Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control

Fabian Peeks,Maaike H Oosterveer,Rob Burghard,Terry G J Derks,Fabienne Rajas,Foekje De Boer,David A Weinstein,Monique Williams,M Estela Rubio‐Gozalbo,Thomas A H Steunenberg

doi:10.1007/s10545-017-0039-1

Abstract

ObjectiveTo 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).Study designDescriptive 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.ResultsPatients 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).ConclusionsDifferences 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.

Highlights

Glycogen storage disease type Ia (GSD Ia; OMIM #232200) is a rare inherited disorder of carbohydrate metabolism caused by mutations in the G6PC gene, resulting in deficiency ofJ Inherit Metab Dis (2017) 40:695–702 glucose-6-phosphatase (G6Pase)
Heterogeneity between GSD Ia patients with homozygous G6PC mutations indicate an important role of the G6PC genotype/mutations
Twenty GSD Ia patients were included from 14 families, 12 males and eight females

Summary

Introduction

Glycogen storage disease type Ia (GSD Ia; OMIM #232200) is a rare inherited disorder of carbohydrate metabolism caused by mutations in the G6PC gene, resulting in deficiency ofJ Inherit Metab Dis (2017) 40:695–702 glucose-6-phosphatase (G6Pase). Glycogen storage disease type Ia (GSD Ia; OMIM #232200) is a rare inherited disorder of carbohydrate metabolism caused by mutations in the G6PC gene, resulting in deficiency of. The subsequently impaired hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate affects the final common pathway of glycogenolysis and gluconeogenesis (Bali et al n.d.; Froissart et al 2011). Symptoms and signs include severe fasting intolerance, failure to thrive, and hepatomegaly. The phenotype is characterized by non-ketotic hypoglycemia, hyperlactidemia, hyperuricaemia, and hyperlipidaemia (Bali et al n.d.). Dietary management has greatly improved the life expectancy of GSD Ia patients, changing from an acute, fatal disease into a chronic disorder. Important long-term complications include the liver (hepatocellular adenomas and carcinomas), kidneys (proteinuria, renal insufficiency, stones), and bone (osteopenia, osteoporosis) (Bali et al n.d.; Rake et al 2002a, b)

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