Vision outcomes in children with fetal alcohol spectrum disorders.

BACKGROUND: Previous studies demonstrated that children with Fetal Alcohol Spectrum Disorders (FASD) are more likely to have vision impairments. However, existing human clinical and epidemiological investigations are few and include limited sample sizes. This study aimed to explore the association between ophthalmologic abnormalities and FASD in a sample of 5-7 year old children in the general population. METHODS: This was a cross-sectional study nested in a larger study intended to estimate the prevalence of FASD in San Diego, California, conducted between 2012 and 2014. Prenatal exposure to alcohol, dysmorphology examinations, and a neurobehavioral testing battery were collected for each child and an FASD diagnosis was assigned. Parents of participating children were asked to release their child's vision screening or diagnostic records. RESULTS: Vision records were obtained for 424 participants in the larger prevalence study. Of these, 53 children were classified as having FASD. A statistically significant association was found between FASD and a diagnosis of strabismus; 5/42 (11.9%) of children who were classified as having FASD had strabismus compared to 6/290 (2.1%) of children who were not classified as having FASD (p = .01). All five cases of strabismus in the FASD group occurred in 19 children classified as having partial fetal alcohol syndrome (pFAS). No association was found between FASD and vision impairment (p = .23), refractive errors (p = .66), glasses/contact lens prescription (p = .30), or having one or more ophthalmological abnormalities (p = .97). CONCLUSIONS: An association between strabismus and FASD, specifically partial FAS, suggests that the effect of alcohol exposure on risk of strabismus must be severe enough to result in facial features consistent with FASD. This emphasizes the importance of vision screening in children with FASD.

Reduced satellite cell number in situ in muscular contractures from children with cerebral palsy.

Satellite cells (SC) are quiescent adult muscle stem cells critical for postnatal development. Children with cerebral palsy have impaired muscular growth and develop contractures. While flow cytometry previously demonstrated a reduced SC population, extracellular matrix abnormalities may influence the cell isolation methods used, systematically isolating fewer cells from CP muscle and creating a biased result. Consequently, the purpose of this study was to use immunohistochemistry on serial muscle sections to quantify SC in situ. Serial cross-sections from human gracilis muscle biopsies (n = 11) were labeled with fluorescent antibodies for Pax7 (SC transcriptional marker), laminin (basal lamina), and 4',6-diamidino-2-phenylindole (nuclei). Fluorescence microscopy under high magnification was used to identify SC based on labeling and location. Mean SC/100 myofibers was reduced by ∼70% (p < 0.001) in children with CP (2.89 ± 0.39) compared to TD children (8.77 ± 0.79). Furthermore, SC distribution across fields was different (p < 0.05) with increased percentage of SC in fields being solitary cells (p < 0.01) in children with CP. Quantification of SC number in situ, without any other tissue manipulation confirms children with spastic CP have a reduced number. This stem cell loss may, in part, explain impaired muscle growth and apparent decreased responsiveness of CP muscle to exercise.

Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients.

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a developmental disease that can cause visual impairment and retinal detachment at a young age. Four genes involved in the Wnt signaling pathway were previously linked to this disease: NDP, FDZ4, LRP5, and TSPAN12. Identification of novel disease-causing alleles allows for a deeper understanding of the disease, better molecular diagnosis, and improved treatment. METHODS: Sequencing libraries from 92 FEVR patients were generated using a custom capture panel to enrich for 163 known retinal disease-causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and small insertions and deletions. Sanger validation and segregation testing were used to verify suspected variants. RESULTS: Of the cohort of 92, 45 patients were potentially solved (48.9%). Solved cases resulted from the determination of 49 unique mutations, 41 of which are novel. Of the novel variants discovered, 13 were highly likely to cause FEVR due to the nature of these variants (frameshifting indels, splicing mutations, and nonsense variants types). To our knowledge, this is the largest study of a FEVR cohort using NGS. CONCLUSIONS: We were able to determine probable disease-causing variants in a large number of FEVR patients, the majority of which were novel. Knowledge of these variants will help to further characterize and diagnose FEVR.

YAP inhibition blocks uveal melanogenesis driven by GNAQ or GNA11 mutations.

Uveal melanoma (UM) is the most common adult intraocular tumor. UM often involves activating mutations in guanine nucleotide binding protein (G protein), q polypeptide (GQ), or G Protein, α 11 (G11). We show that the Yes-associated protein (Yap) inhibitor verteporfin blocks tumor growth of Gq/11-mutated UM cells.

A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa.

PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 60 causative genes known to date. Nevertheless, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing genes are yet to be identified. In this study, we aimed to identify the causative mutation for a large autosomal dominant RP (adRP) family with negative results from known retinal disease gene screening. METHODS: Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation. RESULTS: Linkage analysis identified a minimal disease region of 8 Mb on chromosome 10 with a peak parametric logarithm (base 10) of odds (LOD) score of 3.500. Further whole-exome sequencing identified a heterozygous missense mutation (NM_000188.2:c.2539G>A, p.E847K) in hexokinase 1 (HK1) that segregated with the disease phenotype in the family. Biochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1. CONCLUSIONS: Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism.