions Most parents viewed XLRS as a significant challenge in their sons' lives, but one that could be overcome. Clinical encounters may be enhanced for families with XLRS by providing accurate information, preparing families for potential challenges, anticipating stressful decisions, and meeting other families with XLRS.

Multi-gene panel testing is used increasingly in ophthalmology practice as an efficient and cost-effective method for diagnosing inherited eye conditions. Panel testing is a powerful diagnostic tool, and it has the potential to reveal syndromic information in patients with seemingly isolated eye findings. This case series highlights our experience with 4 children in 3 families who were referred for evaluation of an isolated retinal degeneration and diagnosed with neuronal ceroid lipofuscinosis on panel testing. These cases are important reminders that several neurodegenerative conditions can present initially with isolated eye findings in childhood and pretest genetic counseling is critical.

Author(s): Cukras, Catherine A; Huryn, Laryssa A; Jeffrey, Brett G; Turriff, Amy; Sieving, Paul A | Abstract: PurposeTo examine the symmetry of structural and functional parameters between eyes in patients with X-linked retinoschisis (XLRS), as well as changes in visual acuity and electrophysiology over time.MethodsThis is a single-center observational study of 120 males with XLRS who were evaluated at the National Eye Institute. Examinations included best-corrected visual acuity for all participants, as well as ERG recording and optical coherence tomography (OCT) on a subset of participants. Statistical analyses were performed using nonparametric Spearman correlations and linear regression.ResultsOur analyses demonstrated a statistically significant correlation of structural and functional measures between the two eyes of XLRS patients for all parameters. OCT central macular thickness (n = 78; Spearman r = 0.83, P l 0.0001) and ERG b/a ratio (n = 78; Spearman r = 0.82, P l 0.0001) were the most strongly correlated between a participant's eyes, whereas visual acuity was less strongly correlated (n = 120; Spearman r = 0.47, P l 0.0001). Stability of visual acuity was observed with an average change of less than one letter (n = 74; OD -0.66 and OS -0.70 letters) in a mean follow-up time of 6.8 years. There was no statistically significant change in the ERG b/a ratio within eyes over time.ConclusionsAlthough a broad spectrum of clinical phenotypes is observed across individuals with XLRS, our study demonstrates a significant correlation of structural and functional findings between the two eyes and stability of measures of acuity and ERG parameters over time. These results highlight the utility of the fellow eye as a useful reference for monocular interventional trials.

PURPOSE: To characterize the ocular phenotype of DICER1 syndrome DESIGN: Prospective, single-center, case-control study SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: One hundred and three patients with an identified germline, pathogenic DICER1 variant (DICER1 -carriers) and 69 family control subjects underwent clinical and ophthalmic examination at the National Institutes of Health between 2011 and 2016. METHODS: All participants were evaluated with a comprehensive ophthalmic exam including best corrected visual acuity, slit-lamp biomicroscopy and a dilated fundus examination. A subset of patients returned for a more detailed evaluation including spectral-domain optical coherence tomography, color fundus photography, fundus autofluorescence imaging, visual field testing, full field electroretinogram and genetic testing for inherited retinal degenerative diseases. MAIN OUTCOME MEASURES: Visual acuity and examination findings RESULTS: Most DICERl-carriers (97%) maintained a visual acuity of 20/40 or better in both eyes. Twenty three DICERl-carriers (22%) had ocular abnormalities compared with four (6%) family controls (P=0.005). These abnormalities included retinal pigment abnormalities (N=6, 5.8%), increased cup-to-disc ratio (N=5, 4.9%), optic nerve abnormalities (N=2, 1.9%), epiretinal membrane (N=2, 1.9%) and drusen (N=2, 1.9%). Overall, we observed a significant difference (p= 0.03) in the rate of retinal abnormalities in DICERl-carriers (N=11, 11%) vs. controls (N=1;1.5%). One patient had an unexpected diagnosis of retinitis pigmentosa with a novel variant of unknown significance in PRPF31, and one had optic nerve elevation in the setting of increased intracranial pressure of unclear etiology. Three patients (3%) had DICERl-related ciliary body medulloepithelioma (CBME), two of which were identified during routine examination, a significantly higher rate than that previously reported. CONCLUSIONS: Ophthalmologists should be aware of the ophthalmic manifestations of the DICER1 syndrome and individuals and families should be counseled on the potential signs and symptoms. We recommend that children with a germline pathogenic variant in DICER1, especially those under the age of 10 years, undergo annual dilated ophthalmic examination, looking for evidence of CBME, signs of increased intracranial pressure and perhaps changes in the retinal pigment epithelium.

