Changes in pediatric plasma acylcarnitines upon fasting for refined interpretation of metabolic stress.

BACKGROUND: Childhood fasting intolerance is a life-threatening problem associated with various inborn errors of metabolism. Plasma acylcarnitines reflect fatty acid oxidation and help determine fasting intolerance etiology. Pediatric reference values of plasma acylcarnitines upon fasting are not available, complicating interpretation of stress samples. METHODS: Retrospective analysis of supervised clinical fasting studies between 01/2005-09/2012. Exclusion criteria involved patients with (suspected) disorders, repeated tests or incomplete results. Remaining children were grouped according to age: group A (≤24 months), B (25-84 months) and C (≥85 months). Median and 2.5th to 97.5th percentiles of basic metabolic parameters and acylcarnitines were determined at start and end of testing on the ward and analyzed for significant differences (p<0.05). RESULTS: Out of 127 fasting studies, 48 were included: group A (n=13), B (n=23) and C (n=12). Hypoglycemia occurred in 21%. Children from group C demonstrated significantly higher end glucose concentrations while end ketone body concentrations were significantly lower compared to younger children. In all groups, free carnitine and C3-carnitine significantly decreased upon fasting, while C2-, C6-, C12:1-, C12-, C14:1-, C14-, C16:1- and C16-carnitine significantly increased. End concentrations of C6-, C12:1-, C12-, C14:1-, C14-, C16:1-, C16- and C18:1-carnitine were significantly lower in children ≥85 months compared to younger children. CONCLUSIONS: Fasting-induced counter-regulatory mechanisms to maintain energy homeostasis are age-dependent. This influences the changes in basic metabolic parameters and acylcarnitine profiles. Our data enable improved interpretation of the individual fasting response and may support assessment of minimal safe fasting times or treatment responses in patients.

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease.

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 ß-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.

Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children.

INTRODUCTION: Ketone formation is a normal response when hypoglycemia occurs. Since the majority of children with recurrent hypoglycemia cannot be diagnosed with a known endocrine or metabolic disorder on a critical sample, ketotic hypoglycemia has been described as the most common cause of low blood glucose concentrations in children. Critical samples, however, will miss the ketotic forms of glycogen storage disease (GSD), which present with elevated ketones, hypoglycemia, and normal hormonal concentrations. RESULTS: A total of 164 children (96 boys, 68 girls) were enrolled in the study. Prediction of pathogenicity of DNA changes using computer modeling confirmed pathology in 20 individuals [four GSD 0, two GSD VI, 12 GSD IX alpha, one GSD IX beta, one GSD IX gamma] (12%). Boys were most likely to have changes in the PHKA2 gene, consistent with GSD IX alpha, an X-linked disorder. CONCLUSIONS: Mutations in genes involved in glycogen synthesis and degradation were commonly found in children with idiopathic ketotic hypoglycemia. GSD IX is likely an unappreciated cause of ketotic hypoglycemia in children, while GSD 0 and VI are relatively uncommon. GSD IX alpha should particularly be considered in boys with unexplained hypoglycemia.