title: Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control.
abstract: To study heterogeneity between patients with glycogen storage disease type Ia (GSD Ia), a rare inherited disorder of carbohydrate metabolism caused by the deficiency of glucose-6-phosphatase (G6Pase).
  
  
  
  Descriptive retrospective study of longitudinal clinical and biochemical data and long-term complications in 20 GSD Ia patients. We included 11 patients with homozygous G6PC mutations and siblings from four families carrying identical G6PC genotypes. To display subtle variations for repeated triglyceride measurements with respect to time for individual patients, CUSUM-analysis graphs were constructed.
  
  
  
  Patients with different homozygous G6PC mutations showed important differences in height, BMI, and biochemical parameters (i.e., lactate, uric acid, triglyceride, and cholesterol concentrations). Furthermore, CUSUM-analysis predicts and displays subtle changes in longitudinal blood triglyceride concentrations. Siblings in families also displayed important differences in biochemical parameters (i.e., lactate, uric acid, triglycerides, and cholesterol concentrations) and long-term complications (i.e., liver adenomas, nephropathy, and osteopenia/osteoporosis).
  
  
  
  Differences between GSD Ia patients reflect large clinical and biochemical heterogeneity. Heterogeneity between GSD Ia patients with homozygous G6PC mutations indicate an important role of the G6PC genotype/mutations. Differences between affected siblings suggest an additional role (genetic and/or environmental) of modifying factors defining the GSD Ia phenotype. CUSUM-analysis can facilitate single-patient monitoring of metabolic control and future application of this method may improve precision medicine for patients both with GSD and remaining inherited metabolic diseases.
authors.affiliation: Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, PO Box 30 001, Groningen, 9700 RB, The Netherlands.
authors.forename: Fabian
authors.initials: F
authors.lastname: Peeks
authors.affiliation: Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, PO Box 30 001, Groningen, 9700 RB, The Netherlands.
authors.forename: Thomas A H
authors.initials: TAH
authors.lastname: Steunenberg
authors.affiliation: Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, PO Box 30 001, Groningen, 9700 RB, The Netherlands.
authors.forename: Foekje
authors.initials: F
authors.lastname: de Boer
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands; Laboratory of Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: M Estela
authors.initials: ME
authors.lastname: Rubio-Gozalbo
authors.affiliation: Erasmus MC-Sophia Kinderziekenhuis, Erasmus Universiteit Rotterdam, Rotterdam, Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Williams
authors.affiliation: EnerGQcare BV, Groningen, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Burghard
authors.affiliation: Institut national de la santé et de la recherche médicale U1213, Université Lyon 1, Lyon, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rajas
authors.affiliation: Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.affiliation: Glycogen Storage Disease Program, University of Connecticut School of Medicine and Connecticut Children's Medical Center, Hartford, CT, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Weinstein
authors.affiliation: Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, PO Box 30 001, Groningen, 9700 RB, The Netherlands. t.g.j.derks@umcg.nl.
authors.forename: Terry G J
authors.initials: TGJ
authors.lastname: Derks
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D005260:Female; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation / Q000235:genetics; D012189:Retrospective Studies; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D014280:Triglycerides; D002784:Cholesterol; D005952:Glucose-6-Phosphatase
keywords: CUSUM; ESGSDI; G6PC; GSD Ia; Heterogeneity; Modifying factors