Untargeted plasma metabolomics identifies broad metabolic perturbations in glycogen storage disease type I

Abstract

Background: The 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. Methods: In 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. Results: 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 (ie, nephropathy or liver adenomas). Conclusion:The 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.

Untargeted metabolomic profiling in a patient with glycogen storage disease Ib receiving empagliflozin treatment

“…GSD dietary management was reflected with persistently low fructose and high branched‐chain amino acid intermediates secondary to strict fructose avoidance and protein supplementation in this patient. Lastly, alterations in other metabolic pathways, most noticeably fatty acids and lipids metabolism were observed using metabolomic profiling, similarly to a previous report by Mathis et al 26 Our data suggest that untargeted metabolomics is a useful tool for assessment of metabolic control and adherence to dietary management in patients with GSD using empagliflozin. Likewise, quantification of 1,5‐AG using untargeted metabolomic profiling may be used as a biomarker for future clinical trials of empagliflozin in the GSD‐Ib population.…”

Understanding Inborn Errors of Metabolism through Metabolomics

“…Similar studies were performed on urea cycle disorders [ 32 ], glycogen storage disease [ 33 ], fatty acid disorders [ 34 ], and mitochondrial dysfunction [ 35 ] (see Table A1 ).…”

Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives

“…Thus, GSDI has profound effects on various metabolic pathways in addition to the known typical exceptions. 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 [ 39 ].…”