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

Abstract

IMPORTANCE Steroid 5α-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,

SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

“…31 To confirm the SSBP1 variants to be the most likely disease-associated variants in these individuals, we first excluded all candidate variants occurring in a virtual panel of genes previously shown to be associated with posterior segment disorders or inherited optic neuropathies (https://panelapp.genomicsengland.co. 31 To confirm the SSBP1 variants to be the most likely disease-associated variants in these individuals, we first excluded all candidate variants occurring in a virtual panel of genes previously shown to be associated with posterior segment disorders or inherited optic neuropathies (https://panelapp.genomicsengland.co.…”

Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

“…However, the phenotypic presentations are remarkably different. First, SRD5A3‐CDG patients have specific structural and functional eye defects . Cantagrel et al suggested the existence of an alternative pathway for dolichol synthesis, because residual dolichol was found in SRD5A3‐deficient cells with early truncating mutations.…”

“…Dolichol‐phosphate‐mannose (Dol‐P‐Man) is the mannose donor for N‐glycosylation, O‐mannosylation, C‐mannosylation, and GPI‐anchor biosynthesis. SRD5A3‐CDG patients present with structural and functional eye abnormalities, cerebellar defects, intellectual disability (ID), and muscle hypotonia . PMM2‐CDG patients have characteristic multivisceral symptoms that are associated with generalized N‐glycosylation abnormalities.…”

“…SRD5A3-CDG patients present with structural and functional eye abnormalities, cerebellar defects, intellectual disability (ID), and muscle hypotonia. [3][4][5][6] PMM2-CDG patients have characteristic multivisceral symptoms that are associated with generalized N-glycosylation abnormalities. Patients with mutations in GMPPB have dystroglycanopathy due to reduced O-mannosylation of αDG, 7,8 congenital myasthenic syndrome (CMS), 9 or pseudometabolic myopathy.…”

“…Dashed arrow: alternative pathway suggested by Cantagrel et al 3 2 (PMM2)-CDG (MIM 601785) patients show a very broad phenotype with involvement of nearly all organs. Steroid 5alpha-reductase type 3 (SRD5A3)-CDG (MIM 611715) patients mainly present with eye, skin, and central nervous system involvement, [3][4][5][6] while dolichol kinase (DOLK) deficiency (MIM 610746) results in dilated cardiomyopathy without obvious skeletal muscle abnormalities. 13,14,16 DPM3-CDG (MIM 605951) and patients with mutations in guanosinediphosphate-mannose (GDP-mannose) pyrophosphorylase B (GMPPB, MIM 615320) can present with muscular dystrophy, a symptom of the dystroglycanopathies.…”