[Show abstract][Hide abstract] ABSTRACT: PURPOSE. MUTATIONS IN ZEB1 HAVE BEEN REPORTED IN POSTERIOR POLYMORPHOUS CORNEAL DYSTROPHY (PPCD3; MIM #609141) AND FUCHS ENDOTHELIAL CORNEAL DYSTROPHY (FECD6; MIM #613270). ALTHOUGH PPCD AND KERATOCONUS ARE CLINICALLY AND PATHOLOGICALLY DISTINCT, PPCD HAS BEEN ASSOCIATED WITH KERATOCONUS SUGGESTING A COMMON GENETIC BASIS. THE PURPOSE OF THIS STUDY WAS TO PERFORM MUTATIONAL SCREENING OF THE ZEB1 GENE IN PATIENTS AFFECTED WITH KERATOCONUS OR PPCD. METHODS. SANGER SEQUENCING OF ZEB1 WAS PERFORMED IN 70 UNRELATED PATIENTS WITH KERATOCONUS AND 18 UNRELATED PATIENTS WITH PPCD. RT-QPCR WAS PERFORMED ON RNA FROM CULTURED CORNEAL KERATOCYTES OBTAINED FROM A KERATOCONIC PATIENT HARBOURING A MISSENSE ZEB1 MUTATION (P.GLN640HIS) UNDERGOING CORNEAL TRANSPLANTATION. RESULTS. MUTATIONAL ANALYSIS OF ZEB1 IN PPCD IDENTIFIED A PREVIOUSLY REPORTED FRAMESHIFT MUTATION (C.1578_1579INSG) AND A NOVEL NONSENSE MUTATION (C.2249CA) IN EXON 7 OF ZEB1 CAUSING THE INSERTION OF A STOP CODON: p.Ser750X. In the keratoconus cohort a novel heterozygous pathogenic mutation in exon 7 (c.1920G>T; p.Gln640His) of ZEB1 was identified in a family affected with keratoconus and Fuchs endothelial corneal dystrophy. RT-qPCR performed on cultured corneal keratocytes harbouring the missense ZEB1 mutation (p.Gln640His) demonstrated that COL4A1 and COL4A2 were markedly down-regulated and COL4A3, COL4A4 and COL8A2 were moderately down-regulated. CONCLUSIONS. OUR DATA COMBINED WITH THE PREVIOUSLY REPORTED MUTATIONAL SPECTRUM OF ZEB1 SUPPORTS A GENOTYPE-PHENOTYPE CORRELATION: missense substitutions in the ZEB1 protein are associated with FECD6 and keratoconus whereas protein truncating ZEB1 mutations result in PPCD3. The dysregulation of α-type IV collagens represents a common link between ZEB1 mutation and the clinical phenotypes (PPCD3, FECD and keratoconus).
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To report phenotypic characteristics including macular cone photoreceptor morphology in KCNV2-related cone dystrophy with supernormal rod electroretinogram (CDSR). Methods: Seven affected cases aged 9 to 18 years at last visit, with characteristic full-field electroretinographic (ERG) features of CDSR were screened for mutations in the KCNV2 gene. All cases underwent detailed ophthalmological evaluation, which included distance and color vision testing, contrast sensitivity measurement, fundus photography, fundus autofluorescence (FAF) imaging and spectral domain-optical coherence tomography (SD-OCT). Follow-up visits were available in 6 cases. Rod photoreceptor function was assessed using a bright white flash ERG protocol (240 cd•s•m-2). Macular cone photoreceptor morphology was assessed from 2° × 2° zonal images obtained using adaptive optics scanning laser ophthalmoscopy (AOSLO) in 6 cases. RESULTS: Pathogenic mutations in KCNV2 were identified in all 7 cases. Best corrected vision was 20/125 or worse in all cases at the latest visit (20/125-20/400). Vision loss was progressive in 2 cases. Color vision and contrast sensitivity was abnormal in all cases. Retinal exam revealed minimal pigment epithelial changes at the fovea in 4 cases. A peri- or para-foveal ring of hyper-fluorescence was the most common FAF abnormality noted (5 cases). The SD-OCT showed outer retinal abnormalities in all cases. The rod photoreceptor maximal response was reduced but rod sensitivity was normal. AOSLO showed markedly reduced cone density in all 6 tested. CONCLUSIONS: Central vision parameters progressively worsen in CDSR. Structural retinal and lipofuscin accumulation abnormalities are commonly present. Macular cone photoreceptor mosaic is markedly disrupted early in the disease.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: To determine the role of ultrasound biomicroscopy (UBM) in the management of children affected with retinoblastoma.
A review of clinical records of children with the diagnosis of retinoblastoma at the Hospital for Sick Children from January 1995 to December 2007, for whom UBM was used to determine the extent of intraocular tumor. Clinical characteristics were compared with UBM. Pathological correlation was performed for enucleated eyes.
