Gene therapy: perspectives from young adults with Leber's congenital amaurosis.

AIMS/PURPOSE: To investigate Leber congenital amaurosis (LCA) patients' expectations, decision-making processes and gene therapy-related concerns. METHODS: Using a qualitative approach, we explored perceptions of gene therapy and clinical trials among individuals with LCA. Young adults with a clinical diagnosis of LCA were recruited through the Ocular Genetics Programme at the Hospital for Sick Children. Semi-structured interviews were conducted with ten patients and analysed following the principles of qualitative description. RESULTS: Study participants were aware of ongoing gene therapy research trials and actively sought information regarding advances in ophthalmology and vision restoration. The majority of participants would enrol or were enrolled in a gene-replacement therapy trial, while a minority was ambivalent or would not enrol if provided an opportunity. Participants attributed different values to clinical trials, which influenced their willingness to participate. Intrinsic factors related to coping, adaptation to vision loss and resilience also influenced decision-making. DISCUSSION: This study highlights the complex factors involved in gene-therapy-related decision-making and acts as a proponent for adopting patient-centred care strategies when counselling individuals considering gene therapy or clinical trial participation.

Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is an autosomal recessive retinal dystrophy that manifests with genetic heterogeneity. We sequenced the exome of an individual with LCA and identified nonsense (c.507G>A, p.Trp169*) and missense (c.769G>A, p.Glu257Lys) mutations in NMNAT1, which encodes an enzyme in the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway implicated in protection against axonal degeneration. We also found NMNAT1 mutations in ten other individuals with LCA, all of whom carry the p.Glu257Lys variant.

A novel p.Gly603Arg mutation in CACNA1F causes Åland island eye disease and incomplete congenital stationary night blindness phenotypes in a family.

PURPOSE: To report, for the first time, that X-linked incomplete congenital stationary night blindness (CSNB2A) and Åland island eye disease (AIED) phenotypes coexist in a molecularly confirmed pedigree and to present novel phenotypic characteristics of calcium channel alpha-1F subunit gene (CACNA1F)-related disease. METHODS: Two affected subjects (the proband and his maternal grandfather) and an unaffected obligate carrier (the proband's mother) underwent detailed ophthalmological evaluation, fundus autofluorescence imaging, and spectral-domain optical coherence tomography. Goldmann visual field assessment and full-field electroretinogram (ERG) were performed in the two affected subjects, and multichannel flash visual evoked potential was performed on the proband. Scotopic 15 Hz flicker ERG series were performed in both affected subjects to evaluate the function of the slow and fast rod pathways. Haplotype analysis using polymorphic microsatellite markers flanking CACNA1F was performed in all three family members. The proband's DNA was sequenced for mutations in the coding sequence of CACNA1F and nyctalopin (NYX) genes. Segregation analysis was performed in the family. RESULTS: Both affected subjects had symptoms of nonprogressive nyctalopia since childhood, while the proband also had photophobia. Both cases had a distance visual acuity of 20/50 or better in each eye, normal contrast sensitivity, and an incomplete type of Schubert-Bornschein ERGs. The proband also had high myopia, a mild red-green color deficit, hypopigmented fundus, and foveal hypoplasia with no evidence of chiasmal misrouting. Spectral-domain optical coherence tomography confirmed the presence of foveal hypoplasia in the proband. The clinical phenotype of the proband and his maternal grandfather fit the clinical description of AIED and CSNB2A, respectively. The fundus autofluorescence and the visual fields were normal in both cases; the scotopic 15 Hz flicker ERG demonstrated only fast rod pathway activity in both. Both affected cases shared the same haplotype across CACNA1F. The proband carried a novel hemizygous c.1807G>C mutation (p.G603R) in the CACNA1F gene. The change segregated with the disease phenotypes and was not identified in 360 control chromosomes. No mutations were identified in NYX. CONCLUSIONS: This report of a missense mutation in CACNA1F causing AIED and CSNB2A phenotypes in a family confirms that both diseases are allelic and that other genetic or environmental modifiers influence the expression of CACNA1F. This is the first report to suggest that in CACNA1F-related disease, the rod system activity is predominantly from the fast rod pathways.

Genetic counseling and genetic testing in ophthalmology.

PURPOSE OF REVIEW: To introduce the issues specific to the genetic counseling profession for genetic eye diseases. RECENT FINDINGS: To discuss current issues in ocular genetic counseling including the use of a focused ophthalmology pedigree, informed consent in the blind population, genetic testing trends and psychosocial issues. SUMMARY: Introduce the time-consuming issues to be addressed in genetic counseling for genetic eye disease patients.