Showing papers by "Bart P. Leroy published in 2012"

Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness

Abstract: Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs∗57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Muller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.

BBS1 Mutations in a Wide Spectrum of Phenotypes Ranging From Nonsyndromic Retinitis Pigmentosa to Bardet-Biedl Syndrome

Abstract: Objective To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP). Methods Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment. Results In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed. Conclusions Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype. Clinical Relevance It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

Abstract: Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function

Abstract: We present ophthalmic features and genetic analysis findings of a 44-year-old croatian patient with enhanced S-cone syndrome (ESCS). Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, Goldmann visual field and automated perimetry, full-field electroretinography (ERG), multifocal ERG, S-cone ERG and ON–OFF ERG were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing. The patient has good visual acuity and normal colour vision. Fundus examination showed normal posterior pole and nummular pigment depositions at the level of the retinal pigment epithelium in the mid-periphery of the retina. The SD-OCT images showed normal macular structure and thickness. The ERG showed characteristic findings: photopic and scotopic responses to the same stimulus had a similar waveform and were dominated by short-wavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C > T (p.Leu374Phe). To the best of our knowledge, this is the only ESCS patient older than 40 years who phenotypically has preserved macular structure, good central visual acuity and severely depressed full-field ERG as well as the first reported patient with NR2E3 mutation from Croatia.

Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies).

Abstract: 1.2 OMIM# of the disease Mutations in BEST1 cause a range of clinically heterogeneous retinal dystrophies (collectively termed bestrophinopathies) including; Best disease (OMIM#153700), autosomal dominant vitreoretinochoroidopathy (ADVIRC; OMIM#193220), autosomal recessive bestrophinopathy (ARB: OMIM#611809), adult-onset vitelliform macular dystrophy: OMIM#608161), and retinitis pigmentosa (RP: OMIM#268000 and OMIM#613194).

Birdshot-like chorioretinopathy in common variable immunodeficiency.

Abstract: Purpose To describe a patient with ocular manifestations secondary to common variable immunodeficiency. Methods A 17-year-old adolescent girl presented with asymptomatic bilateral optic disk edema and chorioretinal infiltrates. These findings were noted during routine follow-up visits for hydroxychloroquine use for lymphoid interstitial pneumonia. She underwent a full ophthalmologic and systemic work-up. Results At the age of 13, the patient was diagnosed with common variable immunodeficiency with splenomegaly, lymphadenopathy, and lymphoid interstitial pneumonia. Progressive generalized lymphadenopathy developed thereafter. Since the diagnosis of common variable immunodeficiency, she received monthly intravenous immunoglobulin, systemic corticosteroids and later on, oral hydroxychloroquine. Annual routine screening visits to exclude retinal hydroxychloroquine toxicity were unremarkable until age 17. Unaided visual acuity was 6/5 in both eyes. Slit-lamp examination was normal, whereas fundoscopy revealed bilateral optic disk edema and birdshot-like chorioretinal infiltrates, without signs of vitritis. A bilateral hot disk was seen on fluorescein angiography, but there were no signs of vasculitis. Indocyanine green angiography showed macular and midperipheral choroidal granulomas. A brain magnetic resonance imaging scan revealed no signs of raised intracranial pressure. Human leukocyte antigen-typing was negative for HLA-A29, making birdshot chorioretinopathy highly unlikely. The results of a work-up for sarcoidosis were not typical of that disease. During the past months, a remarkable episode of lacrimal gland swelling with spontaneous recovery was noted. Conclusion We describe a case of ocular manifestations of common variable immunodeficiency, including asymptomatic bilateral chorioretinal granulomas mimicking birdshot chorioretinopathy, combined with optic nerve sheath infiltration, and lacrimal gland involvement.