History
Symptomatic hypoglycemia may be the initial presentation, often shortly after birth, and is detected between feedings. Rarely, individuals have mild cases of hypoglycemia, leading to a diagnosis at a later age. As patients grow older, they develop a round face, full cheeks, and short stature but have failure to thrive with delay in motor development. Recurrent hypoglycemic attacks can cause cognitive developmental delay. Although muscle weakness is not a uniform feature of glycogen storage disease (GSD), type I, Schwahn et al report an association between reduced muscle force and poor metabolic control. [8] Patients may also present with recurrent skin and pulmonary infections with hyperpnea due to lactic acidosis, along with GI symptoms of inflammatory bowel disease, including cramps, fever, and abdominal pain.
Physical Examination
Findings
Physical examination findings are common between GSD type Ia and type Ib, and they include the following:
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Hypotonia (from hypoglycemia in infancy)
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Short for age
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Round face with full cheeks (Cushingoid appearance)
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Hepatomegaly with abdominal protuberance
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Hyperpnea due to lactic acidosis
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Cognitive delay due to recurrent hypoglycemic episodes causing cerebral injury
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Nephromegaly (along with other biochemical abnormalities, is specific to GSD Ia/Ib)
Complications
Multiple organ systems are impacted, with long-term complications being detected with ongoing research.
Hepatic complications
As children grow older, hepatic size decreases; however, there is an increased risk of the development of hepatic adenoma, with a reported incidence of 80% in individuals by age 30. The median age at detection is 15 years (range, 2-30 years). [9] Earlier studies had not suggested that adenomas transform into hepatocellular carcinoma (HCC); however, a single center study of 72 patients with GSD I from Korea in 2020 had 32 individuals who developed hepatic adenomas, with 12.5% who had malignant transformation to HCC, on average 6.7 years after first detection of adenomas. [10] Detection is with doppler ultrasound and MRI, and may detect early cases that require liver transplantation to prevent mortality from HCC.
Gynecologic complications
A high prevalence of polycystic ovaries (PCOs) with insulin resistance has been noted with GSD Ia and reported by Lee et al in 1995, noting the occurence even before puberty in patients with GSD type Ia. [11] More recent studies by Sechi et al in 2012 found only 2 of 7 patients with GSD type Ib with documented PCOs in their review of 32 patients with GSD I, but 5 of the 7 had irregular menstrual cycles. [12] Since the study did not assess insulin resistance, it is not clear whether these 5 of 7 women should in fact be classified as having the clinical syndrome of PCOs. The early start of a proper diet prevented a delay in the onset of puberty; however, fertility did not appear to be impaired. First trimester complications occured with either new development or enlargement of adenomas in GSD type Ia, but only 1 patient with GSD type Ib had pregnancies and had hepatic adenomas, thereby suggesting that the physician should monitor for hepatic adenomas with ultrasound in the first trimester.
Hyperlipidemia
Untreated patients often have very high tryglyceride levels, with moderately increased low-density lipoprotein (LDL) cholesterol and with a low high-density lipoprotein cholesterol level. [5] As a consequence, GSD type Ib patients are at increased risk of atherosclerotic cardiovascular disease and acute pancreatitis, especially if triglyceride levels are >1000 mg/dL. Patients may also develop eruptive xanthomas on extensor surfaces.
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Metabolic pathways of carbohydrates.
