Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency

Abstract

Objective:To describe the variability of muscle symptoms in patients carrying mutations in the GYG1 gene, encoding glycogenin-1, an enzyme involved in the biosynthesis of glycogen, and to discuss genotype-phenotype relations.Methods:We describe 9 patients from 5 families in whom muscle biopsies showed vacuoles with an abnormal accumulation of glycogen in muscle fibers, partially α-amylase resistant suggesting polyglucosan bodies. The patients had either progressive early-onset limb-girdle weakness or late-onset distal or scapuloperoneal muscle affection as shown by muscle imaging. No clear definite cardiac disease was found. Histologic and protein analysis investigations were performed on muscle.Results:Genetic analyses by direct or exome sequencing of the GYG1 gene revealed 6 different GYG1 mutations. Four of the mutations were novel. They were compound heterozygous in 3 families and homozygous in 2. Protein analysis revealed either the absence of glycogenin-1 or reduced glycogenin-1 expression with impaired glucosylation.Conclusions:Our report extends the genetic and clinical spectrum of glycogenin-1–related myopathies to include scapuloperoneal and distal affection with glycogen accumulation.

Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on risk of type 2 diabetes

“…The common P12A variant of PPARG (SLP = 3.45) reduces risk of T2D whereas rare LOF variants and nonsynonymous variants which cause reduced activity (occurring in approximately 1 in 1,000 individuals) substantially increase risk (Majithia et al ., 2014). Damaging variants in GYG1 (SLP = 3.22) cause deficiency of glycogenin 1, resulting in glycogen storage myopathies, but have not been reported to be associated with diabetes (Ben Yaou et al ., 2017). GHRL (SLP = −3.15) encodes the ghrelin-obestatin preproprotein which is cleaved to yield two peptides, ghrelin and obestatin, which are involved in appetite and energy metabolism and there have been some studies which have claimed that the common Leu72Met (rs696217) variant is associated with reduced risk of T2D although the effect does not seem to be consistent and the gene was not highlighted in a large GWAS meta-analysis (Xue et al ., 2018; Rivera-León et al ., 2020).…”

Myopathies with finger flexor weakness: Not only inclusion‐body myositis

“…An sIBM‐like phenotype with finger flexor and proximal lower limb weakness was reported in a single patient with Pompe disease, and, although uncommon, this disorder should be considered in unexplained myopathies affecting finger flexors 83 . Distal upper limb weakness also occurs in other glycogen‐storage disorders (eg, debrancher enzyme deficiency and glycogenin‐1 deficiency), but in these patients finger extensors or intrinsic hand muscles are preferentially affected 84,85 …”

GYG1: A distal myopathy with polyglucosan bodies

“…Mutations in GYG1 cause glycogen storage disease (GSD) XV. c.143+3G>C is the most common pathogenic variant in GYG1 and causes skipping of exon 2, leading to a frameshift and nonsense‐mediated decay 2,3 . The c.819T>A variant is novel and located between the catalytic and C‐terminal glycogen synthase‐binding domains.…”

“…Truncating variants in the catalytic domain result in reduced or absent protein expression, while those in the C‐terminal region result in a protein with reduced glycosylation 1‐3 . Like our patient, those carrying the latter variants also presented with distal weakness 2,3 …”