In total, 101 eyes of 75 patients were included in the final analysis. Only 11 eyes were diagnosed on UBM to have extension of the tumor anterior to the ora serrata, and were enucleated. Histopathological examination confirmed the anterior extension in all the 11 eyes. In total, 50 eyes were enucleated because of various reasons, such as poor visual prognosis (12 eyes), unilateral group D or E (23 eyes), recurrences (8 eyes), and treatment failure (7 eyes). None of those patients were found to have anterior extension of the disease on histopathological examination. UBM did not yield any false negative (0/50) or any false positives (0/11).
The UBM provided a sensitive and reproducible visualization of the anterior retina, ciliary region, and anterior segment allowing a better staging of the advanced disease process. Primary assessment of the true extent of retinoblastoma is critical for the selection of an optimal management approach.
[Show abstract][Hide abstract] ABSTRACT: To describe the spectrum of phenotypic characteristics of BEST1-related autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a family with p.V86M mutation.
A retrospective review of the clinical, psychophysical, and electrophysiological phenotypes of six subjects with ADVIRC. Five family members were sequenced for mutations in the BEST1 gene.
A heterozygous change, p.V86M (c.256G > A), was identified in the BEST1 gene in the three affected subjects tested, and was shown to segregate with the disease phenotype. The distance visual acuity ranged from ≥ 20/25 to absent perception of light. Clinical features observed included angle closure glaucoma (n = 2), microcornea with shallow anterior chamber (n = 1), iris dysgenesis (n = 2), cataracts (n = 4), classical peripheral concentric band of retinal hyperpigmentation (n = 5), and optic nerve dysplasia (n = 1). Full-field electroretinogram response amplitudes ranged from low normal (two cases; 27 and 32 years) to non-recordable (two cases; 42 and 63 years). Goldmann fields were normal in two (27 and 28 years) but were abnormal in two older subjects. Optical coherence tomography showed macular thinning in the proband, whereas his affected daughter had normal macular thickness. Electro-oculography showed borderline Arden's ratio (1.50) in the lone case tested (27 years).
ADVIRC is a slowly progressive vitreoretinal degeneration that demonstrates marked intra-familial phenotypic variability. Optic nerve dysplasia and iris dysgenesis are novel observations that extend the ocular phenotype of ADVIRC.
[Show abstract][Hide abstract] ABSTRACT: Obesity associates with increased health risks such as heart disease, stroke and diabetes. The steady rise in the obese population worldwide poses an increasing burden on health systems. Genetic factors contribute to the development of obesity, and the elucidation of their physiological functions helps to understand the cause, and improve the prevention, diagnosis and treatment for this disorder. Primary cilia are evolutionarily conserved organelles whose dysfunctions lead to human disorders now defined as ciliopathies. Human ciliopathies present pleiotropic and overlapping phenotypes that often include retinal degeneration, cystic renal anomalies and obesity. Increasing evidence implicates an intriguing involvement of cilia in lipid/energy homeostasis. Here we discuss recent studies in support of the key roles of ciliary genes in the development and pathology of obesity in various animal models. Genes affecting ciliary development and function may pose promising candidate underlying genetic factors that contribute to the development of common obesity.
[Show abstract][Hide abstract] ABSTRACT: To perform mutational screening of the visual system homeobox gene 1 (VSX1; MIM#605020) in patients with sporadic and familial keratoconus (MIM#148300) in a European population and, for the first time, report the mutational analysis of the two newly identified VSX1exons.
VSX1sequence variants in patients with keratoconus were evaluated by direct sequencing of the entire coding region, including two novel exons. In familial keratoconus cases, segregation of potentially pathogenic VSX1variants was assessed to determine pathogenicity. Transcript analysis was carried out on splice site and synonymous sequence variants not detected in controls.
A total of 66 unrelated patients with keratoconus from the European population (27 with familial keratoconus; 39 with sporadic keratoconus) were analysed for VSX1 mutations. Four sequence variants were not observed in 100 healthy control individuals: c.432C>G (p.D144E), c.479G>A (p.G160D), c.789C>T (p.S263S), and an intronic change c.844-13T>A (numbered with respect to NM_014588). Segregation was not detected for p.D144E and c.844-13T>A. The change in p.G160D was observed in two patients with sporadic keratoconus. Although predicted to alter VSX1 splicing, p.S263S had no effect on transcript processing. Four known SNPs were detected and the following polymorphic variants were observed in keratoconus patients and controls: c.711T>A (NM_199425; p.P237P), c.844-5_-6insT (NM_014588), c.*28G>T (DQ854811/DQ854812), and c.*50G>A (DQ854809/DQ854810).
VSX1has a minor role in keratoconus pathogenesis. The pathogenicity of p.G160D remains controversial and this change may represent a rare polymorphism or genetic modifier. Further evidence is provided that the previously reported variant, p.D144E, is a polymorphism.
