Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

Abstract

Background: According to the textbooks, the ketotic glycogen storage disease (GSD) types 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia and considered milder as gluconeogenesis is intact.

Methods: A retrospective cohort study of biochemical profiles from supervised clinical fasting studies is performed in ketotic GSD patients in our metabolic center. For data analysis, hypoglycemia was defined as plasma glucose concentration <2.6 mmol/L. Total KB was defined as the sum of blood acetoacetate and β-hydroxybutyrate concentrations. If the product of glucose and KB concentrations was greater than 10, a ketolysis defect was suspected.

Results: Data could be collected from 13 fasting studies in 12 patients with GSD III (n = 4), GSD VI (n = 3), and GSD IX (n = 5). Six patients remained normoglycemic with median glucose concentration of 3.9 mmol/L (range, 2.8–4.6 mmol/L) and median total KB concentration of 1.9 mmol/L (range, 0.6–5.1 mmol/L). The normoglycemic patients included type VI (3 out of 3) and type IX (3 out of 5) patients. All type III patients developed ketotic hypoglycemia. Interestingly, in five patients (one GSD III, one GSD VI, and three GSD IX), the biochemical profile suggested a ketolysis defect.

Conclusion: Normoglycemic ketonemia is a common biochemical presentation in patients with GSD types VI and IX, and ketonemia can precede hypoglycemia in all studied GSD types. Therefore, GSD VI and GSD IX should be added to the differential diagnosis of ketotic normoglycemia, and KB concentrations should be routinely measured in ketotic GSD patients.

Competing interests: None declared

Compliance with Ethics Guidelines

Conflict of Interest

Francjan J. van Spronsen has received research grants and consultancy and speaker’s fees from Merck Serono and Danone Nutricia. He is a member of the scientific advisory board of Merck Serono and chair of the scientific advisory board of Danone Nutricia. In the last 5 years, Terry G. J. Derks has received speaker’s fees from Danone Nutricia, Vitaflo, and Recordati and research fees from Sigma Tau and Vitaflo. Irene J. Hoogeveen, Rixt M. van der Ende, Foekje de Boer, and M. Rebecca Heiner-Fokkema declare that they have no conflict of interest to disclose.

Funding Source

No funding was secured for this study.

Financial Disclosure

The authors have no financial relationship relevant to this article.

Contributions of Individual Authors

Irene J. Hoogeveen and Rixt M. van der Ende collected and analyzed data from supervised clinical fasting studies, performed the data analysis, drafted the first version of the manuscript, and wrote the final manuscript.

Francjan J. van Spronsen was involved in clinical management and monitoring, critically reviewed and revised the manuscript, and approved the final manuscript as submitted.

Foekje de Boer was involved in dietary management, critically reviewed and revised the manuscript, and approved the final manuscript as submitted.

M. Rebecca Heiner-Fokkema supervised the data analysis of the fasting studies, critically reviewed and revised the manuscript, and approved the final manuscript as submitted.

Terry G. J. Derks initiated this study, was involved in clinical management and monitoring, drafted the first version of the manuscript, critically reviewed and revised the manuscript, and wrote the final manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All authors confirm the absence of previous similar or simultaneous publications.

Informed Consent

All procedures followed were in accordance with the ethical standards of the institutional responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Since all data were retrieved retrospectively and analyses anonymously, no informed consent was needed.