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).

PURPOSE Progressive decline of psychophysical cone-mediated measures has been reported in type 1 (USH1) and type 2 (USH2) Usher syndrome. Conventional cone electroretinogram (ERG) responses in USH demonstrate poor signal-to-noise ratio. We evaluated cone signals in USH1 and USH2 by recording microvolt level cycle-by-cycle (CxC) ERG. METHODS Responses of molecularly genotyped USH1 (n = 18) and USH2 (n = 24) subjects (age range, 15-69 years) were compared with those of controls (n = 12). A subset of USH1 (n = 9) and USH2 (n = 9) subjects was examined two to four times over 2 to 8 years. Photopic CxC ERG and conventional 30-Hz flicker ERG were recorded on the same visits. RESULTS Usher syndrome subjects showed considerable cone flicker ERG amplitude losses and timing phase delays (P < 0.01) compared with controls. USH1 and USH2 had similar rates of progressive logarithmic ERG amplitude decline with disease duration (-0.012 log μV/y). Of interest, ERG phase delays did not progress over time. Two USH1C subjects retained normal response timing despite reduced amplitudes. The CxC ERG method provided reliable responses in all subjects, whereas conventional ERG was undetectable in 7 of 42 subjects. CONCLUSIONS Cycle-by-cycle ERG showed progressive loss of amplitude in both USH1 and USH2 subjects, comparable to that reported with psychophysical measures. Usher subjects showed abnormal ERG response latency, but this changed less than amplitude with time. In USH syndrome, CxC ERG is more sensitive than conventional ERG and warrants consideration as an outcome measure in USH treatment trials.

Klinefelter syndrome (XXY) is a common yet significantly underdiagnosed condition with considerable medical, psychological and social implications. Many health care providers lack familiarity with XXY, resulting in medical management challenges and a limited understanding of the personal impact of the condition. Genetic counselors benefit from understanding the challenges adolescents and men with XXY face to effectively address their medical and psychosocial needs. The purpose of this study was to understand the impact of living with XXY as an adolescent or an adult. Individuals aged 14 to 75 years with self-reported XXY were recruited from online support networks to complete a web-based survey that included open-ended questions. Open-ended responses were coded and analyzed thematically (n = 169 to 210 for each open-ended question). Over half of respondents to the open-ended questions reported challenges in finding health care providers who are knowledgeable about XXY, with many describing an extensive diagnostic odyssey and relief when receiving a diagnosis. Individuals sought support coping with the challenges they face and acknowledgement of the positive aspects of XXY. Recommendations are made for how genetic counseling can enhance quality of life for individuals living with XXY.

Background Recessive mutant alleles of MYO7A , USH1C , CDH23 , and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23 , encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23 , all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth. Methods and results To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23 , where one mutation is a known or predicted USH1 allele. Conclusions 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.

BackgroundInherited retinal diseases are uncommon, and the likelihood of having more than one hereditary disorder is rare. Here, we report a case of Stargardt disease and congenital stationary night blindness (CSNB) in the same patient, and the identification of two novel in-frame deletions in the GRM6 gene.Materials and methodsThe patient underwent an ophthalmic exam and visual function testing including: visual acuity, color vision, Goldmann visual field, and electroretinography (ERG). Imaging of the retina included fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence. Genomic DNA was PCR-amplified for analysis of all coding exons and flanking splice sites of both the ABCA4 and GRM6 genes.ResultsA 46-year-old woman presented with recently reduced central vision and clinical findings of characteristic yellow flecks consistent with Stargardt disease. However, ERG testing revealed an ERG phenotype unusual for Stargardt disease but consistent with CSNB1. Genetic testing revealed two previously reported mutations in the ABCA4 gene and two novel deletions in the GRM6 gene.ConclusionsDiagnosis of concurrent Stargardt disease and CSNB was made on the ophthalmic history, clinical examination, ERG, and genetic testing. This case highlights that clinical tests need to be taken in context, and that co-existing retinal dystrophies and degenerations should be considered when clinical impressions and objective data do not correlate.