[Show abstract][Hide abstract] ABSTRACT: The cases of Peters' anomaly seen over the past decade, at Hospital Ste-Justine in Montreal, are reviewed. Associated ocular anomalies were observed in 50% of cases while 60% of patients presented with associated systemic defects. It is clear, from these patients and those reported in the literature, that Peters' anomaly can be an isolated condition, or part of distinct syndromes: the Krause-Kivlin syndrome or the Peters'-plus syndrome. The authors emphasize the importance for the ophthalmologist to recognize these possibilities if proper management is to be provided.
[Show abstract][Hide abstract] ABSTRACT: To investigate retinal microstructure of patients affected with malattia leventinese (MLVT) and mutation in the EFEMP1 gene using high-resolution optical coherence tomography (OCT).
Patients diagnosed with MLVT received a comprehensive eye exam, full-field and multifocal electroretinogram testing and imaging with a high-resolution Fourier domain OCT (Fd-OCT, UC Davis Medical Center, Davis, USA; axial resolution: 4.5 microm, acquisition speed: 9 frames s(-1), 1000 A scans s(-1)) combined with a flexible scanning head (Bioptigen Inc. Durham, NC, USA).
Two related patients aged 30 and 60 years, with MLVT and identified c.R345W mutation in the EFEMP1 gene, were tested. Mother and daughter showed a variable phenotype with reduced vision function in the younger patient, whereas the mother had a 'form frustre'. Fd-OCT revealed extensive or focal sub-retinal pigment epithelium (RPE) deposits, separation of RPE and Bruch's membrane, and disruption of the photoreceptor outer and inner segment layers. No outer retinal changes were visible outside areas with sub-RPE deposits.
Retinal structure in EFEMP1 retinal dystrophy is reflected by morphological changes within the RPE/Bruch's membrane complex with accumulation of sub-RPE material associated with disrupted photoreceptor integrity. The pattern of microstructural retinal abnormalities is similar but with a different extent in patients with variable phenotypes.
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy with aggressive focal ablative therapy is now the mainstay of retinoblastoma therapy. Our experience presents an evolution from conventional radiotherapy by treating posterior pole tumours with focal stereotactic fractionated radiotherapy (SRT).
A retrospective chart review was conducted of five patients (six eyes) treated with SRT at the Hospital for Sick Children and Princess Margaret Hospital, Toronto, Canada, between 1999 and 2004. The prescribed dose was 40 Gy delivered in 20 fractions once daily using 6 MV photons.
Five patients (six eyes) were treated. The median age at the time of SRT was 18 months. The median follow-up was 46.5 months as of September 2004. Four patients were treated for a posterior pole focal tumour by focal SRT, and one patient was treated for vitreous seeding with whole-eye SRT. In patients treated with focal SRT, the median doses to the tumour, optic chiasm and brainstem were 41.92, 0.25 and 0.07 Gy, respectively, and to the ipsilateral optic nerve, globe and lens were 9.98, 19.11 and 3.74 Gy, respectively. The median doses to the ipsilateral and contralateral orbital bone were 6.73 Gy (range 5.99-8.29 Gy) and 2.31 Gy (range 0.88-7.08 Gy), respectively. A complete response (residual inactive scar tissue) was seen in four of the five focal tumours treated, with one tumour responding with a partial response (suspicious residual scar tissue). No acute or late side-effects occurred in patients treated with focal SRT. Only the patient treated with whole-eye SRT developed late effects of cataract and corneal ulceration. One patient suffered recurrence within the radiation field 5 months after focal SRT. Control of this recurrence was successful using chemotherapy and focal therapy. No eye has been enucleated.
Vision-sparing focal SRT for localised tumour masses in critical locations can control tumours with minimal side-effects and a minimal dose to the surrounding critical normal tissue.
[Show abstract][Hide abstract] ABSTRACT: Corneal dystrophies refer to a group of corneal diseases and that are genetically determined. These have been traditionally classified with respect to the layer of cornea involved. We now know that this does not reflect the underlying pathobiology. Most of the corneal dystrophies are of Mendelian inheritance with some phenotype diversity and a variable degree of penetrance. The dystrophies involving enzymatic processes tend to be of autosomal recessive inheritance. In some cases, such as keratoconus, the inheritance pattern is not always clear and is considered complex. The age of onset of the disease, as in most inherited eye disorders, is variable and does not reflect the underlying pathogenic defect. Few cases are congenital. Our understanding of corneal dystrophies is undergoing somewhat of a revolution as over 12 chromosomes have been associated with corneal dystrophies with mutations identified in at least 14 genes if one includes anterior segment dysgenesis in this group of conditions. Several dystrophies remain without a gene or a genetic location (locus) and more familial studies are required. The new molecular information is challenging the traditional thinking about these conditions that was usually guided by the histopathological findings. As this new knowledge becomes more refined, the classification of this group of disorders will eventually be revisited to have a molecular basis. The elucidation of the underlying biochemical pathways may allow us to envisage the possibility of modulating these phenotypes in the future.