Abstract
BackgroundThe metabolic defect in glycogen storage disease type I (GSDI) results in fasting hypoglycemia and typical secondary metabolic abnormalities (eg, hypertriglyceridemia, hyperlactatemia, hyperuricemia). The aim of this study was to assess further perturbations of the metabolic network in GSDI patients under ongoing treatment.MethodsIn this prospective observational study, plasma samples of 14 adult patients (11 GSDIa, 3 GSDIb. Mean age 26.4 years, range 16‐46 years) on standard treatment were compared to a cohort of 31 healthy controls utilizing ultra‐high performance liquid chromatography (UHPLC) in combination with high resolution tandem mass spectrometry (HR‐MS/MS) and subsequent statistical multivariate analysis. In addition, plasma fatty acid profiling was performed by GC/EI‐MS.ResultsThe metabolomic profile showed alterations of metabolites in different areas of the metabolic network in both GSD subtypes, including pathways of fuel metabolism and energy generation, lipids and fatty acids, amino acid and methyl‐group metabolism, the urea cycle, and purine/pyrimidine metabolism. These alterations were present despite adequate dietary treatment, did not correlate with plasma triglycerides or lactate, both parameters typically used to assess the quality of metabolic control in clinical practice, and were not related to the presence or absence of complications (ie, nephropathy or liver adenomas).ConclusionThe metabolic defect of GSDI has profound effects on a variety of metabolic pathways in addition to the known typical abnormalities. These alterations are present despite optimized dietary treatment, which may contribute to the risk of developing long‐term complications, an inherent problem of GSDI which appears to be only partly modified by current therapy.
Highlights
Glycogen storage disease type I (GSDI, van Gierke’s disease OMIM 232200) is an inherited metabolic disorder resulting from a defect of either glucose-6-phosphatase-α (GSDIa) or the glucose-6phosphate-transporter (GSDIb), translocating glucose-6-phosphate into the lumen of the endoplasmic reticulum for hydrolysis by glucose-6-phosphatase
The metabolomic profile showed alterations of metabolites in different areas of the metabolic network in both GSD subtypes, including pathways of fuel metabolism and energy generation, lipids and fatty acids, amino acid and methyl-group metabolism, the urea cycle, and purine/pyrimidine metabolism. These alterations were present despite adequate dietary treatment, did not correlate with plasma triglycerides or lactate, both parameters typically used to assess the quality of metabolic control in clinical practice, and were not related to the presence or absence of complications
The metabolic defect of glycogen storage disease type I (GSDI) has profound effects on a variety of metabolic pathways in addition to the known typical abnormalities. These alterations are present despite optimized dietary treatment, which may contribute to the risk of developing long-term complications, an inherent problem of GSDI which appears to be only partly modified by current therapy
Summary
Glycogen storage disease type I (GSDI, van Gierke’s disease OMIM 232200) is an inherited metabolic disorder resulting from a defect of either glucose-6-phosphatase-α (GSDIa) or the glucose-6phosphate-transporter (GSDIb), translocating glucose-6-phosphate into the lumen of the endoplasmic reticulum for hydrolysis by glucose-6-phosphatase. Hepatic cytoplasmic accumulation of glucose-6-phosphate and subsequent increases of other phosphomonoesters (i.e. glycolytic intermediates) trigger a series of changes in metabolic fluxes, such as enhanced glycolytic flux with production of excessive lactate, and markedly increased hepatic de novo lipogenesis (from increased availability of substrates, and by increased expression and activity of lipogenic transcription factors) with profound changes in lipid metabolism and liver steatosis (Greene et al 1978; Greene et al 1979; Oberhaensli et al 1988; Bandsma et al 2002; Bandsma et al 2008; Derks and van Rijn 2015; Cho et al 2018; Hornemann et al 2018). The aim of this study was to assess further perturbations of the metabolic network in GSDI patients under ongoing treatment
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