Long-Term Follow-Up of Patients With Retinitis Pigmentosa Type 12 Caused by Crb1 Mutations

Mathijssen, Inge B.; Florijn, Ralph J.; Born, L. Ingeborgh van den; Zekveld-Vroon, Renate C.; Brink, Jacoline B. ten; Plomp, Astrid S.; Baas, Frank; Meijers-Heijboer, Hanne; Bergen, Arthur A. B.; Schooneveld, Mary J. van

doi:10.1097/iae.0000000000001127

Cited by 33 publications

(49 citation statements)

References 34 publications

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“…These ages scan shows small hyperreflective outer retinal accumulations right above the retinal pigment epithelium (RPE) that seem to correspond with a reticular pseudodrusenoid-like aspect on funduscopy (Fig 2E). are comparable with those reported by Mathijssen et al, 17 who found median ages of 18 and 35 years for reaching a VA of 0.3 or less and 0.1 or less, respectively. When testing for statistical difference between the survival curves, we found no significant difference between the GI patients and the non-GI patients in this study.…”

Section: Discussionsupporting

confidence: 91%

“…Optic disc drusen in this GI population carrying a homozygous p.(Met1041Thr) mutation in CRB1 previously were reported in similar numbers. 5,17 We found no optic disc drusen in the non-GI patients. Interestingly, optic disc drusen have been reported in patients with different CRB1 genotypes.…”

Section: Discussionmentioning

confidence: 55%

“…Previous reports have found Coats-like exudates in 0% to 25%. 12,17,18,29 Full-field electroretinography responses became unrecordable on average in the second decade of life in 50% of our RP cohort and in the first decade of life in our LCA cohort, with high intrafamilial and interfamilial variability in the RP group. These electroretinography results indicate that most patients with CRB1-associated RP and LCA are affected by early panretinal rod and cone dysfunction.…”

Section: Discussionmentioning

confidence: 70%

“…Previous studies have reported retinal thinning with advancing age. 12,17 A relatively disorganized retina with suboptimally visible retinal layers on OCT was present in 9% of patients, and outer retinal layers were more difficult to discern than inner retinal layers in 36% of the total population. The retinal laminar structure on SD OCT in our patient cohort was relatively intact compared with that of earlier studies that described coarse lamination, defined as unclearly delineated retinal layers, in mice and patients with CRB1-associated retinal dystrophies, in both thickened and atrophic areas of retina.…”

Section: Discussionmentioning

confidence: 99%

“…16 We included patients from a previously described Dutch GI 5,17 and patients from outside this GI. Inclusion criteria were a confirmed molecular diagnosis of 2 likely disease-causing variants in the CRB1 gene or a clinical diagnosis of an inherited retinal dystrophy in a patient with a first-degree relative with 2 likely disease-causing variants in CRB1.…”

Section: Study Populationmentioning

confidence: 99%

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Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

et al. 2017

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Purpose: To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies.Design: Retrospective cohort study. Participants: Fifty-five patients with CRB1-associated retinal dystrophies from 16 families. Methods: A medical record review of 55 patients for age at onset, medical history, initial symptoms, bestcorrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography.Main Outcome Measures: Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings.Results: A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0e55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly (P ¼ 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rodecone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients.Conclusions: Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life. Ophthalmology 2017;124:884-895 ª 2017 by the American Academy of Ophthalmology Supplemental material available at www.aaojournal.org.Mutations in the CRB1 gene are associated with a wide variety of severe retinal dystrophies with variable phenotypes, including panretinal dystrophies such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and coneerod dystrophy, as well as central phenotypes such as isolated macular dystrophy and foveal retinoschisis. Retinitis pigmentosa is a clinically and genetically heterogeneous disorder. Mutations in the CRB1 gene have been associated with RP12, a distinct form of RP characterized by preservation of para-arteriolar retinal pigment epithelium, progressive visual field (VF) loss starting from the first decade of life, and early macular involvement. 4 Other common features are hyperopia and optic disc drusen, previously described in a Dutch genetic isolate (GI). 5Classic forms of earl...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

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Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

et al. 2017

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Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations inPDE6AandPDE6B

et al. 2019

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IMPORTANCE A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. OBJECTIVE To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B. DESIGN, SETTING, AND PARTICIPANTS In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. MAIN OUTCOMES AND MEASURES Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B. RESULTS Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A, and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B, accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA (P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF (P = .48). CONCLUSIONS AND RELEVANCE Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.

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With expanded carrier screening, founder populations run the risk of being overlooked

et al. 2017

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Genetically isolated populations exist worldwide. Specific genetic disorders, including rare autosomal recessive disorders may have high prevalences in these populations. We searched for Dutch genetically isolated populations and their autosomal recessive founder mutations. We investigated whether these founder mutations are covered in the (preconception) expanded carrier screening tests of five carrier screening providers. Our results show that the great majority of founder mutations are not covered in these screening panels, and these panels may thus not be appropriate for use in founder populations. It is therefore important to be aware of founder mutations in a population when offering carrier tests.

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Long-Term Follow-Up of Patients With Retinitis Pigmentosa Type 12 Caused by Crb1 Mutations

Cited by 33 publications

References 34 publications

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations inPDE6AandPDE6B

With expanded carrier screening, founder populations run the risk of being overlooked

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