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.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).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.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.Clinical interventions can be designed based on PAS data to enhance dimensions of psychological adaptation to a chronic health condition or risk.

To determine the prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome.Individuals (n = 310) aged 14-75 years with self-reported Klinefelter syndrome 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.Overall, 68.8% of the study participants reported clinically significant levels of depressive symptoms as indicated by a Center for Epidemiologic Studies Depression Scale score ≥16. The use of emotion-focused coping strategies (P0.01), perceptions of stigmatization (P0.01), perceived negative consequences of Klinefelter syndrome (P0.01), and the importance of having children in the future (P0.05) were all significantly associated with depressive symptoms.Individuals with Klinefelter syndrome may be at increased risk for depression. Routine screening for depressive symptoms and appropriate referral and evaluation may be warranted.

A monogenic condition, X-linked retinoschisis (XLRS) is a leading genetic cause of macular degeneration in young males and affects 1:5000 to 1:25,000.1 It is caused by mutations in the retinoschisin gene (RS1) at Xp22.2 Nearly 150 disease-causing RS1 mutations have been identified.3 RS1 encodes a 24-kDa protein, retinoschisin (RS), which contains a discoidin domain and is found in the retina and pineal gland.4 Retinoschisin is thought to be important for cell adhesion and cell signaling because the protein has been demonstrated in the photoreceptor synapse onto bipolar cells.5 RS is associated with the Na+/K+ ATPase in the photoreceptor inner segment membrane.6 Atomic force microscopy implicates a structural role for retinoschisin in organizing lipid membranes, which may help to stabilize retinal cell integrity.7 XLRS subjects exhibit considerable heterogeneity on clinical examination and functional vision testing.8 Although most XLRS-affected males first come to attention for reduced acuity during school screening, some XLRS experience retinal detachments in infancy. In addition, our clinical cohort suggests that XLRS subjects rarely retain sufficient visual function to obtain an unrestricted driver's license by the fourth and fifth decades of life. The consequence of abnormal retinoschisin protein or complete absence of RS on retinal function can be evaluated clinically using the full-field electroretinogram (ERG). The characteristic dark-adapted bright-flash ERG response in XLRS is an “electronegative waveform” in which the b-wave amplitude is disproportionately smaller than the normal or near-normal a-wave. ERG a-wave modeling has shown that phototransduction remains normal in some XLRS subjects despite reduced b-waves,9 indicating that one site of dysfunction lies beyond the photoreceptors. Abnormal timing of the light-adapted 30-Hz cone flicker ERG response is also reported, further suggesting dysfunction of the inner retina when associated with normal a-wave responses.10 In this genotype-phenotype study, we used the full-field ERG to evaluate retinal function of 68 XLRS subjects who were examined and genotyped at the National Eye Institute (NEI). The RS1 gene contains six exons that encode for a signal sequence (exons 1 and 2), a retinoschisin domain (exon 3), and the discoidin domain (exons 4–6).2 Most RS1 mutations analyzed to date have implicated primarily a loss function rather than an abnormal function from the mutant protein.7 Signal sequence domain mutations impair protein transport to the endoplasmic reticulum and consequently yield a functional null-protein effect. Some discoidin domain mutations allow the production of retinoschisin mutant protein, but it is rapidly degraded and lost.11 The diversity and complexity of RS1 mutations precluded our incorporating all molecular nuances in a phenotype analysis. Instead, we simplified the approach by segregating the RS1 mutations into two groups based on the putative severity of effect on protein function. We included molecular modeling12 and, in some cases, biochemical analysis11 in this approach to classify our subjects as having either a less or a more severe mutation and a putative effect on the resultant protein. We then examined for an association of disease phenotype (ERG measurements) with genotype severity.

Purpose Ciliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple nonhuman models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia. Methods A five-subject, open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/d) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for 1 year. Results Pupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark-adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone-rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, or the photopic ERG. Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors. Conclusions Ciliary neurotrophic factor did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in response to CNTF. (ClinicalTrials.gov number, NCT01648452.).