title: Glycogen storage disease type IX: High variability in clinical phenotype.
abstract: Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four subunits (alpha, beta, gamma and delta). The liver isoforms of the alpha-, beta- and gamma-subunits are encoded by PHKA2, PHKB and PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the PHKA2 gene in ten patients from eight families, in PHKG2 in two unrelated patients and in the PHKB gene in three patients from two families. Seven novel mutations were identified in PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in PHKG2 (p.L144P and p.H48QfsX5) and two in PHKB (p.Y419X and c.2336+965A>C). There was a severe phenotype in patients with PHKG2 mutations, a mild phenotype with patients PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies.
authors: Academic Unit of Child Health, University of Sheffield, Stephenson Wing, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield S10 2TH, and Department of Paediatrics, Addenbrook's Hospital, Cambridge, UK. n.j.beauchamp@sheffield.ac.uk
authors: Nicholas James
authors: NJ
authors: Beauchamp
authors: Ann
authors: A
authors: Dalton
authors: Uma
authors: U
authors: Ramaswami
authors: Harri
authors: H
authors: Niinikoski
authors: Karine
authors: K
authors: Mention
authors: Patricio
authors: P
authors: Kenny
authors: Kaija-Leena
authors: KL
authors: Kolho
authors: Julian
authors: J
authors: Raiman
authors: John
authors: J
authors: Walter
authors: Eileen
authors: E
authors: Treacy
authors: Stuart
authors: S
authors: Tanner
authors: Mark
authors: M
authors: Sharrard
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D006008:Glycogen Storage Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D010764:Phosphorylase Kinase / Q000235:genetics*; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D010764:Phosphorylase Kinase