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Inborn error of metabolism of glucose caused by decreased
glycogen synthetase activity and characterized by fasting hypoglycemia with
ketosis beginning in early infancy. Unlike other GSDs, GSD 0 does not result
in tissue accumulation of normal or abnormal glycogen.
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Glycogen Synthetase Deficiency.
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Less than 1:250,000 live births.
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Autosomal recessive trait. Male-to-female
ratio is 1:1. Disease is caused by a defect in the gene coding for liver
glycogen synthetase (GYS2), which is located on chromosome band 12p12.2.
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A decrease or absence of hepatic glycogen
synthetase, which is the rate-limiting enzyme for glycogen synthesis, by
transferring glucose units from UDP-glucose to a glycogen primer. This
action depends on phosphorylation/dephosphorylation mechanisms and is
regulated by several hormones, including insulin, epinephrine, and glucagon.
Secondary to a lack of storage of glycogen, GSD 0 patients develop
hypoglycemia in the early stages of fasting, when the main source of glucose
is provided by glycogenolysis, while gluconeogenesis is not able to maintain
normoglycemia. On the other hand, feeding results in postprandial
hyperglycemia and increased blood lactate levels because glycogen synthesis
is very limited; excess glucose mainly undergoes lactate conversion through
the glycolytic pathway. Muscle glycogen synthetase is coded by a different
gene and is not affected in patients with GSD 0.
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After 5 to 7 hours of fasting, patients demonstrate
hypoglycemia and ketosis (and ketonuria), while lactate and alanine levels
remain normal. Injection of glucagon fails to elicit a rise in plasma
glucose in fasted patients, whereas after a meal, it elicits hyperglycemia
and decreased levels of plasma lactate and alanine. Oral intake of glucose,
fructose, or galactose elicits a consistent rise in blood lactate. Definitive
diagnosis of GSD 0 requires a liver biopsy for enzyme assay (defective
glycogen synthetase activity) and microscopic analysis (decreased amounts of
normal glycogen stores, increased fat accumulation).
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Early-onset symptomatic hypoglycemia in infancy,
commonly presenting as seizures, disorientation, abnormal eye movements,
and/or coma occurring in the morning before breakfast or after inadvertent
fasting. Mild forms may display less suggestive signs, such as drowsiness,
lethargy, mental confusion, sweating, pallor, attention deficit, and
headache. Evolution is characterized by growth retardation. Physical
examination may reveal mild hepatomegaly.
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Preoperative examination of a child
with GSD 0 must document the presence or absence of hepatomegaly, lactic
acidosis, hyperketosis or hypoketosis, and associated signs of hepatic
insufficiency. The characteristic schedule of hypoglycemia following fasting (delay,
intensity, predictability, precipitating factors) should be closely
evaluated; this can be achieved only by monitored assessment of fasting
adaptation in an inpatient setting. Outpatient surgery is contraindicated in
GSD 0 patients. Evaluate serum electrolytes to calculate the anion gap, thus
determining the existence of metabolic acidosis (which is absent in typical
GSD 0 patients). Evaluate liver enzymes; mild elevations of aspartate
aminotransferase and alanine aminotransferase are consistent with mild
hepatocellular damage.
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Aim to maintain normal intake of
carbohydrate by intravenous glucose infusion during ...