Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

Laurence H M Pierrache, Bas P. Hartel, Erwin van Wijk, Magda A. Meester-Smoor, Frans P M Cremers, Elfride de Baere, Julie de Zaeytijd, Mary J. van Schooneveld, Cor W R J Cremers, Gislin Dagnelie, Carel B. Hoyng, Arthur A. Bergen, Bart P. Leroy, Ronald J E Pennings, L. Ingeborgh van den Born, Caroline C W Klaver

Research output: Contribution to journalArticle

Abstract

Purpose: USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Design: Clinic-based, longitudinal, multicenter study. Participants: Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. Methods: Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. Main Outcome Measures: Low vision and blindness. Results: Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P <0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P <0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P <0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P <0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. Conclusions: Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.

Original languageEnglish (US)
JournalOphthalmology
DOIs
StateAccepted/In press - Sep 22 2015

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Usher Syndromes
Retinitis Pigmentosa
Low Vision
Mutation
Vision Disorders
Blindness
Hearing Loss
RNA Splice Sites
Frameshift Mutation
Nonsense Codon
Belgium
Kaplan-Meier Estimate
Genetic Association Studies
Missense Mutation
Survival Analysis
Visual Fields
Netherlands
Visual Acuity
Multicenter Studies
Longitudinal Studies

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Pierrache, L. H. M., Hartel, B. P., van Wijk, E., Meester-Smoor, M. A., Cremers, F. P. M., de Baere, E., ... Klaver, C. C. W. (Accepted/In press). Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. Ophthalmology. https://doi.org/10.1016/j.ophtha.2016.01.021

Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. / Pierrache, Laurence H M; Hartel, Bas P.; van Wijk, Erwin; Meester-Smoor, Magda A.; Cremers, Frans P M; de Baere, Elfride; de Zaeytijd, Julie; van Schooneveld, Mary J.; Cremers, Cor W R J; Dagnelie, Gislin; Hoyng, Carel B.; Bergen, Arthur A.; Leroy, Bart P.; Pennings, Ronald J E; van den Born, L. Ingeborgh; Klaver, Caroline C W.

In: Ophthalmology, 22.09.2015.

Research output: Contribution to journalArticle

Pierrache, LHM, Hartel, BP, van Wijk, E, Meester-Smoor, MA, Cremers, FPM, de Baere, E, de Zaeytijd, J, van Schooneveld, MJ, Cremers, CWRJ, Dagnelie, G, Hoyng, CB, Bergen, AA, Leroy, BP, Pennings, RJE, van den Born, LI & Klaver, CCW 2015, 'Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa', Ophthalmology. https://doi.org/10.1016/j.ophtha.2016.01.021
Pierrache, Laurence H M ; Hartel, Bas P. ; van Wijk, Erwin ; Meester-Smoor, Magda A. ; Cremers, Frans P M ; de Baere, Elfride ; de Zaeytijd, Julie ; van Schooneveld, Mary J. ; Cremers, Cor W R J ; Dagnelie, Gislin ; Hoyng, Carel B. ; Bergen, Arthur A. ; Leroy, Bart P. ; Pennings, Ronald J E ; van den Born, L. Ingeborgh ; Klaver, Caroline C W. / Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. In: Ophthalmology. 2015.
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title = "Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa",
abstract = "Purpose: USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Design: Clinic-based, longitudinal, multicenter study. Participants: Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. Methods: Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. Main Outcome Measures: Low vision and blindness. Results: Participant groups had similar distributions of gender (48{\%} vs. 45{\%} males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97{\%} vs. 99{\%} European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P <0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P <0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P <0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P <0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25{\%}) and nonsyndromic RP (19{\%}): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. Conclusions: Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.",
author = "Pierrache, {Laurence H M} and Hartel, {Bas P.} and {van Wijk}, Erwin and Meester-Smoor, {Magda A.} and Cremers, {Frans P M} and {de Baere}, Elfride and {de Zaeytijd}, Julie and {van Schooneveld}, {Mary J.} and Cremers, {Cor W R J} and Gislin Dagnelie and Hoyng, {Carel B.} and Bergen, {Arthur A.} and Leroy, {Bart P.} and Pennings, {Ronald J E} and {van den Born}, {L. Ingeborgh} and Klaver, {Caroline C W}",
year = "2015",
month = "9",
day = "22",
doi = "10.1016/j.ophtha.2016.01.021",
language = "English (US)",
journal = "Ophthalmology",
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TY - JOUR

T1 - Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

AU - Pierrache, Laurence H M

AU - Hartel, Bas P.

AU - van Wijk, Erwin

AU - Meester-Smoor, Magda A.

AU - Cremers, Frans P M

AU - de Baere, Elfride

AU - de Zaeytijd, Julie

AU - van Schooneveld, Mary J.

AU - Cremers, Cor W R J

AU - Dagnelie, Gislin

AU - Hoyng, Carel B.

AU - Bergen, Arthur A.

AU - Leroy, Bart P.

AU - Pennings, Ronald J E

AU - van den Born, L. Ingeborgh

AU - Klaver, Caroline C W

PY - 2015/9/22

Y1 - 2015/9/22

N2 - Purpose: USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Design: Clinic-based, longitudinal, multicenter study. Participants: Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. Methods: Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. Main Outcome Measures: Low vision and blindness. Results: Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P <0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P <0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P <0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P <0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. Conclusions: Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.

AB - Purpose: USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Design: Clinic-based, longitudinal, multicenter study. Participants: Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. Methods: Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. Main Outcome Measures: Low vision and blindness. Results: Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P <0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P <0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P <0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P <0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. Conclusions: Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.

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