IMPG2-Related Maculopathy

TY - JOUR

T1 - IMPG2-Related Maculopathy

AU - Birtel, Johannes

AU - Caswell, Richard

AU - De Silva, Samantha R

AU - Herrmann, Philipp

AU - Rehman, Salwah

AU - Lotery, Andrew J

AU - Mahroo, Omar A

AU - Michaelides, Michel

AU - Webster, Andrew R

AU - MacLaren, Robert E

AU - Charbel Issa, Peter

N1 - Copyright © 2023 Elsevier Inc. All rights reserved.

PY - 2024/2

Y1 - 2024/2

N2 - PURPOSE: To investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy.DESIGN: Retrospective observational case series.METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling.RESULTS: A total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect.CONCLUSIONS: Mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.

AB - PURPOSE: To investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy.DESIGN: Retrospective observational case series.METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling.RESULTS: A total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect.CONCLUSIONS: Mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.

KW - Humans

KW - Middle Aged

KW - Fluorescein Angiography

KW - Macular Degeneration/genetics

KW - Proteoglycans/genetics

KW - Retinal Diseases

KW - Retinitis Pigmentosa/diagnosis

KW - Retrospective Studies

KW - Tomography, Optical Coherence

KW - Visual Acuity

U2 - 10.1016/j.ajo.2023.10.002

DO - 10.1016/j.ajo.2023.10.002

M3 - SCORING: Journal article

C2 - 37806544

VL - 258

SP - 32

EP - 42

JO - AM J OPHTHALMOL

JF - AM J OPHTHALMOL

SN - 0002-9394

ER -