Genotypic and Phenotypic Characteristics of CRB1-Associated Retinal Dystrophies: A Long-Term Follow-up Study.
To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies.



Retrospective cohort study.



Fifty-five patients with CRB1-associated retinal dystrophies from 16 families.



A medical record review of 55 patients for age at onset, medical history, initial symptoms, best-corrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography.



Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings.



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, 0-55.5 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 = 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 rod-cone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients.



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.
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
Mays
M
Talib
Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands.
Mary J
MJ
van Schooneveld
Bartiméus, Diagnostic Centre for Complex Visual Disorders, Zeist, The Netherlands.
Maria M
MM
van Genderen
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
Jan
J
Wijnholds
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Ralph J
RJ
Florijn
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Jacoline B
JB
Ten Brink
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
Nicoline E
NE
Schalij-Delfos
Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
Gislin
G
Dagnelie
Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans P M
FPM
Cremers
Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
Ron
R
Wolterbeek
Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands; Mathematical Institute, Leiden University, Leiden, The Netherlands.
Marta
M
Fiocco
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
Alberta A
AA
Thiadens
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Carel B
CB
Hoyng
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Caroline C
CC
Klaver
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; The Netherlands Institute for Neuroscience (NIN-KNAW), Amsterdam, The Netherlands.
Arthur A
AA
Bergen
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands; Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: c.j.f.boon@lumc.nl.
Camiel J F
CJF
Boon
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009887:Ophthalmoscopy; D010641:Phenotype; D012160:Retina / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology
C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins