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Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

  • Irene J. Hoogeveen
  • Rixt M. van der Ende
  • Francjan J. van Spronsen
  • Foekje de Boer
  • M. Rebecca Heiner-Fokkema
  • Terry G. J. DerksEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 28)

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.

Keywords

Plasma Glucose Concentration Glycogen Storage Disease Glycogen Storage Disease Type Dietary Management Mitochondrial Fatty Acid Oxidation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

FI

Fasting intolerance

GSD

Glycogen storage disease

KBs

Ketone bodies

References

  1. Bali D, Goldstein J, Fredrickson K, Rehder C, Boney A, Austin S (2014) Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene. Mol Genet Metab 111:309–313CrossRefPubMedGoogle Scholar
  2. Beauchamp NJ, Taybert J, Champion MP, Layet V, Heinz-Erian P, Dalton A et al (2007a) High frequency of missense mutations in glycogen storage disease type VI. J Inherit Metab Dis 30:722–734CrossRefPubMedGoogle Scholar
  3. Beauchamp NJ, Dalton A, Ramaswami U, Niinikoski H, Mention K, Kenny P et al (2007b) Glycogen storage disease type IX: high variability in clinical phenotype. Mol Genet Metab 92:88–99CrossRefPubMedGoogle Scholar
  4. Bonnefont JP, Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JBC et al (1990) The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr 150:80–85CrossRefPubMedGoogle Scholar
  5. Brown LM, Corrado MM, van der Ende RM, Derks TGJ, Chen M, Siegel S et al (2014) Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children. J Inherit Metab Dis 38:489–493CrossRefPubMedGoogle Scholar
  6. Clemente M, Gussinyer M, Arranz JA, Riudor E, Yeste D, Albisa M, Carrascosa A (2010) Glycogen storage disease type III with hypoketosis. J Pediatr Endocrinol Metab 23:833–836CrossRefPubMedGoogle Scholar
  7. Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R et al (2000) Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics 105:1141–1145CrossRefPubMedGoogle Scholar
  8. D’Orazio P, Burnett R, Fogh-Andersen N, Jacobs E, Kuwa K, Kulpman W et al (2005) Approved IFCC recommendation on reporting results for blood glucose. Clin Chem 51:1573–1576CrossRefPubMedGoogle Scholar
  9. Dagli A, Weinstein D (2009) Glycogen storage disease type VI. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews. University of Washington, SeattleGoogle Scholar
  10. Dagli A, Sentner C, Weinstein D (2010) Glycogen storage disease type III. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews. University of Washington, SeattleGoogle Scholar
  11. Derks TGJ, Smit GPA (2015) Dietary management in glycogen storage disease type III: what is the evidence ? J Inherit Metab Dis 38:545–550CrossRefPubMedGoogle Scholar
  12. Derks TGJ, van Rijn M (2015) Lipids in hepatic glycogen storage diseases: pathophysiology monitoring of dietary management and future directions. J Inherit Metab Dis 38:537–543CrossRefPubMedPubMedCentralGoogle Scholar
  13. Goldstein J, Austin S, Kishnani P et al (2011) Phosphorylase kinase deficiency. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews. University of Washington, SeattleGoogle Scholar
  14. Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE et al (2010) Glycogen storage disease type III diagnosis and management guidelines. Genet Med 12:446–463CrossRefPubMedGoogle Scholar
  15. Koh TH, Aynsley-Green A, Tarbit M, Eyre J (1988) Neural dysfunction during hypoglycaemia. Arch Dis Child 63:1353–1358CrossRefPubMedPubMedCentralGoogle Scholar
  16. Laforêt P, Weinstein DA, Smit GPA (2012) The glycogen storage diseases and related disorders. In: Saudubray JM, van de Berghe G, Walter J (eds) Inborn metabolic diseases: diagnosis and treatment. Springer, BerlinGoogle Scholar
  17. Millington DS, Kodo N, Norwood DL, Roe CR (1990) Tandem mass-spectrometry - a new method for acylcarnitine profiling with potential for neonatal screening for inborn-errors of metabolism. J Inherit Metab Dis 13:321–324CrossRefPubMedGoogle Scholar
  18. Seigel J, Weinstein DA, Hillman R, Colbert B, Matthews B, Bachrab B (2008) Glycogen storage disease type IIIa presenting as non-ketotic hypoglycemia: use of a newly approved commercially available mutation analysis to non-invasively confirm the diagnosis. J Pediatr Endocrinol Metab 6:587–590Google Scholar
  19. Touati G, Mochel F, Rabier D (2012) Diagnostic procedures: functional tests and post-mortem protocol. In: Saudubray JM, van den Berghe G, Walter J (eds) Inborn metabolic diseases: diagnosis and treatment. Springer, BerlinGoogle Scholar
  20. Van Veen MR, van Hasselt PM, de Sain-van der Velden MGM, Verhoeven N, Hofstede FC, de Koning TJ et al (2011) Metabolic profiles in children during fasting. Pediatrics 127:1021–1027CrossRefGoogle Scholar
  21. Wang J, Cui H, Lee N-C, Hwu W-L, Chien Y-H, Craigen WJ et al (2012) Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genet Med 15:106–114CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Irene J. Hoogeveen
    • 1
  • Rixt M. van der Ende
    • 1
  • Francjan J. van Spronsen
    • 1
  • Foekje de Boer
    • 1
  • M. Rebecca Heiner-Fokkema
    • 1
    • 2
  • Terry G. J. Derks
    • 1
    Email author
  1. 1.Section of Metabolic DiseasesBeatrix Children’s Hospital, University of Groningen, University Medical Center GroningenGroningenThe Netherlands
  2. 2.Laboratory of Metabolic Diseases, Department of Laboratory MedicineUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands

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