History

Initial symptoms of neonatal hypoglycemia occur shortly after birth in patients with glycogen-storage disease type I (GSD I), and patients do not respond to glucagon administration. Symptoms include the following:

Tremors
Irritability
Cyanosis
Seizures
Apnea
Coma

Older infants may present with the following:

Frequent lethargy
Difficult arousal from overnight sleep
Tremors
Overwhelming hunger
Poor growth
Apparent increase in abdominal girth, although extremities appear thin
A doll-like facial appearance caused by adipose tissue deposition in the cheeks

Young children with glycogen-storage disease type Ia may experience nosebleeds.

Young children with glycogen-storage disease Ib may have frequent otitides, gingivitis, and boils.

Symptoms of severe hypoglycemia in patients of all ages are likely to follow any illness that causes mild anorexia or fasting (eg, viral gastroenteritis).

In middle childhood, patients may manifest evidence of rickets and anemia.

Patients with glycogen-storage disease Ib at all ages may be affected by a Crohnlike ileocolitis (pseudocolitis). The severity of the primary disorder is not correlated with the intestinal symptoms.

Physical

Affected infants are healthy at birth, although some are born with an enlarged liver.

Careful abdominal examination is mandatory for any neonate with hypoglycemia.
Abdominal protuberance develops early because of massive hepatomegaly.
Splenomegaly does not occur.
The liver is firm and uniform in consistency in early life but may become nodular with the development of adenoma.

The patient may present with poor growth, short stature, and rachitic changes.

Gingivitis and compromised dentition may be present.

Xanthoma may be found on extensor surfaces, such as the elbows and knees.

Ultrasonography may reveal large kidneys in patients of all ages. Proteinuria may accompany this finding.

In addition to hypoglycemia, an increased plasma lactate value is a characteristic laboratory finding in a symptomatic newborn with glycogen-storage disease I. The increased lactate originates from the flooding of the glycolytic pathway by glucose-6-phosphate, which is derived from breakdown of glycogen, cannot be cleaved to free glucose, and is released into blood.

Causes

Glycogen-storage disease Ia and Ib are autosomal recessive genetic traits caused by mutations at loci 17q21 and 11q23, respectively.

Glycogen-storage disease Ia is caused by deficient activity of the enzyme glucose-6-phosphatase, representing at least 14 distinct allelic variants.

Glycogen-storage disease Ib is caused by deficiency of glucose-6-phosphate translocase, which is responsible for importing glucose-6-phosphate from the cytosol to the interior of the microsome, thus bringing substrate into contact with enzyme. To date, allelic variation in this disorder has not been explored.^[9]

A particular molecular pattern has been suggested in hepatocytes, which are transformed into adenomata.^[10]

Differential Diagnoses

Cori GT, Cori CF. Glucose-6-phosphatase of the liver in glycogen storage disease. J Biol Chem. 1952 Dec. 199(2):661-7. [Medline].
Narisawa K, Igarashi Y, Otomo H, Tada K. A new variant of glycogen storage disease type I probably due to a defect in the glucose-6-phosphate transport system. Biochem Biophys Res Commun. 1978 Aug 29. 83(4):1360-4. [Medline].
Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov. 16 (11):e1. [Medline].
Nguyen AD, Pan CJ, Weinstein DA, Chou JY. Increased scavenger receptor class B type I-mediated cellular cholesterol efflux and antioxidant capacity in the sera of glycogen storage disease type Ia patients. Mol Genet Metab. 2006 Nov. 89(3):233-8. [Medline].
Melis D, Cozzolino M, Minopoli G, et al. Progression of renal damage in glycogen storage disease type I is associated to hyperlipidemia: a multicenter prospective Italian study. J Pediatr. April 2015. 166:1079-1082. [Medline].
Bernier AV, Correia CE, Haller MJ, et al. Vascular dysfunction in glycogen storage disease type I. J Pediatr. 2009 Apr. 154(4):588-91. [Medline].
Cabrera-Abreu J, Crabtree NJ, Elias E, et al. Bone mineral density and markers of bone turnover in patients with glycogen storage disease types I, III and IX. J Inherit Metab Dis. 2004. 27(1):1-9. [Medline].
Minarich LA, Kirpich A, Fiske LM, Weinstein DA. Bone mineral density in glycogen storage disease type Ia and Ib. Genet Med. 2012 Apr 5. [Medline].
Sim SW, Park TS, Kim SJ, Park BC, Weinstein DA, Lee YM, et al. Aberrant proliferation and differentiation of glycogen storage disease type Ib mesenchymal stem cells. FEBS Lett. 2018 Jan. 592 (2):162-171. [Medline].
Calderaro J, Labrune P, Morcrette G, et al. Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I. J Hepatol. 2013 Feb. 58(2):350-7. [Medline].
Correia CE, Bhattacharya K, Lee PJ, et al. Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib. Am J Clin Nutr. 2008 Nov. 88(5):1272-6. [Medline].
Koeberl DD. In search of proof-of-concept: gene therapy for glycogen storage disease type Ia. J Inherit Metab Dis. 2012 Feb 7. [Medline].
Das AM, Lücke T, Meyer U, Hartmann H, Illsinger S. Glycogen storage disease type 1: impact of medium-chain triglycerides on metabolic control and growth. Ann Nutr Metab. 2010. 56(3):225-32. [Medline].
Melis D, Pivonello R, Cozzolino M, et al. Impaired bone metabolism in glycogen storage disease type I is associated with poor metabolic control in type Ia and with granulocyte-colony stimulating factor therapy in type Ib. Horm Res Paediatr. January 2014. 81:55-62. [Medline].

Media Gallery

Microsome is shown in relation to the substrate, glucose-6-phosphate, which has been released from cytosolic glycogen. This substrate is transferred across the microsomal membrane by the protein translocase, where by glucose-6-phosphatase acts on it to release free glucose and inorganic phosphate. Patients with glycogen-storage disease type Ia are genetically deficient in glucose-6-phosphate activity, while those affected with glycogen-storage disease type Ib lack translocase.

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