Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort

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.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154406/1/ajmga61484_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154406/2/ajmga61484.pd

The Relevance of Marine Chemical Ecology to Plankton and Ecosystem Function: An Emerging Field

Marine chemical ecology comprises the study of the production and interaction of bioactive molecules affecting organism behavior and function. Here we focus on bioactive compounds and interactions associated with phytoplankton, particularly bloom-forming diatoms, prymnesiophytes and dinoflagellates. Planktonic bioactive metabolites are structurally and functionally diverse and some may have multiple simultaneous functions including roles in chemical defense (antipredator, allelopathic and antibacterial compounds), and/or cell-to-cell signaling (e.g., polyunsaturated aldehydes (PUAs) of diatoms). Among inducible chemical defenses in response to grazing, there is high species-specific variability in the effects on grazers, ranging from severe physical incapacitation and/or death to no apparent physiological response, depending on predator susceptibility and detoxification capability. Most bioactive compounds are present in very low concentrations, in both the producing organism and the surrounding aqueous medium. Furthermore, bioactivity may be subject to synergistic interactions with other natural and anthropogenic environmental toxicants. Most, if not all phycotoxins are classic secondary metabolites, but many other bioactive metabolites are simple molecules derived from primary metabolism (e.g., PUAs in diatoms, dimethylsulfoniopropionate (DMSP) in prymnesiophytes). Producing cells do not seem to suffer physiological impact due to their synthesis. Functional genome sequence data and gene expression analysis will provide insights into regulatory and metabolic pathways in producer organisms, as well as identification of mechanisms of action in target organisms. Understanding chemical ecological responses to environmental triggers and chemically-mediated species interactions will help define crucial chemical and molecular processes that help maintain biodiversity and ecosystem functionality

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Sorting out Co-occurrence of Rare Monogenic Retinopathies: Stargardt Disease Co-existing with Congenital Stationary Night Blindness

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

Analysis of Anatomic and Functional Measures in X-Linked Retinoschisis.

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 < 0.0001) and ERG b/a ratio (n = 78; Spearman r = 0.82, P < 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 < 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

“There Are Hills and Valleys”: Experiences of Parenting a Son With X-Linked Retinoschisis

PurposeTo explore the experiences of parents of sons with X-linked retinoschisis (XLRS).DesignMixed methods-qualitative interviews with quantitative survey.MethodsParents 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.ResultsEleven 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.ConclusionsMost 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