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Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency
Rabah Ben Yaou1, Aurélie Hubert1, Isabelle Nelson1
1Assistance Publique-Hôpitaux de Paris (APHP) (R.B.Y., B.E., P.L.), Groupe Hospitalier Universitaire la Pitié-Salpêtrière, Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie; Sorbonne Universités (R.B.Y., I.N., M.B., G.B.), UPMC Université Paris 06, INSERM UMRS 974, Center of Research in Myology, Institut de Myologie, Paris; Department of Molecular Genetics (A.H., F.P., F.M.P.), Assistance Publique-Hôpitaux de Paris (APHP), Hôpitaux Universitaires Paris Sud, Antoine Béclère Hospital, Clamart; Department of Pediatrics (A.H., P.L.), Assistance Publique-Hôpitaux de Paris (APHP), Hôpitaux Universitaires Paris Sud, Antoine Béclère Hospital, Referal Center for Metabolic Liver Inherited Diseases, Clamart, and Université Paris-Sud, France; Department of Neurology (J.R.D., T.K., J.V.), Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen; Department of Neurology (D.G.), Odense University Hospital, Denmark; Hospices Civils de Lyon (N.S.), Groupement Hospitalier Est, Centre de Pathologie et Neuropathologie Est, Service de Neuropathologie, Université Claude-Bernard Lyon 1, CNRS UMR5239, LBMC, ENS; AP-HM, Département de Génétique Médicale (M.K., M.C., M.B.), Hôpital Timone Enfants; Aix Marseille Université (M.K., M.C., M.B.), Inserm, GMGF, UMR_S910; Hospices Civils de Lyon (P.P.), Hôpital la Croix-Rousse, Département de Neurologie, Université Claude Bernard Lyon 1; CHU Besançon (F.M.), Hôpital Jean Minjoz, Centre de Référence de Pathologie Neuromusculaire; Unité de morphologie neuromusculaire (E.M., N.R.), Groupe Hospitalier Universitaire La Pitié-Salpêtrière; Sorbonne Universités UPMC Université Paris 06; Assistance Publique-Hôpitaux de Paris (APHP) (R.Y.C.), Service d'imagerie Médicale, CIC-IT Handicap, Hôpital Raymond Poincaré, Garches, France; and Department of Clinical Genetics (M.D.), Rigshospitalet, University of Copenhagen, Denmark.
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.
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