title: Liver glycogen storage diseases due to phosphorylase system deficiencies: diagnosis thanks to non invasive blood enzymatic and molecular studies.
abstract: Glycogen storage disease (GSD) due to a deficient hepatic phosphorylase system defines a genetically heterogeneous group of disorders that mainly manifests in children. We investigated 45 unrelated children in whom a liver GSD VI or IX was suspected on the basis of clinical symptoms including hepatomegaly, increased serum transaminases, postprandial lactatemia and/or mild fasting hypoglycemia. Liver phosphorylase and phosphorylase b kinase activities studied in peripheral blood cells allowed to suspect diagnosis in 37 cases but was uninformative in 5. Sequencing of liver phosphorylase genes was useful to establish an accurate diagnosis. Causative mutations were found either in the PYGL (11 patients), PHKA2 (26 patients), PHKG2 (three patients) or in the PHKB (three patients) genes. Eleven novel disease causative mutations, five missense (p.N188K, p.D228Y, p.P382L, p.R491H, p.L500R) and six truncating mutations (c.501_502ins361pb, c.528+2T>C, c.856-29_c.1518+614del, c.1620+1G>C, p.E703del and c.2313-1G>T) were identified in the PYGL gene. Seventeen novel disease causative mutations, ten missense (p.A42P, p.Q95R, p.G131D, p.G131V, p.Q134R, p.G187R, p.G300V, p.G300A, p.C326Y, p.W820G) and seven truncating (c.537+5G>A, p.G396DfsX28, p.Q404X, p.N653X, p.L855PfsX87, and two large deletions) were identified in the PHKA2 gene. Four novel truncating mutations (p.R168X, p.Q287X, p.I268PfsX12 and c.272-1G>C) were identified in the PHKG2 gene and three (c.573_577del, p.R364X, c.2427+3A>G) in the PHKB gene. Patients with PHKG2 mutations evolved towards cirrhosis. Molecular analysis of GSD VI or IX genes allows to confirm diagnosis suspected on the basis of enzymatic analysis and to establish diagnosis and avoid liver biopsy when enzymatic studies are not informative in blood cells.
authors.affiliation: Biochemistry Unit, CHU Bicêtre, Assistance Publique-Hôpitaux de Paris, France. anne.spraul@bct.aphp.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Davit-Spraul
authors.forename: Monique
authors.initials: M
authors.lastname: Piraud
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Philippe
authors.initials: P
authors.lastname: Labrune
authors.forename: Dalila
authors.initials: D
authors.lastname: Habes
authors.forename: Olivier
authors.initials: O
authors.lastname: Bernard
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
authors.forename: Christiane
authors.initials: C
authors.lastname: Baussan
mesh_terms: D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006008:Glycogen Storage Disease / Q000097:blood* / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007223:Infant; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000235:genetics; D010764:Phosphorylase Kinase / Q000172:deficiency* / Q000235:genetics; D006005:Phosphorylases / Q000172:deficiency* / Q000235:genetics
chemical_list: D006005:Phosphorylases; D010764:Phosphorylase Kinase