PEDIATRICS Vol. 108 No. 2 August 2001, pp. 495-497

EXPERIENCE AND REASON:
Case Report: Liver Glycogen Synthase DeficiencyA Cause of Ketotic Hypoglycemia

	ABSTRACT

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Glycogen synthase deficiency is a rare inborn error of metabolism, characterized by fasting hypoglycemia, hypoglycemic seizures, and ketonuria. Only 7 families with 14 affected children have been reported. Here, we report an additional patient with this deficiency. Findings in this patient were clinically and biochemically consistent with those reported in patients with ketotic hypoglycemia and may alert the clinician to consider glycogen synthase deficiency.

Glycogen synthase deficiency is a rare inborn error of metabolism, characterized by morning drowsiness, fasting hypoglycemia, and hypoglycemic seizures, and accompanied by ketonuria. Only 7 families with 14 affected children have been reported; in 7 glycogen synthase deficiency was confirmed biochemically and in 9 the mutation in the GYS2 gene was found.^1-7 Here, we report an additional patient with this enzyme deficiency. Findings in this patient may alert the clinician to distinguish glycogen synthase deficiency from other conditions with ketotic hypoglycemia.

	CASE REPORT

L. R. was a 2900 g, 35-week product of an uncomplicated pregnancy and delivery. She required oxygen supplementation for 6 days but otherwise had an unremarkable neonatal course. In the first year of life, she ate every 3 to 4 hours. She never slept through the night, awakening spontaneously every 3 to 4 hours to feed.

At 15 months, she slept through the night for the first time. She was found at 6 AM the following morning in a generalized tonic-clonic seizure. Blood glucose was 1.5 mmol/L (27 mg/dL) and urinary ketones were present. A second hypoglycemic seizure (blood glucose 1.3 mmol/L, 23 mg/dL) occurred 6 weeks later, once again after she slept through the night without eating. Hormonal evaluation revealed appropriate responses of cortisol, insulin, C-peptide, and growth hormone to hypoglycemia. At 16 months she was referred for metabolic evaluation of recurrent hypoglycemia. Growth at 16 months was normal including height (25th percentile), weight (75th percentile), and head circumference (90th percentile). Development was normal, with walking since 11 months old and 4 to 5 words at 16 months. Fasting studies revealed hypoglycemia at 360 minutes of fasting with an increase in -hydroxybutyrate to 1.3 mmol/L (normal <0.4) consistent with ketotic hypoglycemia. Lactate was not increased with hypoglycemia. Glucagon produced no change in blood glucose in the fasting state, but in the fed state it produced an increase of both glucose and lactate (Table 1). Liver ultrasound showed normal liver size and echogenicity. Liver biopsy at 2 years old revealed very low glycogen content (0.4%, normal 3.3%) and normal glucose-6-phosphatase, debranching enzyme, and phosphorylase activities (Y. T. Chen, Duke University Medical Center, Raleigh, NC). She was treated for presumed glycogen synthase deficiency, which was confirmed 4 years later on a repeat liver biopsy from which glycogen synthase activity was 0.03 U/g liver with control values of 1.1 to 5.5.⁶

	DISCUSSION

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Glycogen synthase (EC 2.4.1.11) catalyzes glycogen synthesis from UDPglucose in liver, muscles, and other tissues. Liver glycogen synthase deficiency is a rare disorder, but may be underdiagnosed, as there is no hepatomegaly or typical body habitus appearance, as seen in glycogenosis type 1, to help pinpoint the diagnosis. The diagnosis must be suspected and the patient's blood chemistry profile must be studied in both the fed and fasting state; biochemical confirmation requires liver biopsy as the enzyme deficiency is not expressed in muscle, blood cells, or fibroblasts.^8,9

Clinical symptoms are all related to hypoglycemia and include episodes of morning drowsiness and/or seizures with fasting and a history of requiring frequent feeds.^1,3 Treatment consists of providing a constant source of glucose (frequent feeds, overnight feeds, and raw cornstarch). In the few patients reported to date, no long-term liver or renal complications have been seen.^1-3 In fact, 1 adult patient developed better fasting tolerance with age and has had a successful pregnancy.¹⁰

Abnormalities in blood chemistry profiles are the key to the diagnosis. In the fasting state, hypoglycemia develops, plasma lactate decreases but remains in the low normal range, and there is a marked ketotic response to the hypoglycemia.^1-3 There is no response of blood glucose to glucagon in the fasting state (Table 1). Although some glycogen is present and of normal appearance by electron microscopy,⁶ it seems to be unavailable for glycogenolysis and glucose release.^2,3 With feeding, patients become hyperglycemic because excess glucose cannot be shuttled to glycogen synthesis and plasma lactate increases to higher than normal levels as this excess glucose is converted to lactate.^2,3 There is an increase of blood glucose to glucagon in the fed state.³

Glycogen synthase deficiency should be considered in patients with ketotic hypoglycemia and normal liver size. The response of blood glucose to glucagon in the fasting state is impaired in children with ketotic hypoglycemia¹¹ and in children with glycogen synthase deficiency. The response of blood glucose to glucagon in the fed state is normal in ketotic hypoglycemia¹¹ and normal to increased in children with glycogen synthase deficiency. In addition, children with glycogen synthase deficiency become hyperglycemic with increased lactate with feeding, biochemical abnormalities not seen in ketotic hypoglycemia. Thus, a postprandial lactate measurement and a glucagon stimulation test in the fed state should help differentiate ketotic hypoglycemia and glycogen synthase deficiency. The latter must be confirmed by liver biopsy for assay of glycogen content, which usually is below the normal range but not nil, and for enzyme assay.⁶ Mutation analysis is possible as well.⁷

	CONCLUSION

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A diagnosis of liver glycogen synthase deficiency should be considered in a child presenting with ketotic hypoglycemia. Biochemical testing in both the fed and fasting state can differentiate the 2 diagnoses. Diagnosis of this enzyme deficiency as the source of ketotic hypoglycemia may affect treatment and prognosis.

S. Lane Rutledge, MD^*
Joycelyn Atchison, MD
^* Division of Neurology
 Division of Endocrinology
Department of Pediatrics
University of Alabama at Birmingham
Birmingham, AL 35233

Nils U. Bosshard, PhD
Beat Steinmann, MD
Division of Metabolism and Molecular Pediatrics
Department of Pediatrics
University of Zurich
Zurich CH 8032 Switzerland

	FOOTNOTES

Received for publication Jan 31, 2000; accepted Mar 20, 2001.

Reprint requests to (S.L.R.) Children's Hospital, 1600 7th Ave S, ACC 516, Birmingham, AL 35233. E-mail: lrutledge{at}peds.uab.edu

	REFERENCES

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