Association of Steroid 5 alpha-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy

作者:Taylor Rachel L; Arno Gavin; Poulter James A; Khan Kamron N; Morarji Jiten; Hull Sarah; Pontikos Nikolas; Martin Antonio Rueda; Smith Katherine R; Ali Manir; Toomes Carmel; McKibbin Martin; Clayton Smith Jill; Grunewald Stephanie; Michaelides Michel; Moore Anthony T; Hardcastle Alison J; Inglehearn Chris F; Webster Andrew R; Black Graeme C*
来源:JAMA Ophthalmology, 2017, 135(4): 339-347.
DOI:10.1001/jamaophthalmol.2017.0046

摘要

IMPORTANCE Steroid 5 alpha-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature. OBJECTIVE To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features. DESIGN, SETTING AND PARTICIPANTS Seven affected individuals from 4 unrelated families with early-onset retinal dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016. MAIN OUTCOMES AND MEASURES Detailed clinical phenotypes aswell as genetic and biochemical results. RESULTS The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c. 57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset retinal dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged <3 years) visual loss (mean [SD] best-corrected visual acuity, + 0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested. CONCLUSIONS AND RELEVANCE Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of retinal dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression.

  • 出版日期2017-4-1

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