CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

Xuan-Thanh-An Nguyen¹, Mays Talib¹, Mary J van Schooneveld², Jan Wijnholds³, Maria M van Genderen⁴, Nicoline E Schalij-Delfos¹, Caroline C W Klaver⁵, Herman E Talsma⁶, Marta Fiocco⁷, Ralph J Florijn⁸, Jacoline B Ten Brink⁸, Frans P M Cremers⁹, Magda A Meester-Smoor¹⁰, L Ingeborgh van den Born¹¹, Carel B Hoyng¹², Alberta A H J Thiadens¹⁰, Arthur A Bergen¹³, Camiel J F Boon¹⁴

Affiliations

¹ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands.
² Department of Ophthalmology (M.J.v.S., C.J.F.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands.
³ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; The Netherlands Institute for Neuroscience (NIN-KNAW) (J.W., A.A.B.), Amsterdam, the Netherlands.
⁴ Bartiméus Diagnostic Centre for Complex Visual Disorders (M.M.v.G., H.E.T.), Zeist, the Netherlands; Department of Ophthalmology (M.M.v.G.), University Medical Centre Utrecht, Utrecht, the Netherlands.
⁵ Department of Ophthalmology (C.C.W.K., M.A.M.-S., A.A.H.J.T.); Department of Epidemiology (C.C.W.K.), Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology (C.C.W.K., C.B.H.), Radboud University Medical Center, Nijmegen, the Netherlands; Institute for Molecular and Clinical Ophthalmology (C.C.W.K.), Basel, Switzerland.
⁶ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; Bartiméus Diagnostic Centre for Complex Visual Disorders (M.M.v.G., H.E.T.), Zeist, the Netherlands.
⁷ Mathematical Institute (M.F.), and Department of Biomedical Data Sciences (M.F.), Leiden University Medical Center, Leiden, the Netherlands.
⁸ Department of Clinical Genetics (R.J.F., J.B.t.B., A.A.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands.
⁹ Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour (F.P.M.C.), Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁰ Department of Ophthalmology (C.C.W.K., M.A.M.-S., A.A.H.J.T.).
¹¹ Rotterdam Eye Hospital (L.I.v.d.B.), Rotterdam, the Netherlands.
¹² Department of Ophthalmology (C.C.W.K., C.B.H.), Radboud University Medical Center, Nijmegen, the Netherlands.
¹³ The Netherlands Institute for Neuroscience (NIN-KNAW) (J.W., A.A.B.), Amsterdam, the Netherlands; Department of Clinical Genetics (R.J.F., J.B.t.B., A.A.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands.
¹⁴ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Ophthalmology (M.J.v.S., C.J.F.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.j.f.boon@lumc.nl.

PMID: 34320374
DOI: 10.1016/j.ajo.2021.07.021

Free article

CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

Xuan-Thanh-An Nguyen et al. Am J Ophthalmol. 2022 Feb.

Free article

. 2022 Feb:234:37-48.

doi: 10.1016/j.ajo.2021.07.021. Epub 2021 Jul 25.

Authors

Affiliations

¹ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands.
² Department of Ophthalmology (M.J.v.S., C.J.F.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands.
³ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; The Netherlands Institute for Neuroscience (NIN-KNAW) (J.W., A.A.B.), Amsterdam, the Netherlands.
⁴ Bartiméus Diagnostic Centre for Complex Visual Disorders (M.M.v.G., H.E.T.), Zeist, the Netherlands; Department of Ophthalmology (M.M.v.G.), University Medical Centre Utrecht, Utrecht, the Netherlands.
⁵ Department of Ophthalmology (C.C.W.K., M.A.M.-S., A.A.H.J.T.); Department of Epidemiology (C.C.W.K.), Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology (C.C.W.K., C.B.H.), Radboud University Medical Center, Nijmegen, the Netherlands; Institute for Molecular and Clinical Ophthalmology (C.C.W.K.), Basel, Switzerland.
⁶ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; Bartiméus Diagnostic Centre for Complex Visual Disorders (M.M.v.G., H.E.T.), Zeist, the Netherlands.
⁷ Mathematical Institute (M.F.), and Department of Biomedical Data Sciences (M.F.), Leiden University Medical Center, Leiden, the Netherlands.
⁸ Department of Clinical Genetics (R.J.F., J.B.t.B., A.A.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands.
⁹ Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour (F.P.M.C.), Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁰ Department of Ophthalmology (C.C.W.K., M.A.M.-S., A.A.H.J.T.).
¹¹ Rotterdam Eye Hospital (L.I.v.d.B.), Rotterdam, the Netherlands.
¹² Department of Ophthalmology (C.C.W.K., C.B.H.), Radboud University Medical Center, Nijmegen, the Netherlands.
¹³ The Netherlands Institute for Neuroscience (NIN-KNAW) (J.W., A.A.B.), Amsterdam, the Netherlands; Department of Clinical Genetics (R.J.F., J.B.t.B., A.A.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands.
¹⁴ From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Ophthalmology (M.J.v.S., C.J.F.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.j.f.boon@lumc.nl.

PMID: 34320374
DOI: 10.1016/j.ajo.2021.07.021

Abstract

Purpose: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials.

Design: Single-center, prospective case series.

Methods: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging.

Results: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up.

Conclusion: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.

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CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

Affiliations

CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

Authors

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Abstract

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Molecular Biology Databases

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