Genetics of von Gierke Disease (Glycogen-Storage Disease Type 1)

In 1929, von Gierke provided the initial description of glycogen-storage disease type I (GSD I) from autopsy reports of 2 children whose large livers contained excessive glycogen. He also reported similar findings in the kidneys. Both children had frequent nosebleeds before their deaths, consistent with histories documented in current patients.

In 1952, Cori and Cori reported 6 similar patients.[1] Two of the patients had almost total deficiency of hepatic glucose-6-phosphatase, whereas the remaining 4 had normal enzyme activity. These authors recognized that defects in the enzymology of hepatic glycogen-storage disease may cause a heterogeneous group of disorders. However, the mystery of patients with these clinical symptoms (despite normal phosphatase activity) remained unsolved until 1978, when Narisawa et al identified a defect in intracellular transport of the enzyme substrate.[2]

In recognition of the original clinical description of the disease, the type I Cori classification has been preserved; glycogen-storage disease type Ia (GSD Ia) designates the true enzyme defect, and glycogen-storage disease type Ib (GSD Ib) designates the intracellular transport defect. Because free glucose is the product of the hepatic glucose-6-phosphatase reaction, either type leads to accumulation of liver glycogen, accompanied by fasting hypoglycemia. Hepatomegaly, the natural consequence of glycogen accumulation, is the clinical hallmark of the disease.

In 2014, the American College of Genetics and Genomics issued an updated practice guideline on the diagnosis and management of types Ia and Ib.[3]

More than 80 discrete mutations have been identified for both types Ia and Ib.

The liver loses its capacity as a glucose-homeostatic organ because of a fundamental inability to release free glucose. Glycogen-storage disease type I (subtypes Ia and Ib) is one of the few genetic-biochemical causes of hypoglycemia in newborns. The usual homeostatic mechanism cannot halt the rapid drop in blood glucose levels that normally occurs during the first several hours after birth (reflecting consumption of maternal glucose), and the decrease continues. This decrease in circulating glucose can be precipitous, resulting in no measurable blood level. Seizures, cyanosis, and apnea may ensue. In older children, repeated episodes of hypoglycemia may result in brain damage, as measured on performance testing and assessment of brainstem auditory-evoked potentials.

In the hepatocyte, the glycogen catabolic machinery normally responds to stimuli caused by hypoglycemia (eg, neural, hormonal), ending in a flood of glucose-6-phosphate that cannot be released from the cell. However, glucose-6-phosphate is also the substrate for glycolysis and produces lactate. Lactate exits the hepatocyte, causing clinically significant lactic acidemia in proportion to the degree of stimulus for glycogen breakdown. The accumulation of lactic acid in blood can cause true acidosis with a large anion gap, a characteristic of glycogen-storage disease type I.

The immense increase in the intracellular phosphorylated intermediate compounds of glycolysis concurrently inhibits rephosphorylation of adenine nucleotides, activating the nucleic acid degradation pathway and resulting in increased uric acid, the end product. Hyperuricemia can reach levels that require use of xanthine oxidase inhibitors to prevent nephrolithiasis. Nephrolithiasis secondary to increased uric acid is a constant threat to patients with poorly controlled disease.

Severe hypoglycemia stimulates epinephrine secretion, which activates lipoprotein lipase and the release of free fatty acids. These fatty acids are transported to the liver, where they are used for triglyceride synthesis and are exported as very-low-density lipoprotein (VLDL), which is elevated in these patients. Paradoxically, even in the face of hypoglycemia, patients with glycogen-storage disease I do not develop significant ketosis because the abundance of acetyl coenzyme A (CoA) derived from glycolysis activates the acetyl CoA carboxylase enzyme that produces malonyl CoA in the first step of fatty acid synthesis. Because malonyl CoA inhibits transport of fatty acid into the mitochondrion, beta-oxidation of fatty acids for energy to support the hypoglycemic cells does not occur. This causes a continuing drop in blood glucose levels and explains the absence of ketone bodies.

The lipid abnormalities, which include hypercholesterolemia (decreased high-density lipoprotein [HDL] cholesterol and increased low-density lipoprotein [LDL] cholesterol), together with the characteristic hypertriglyceridemia do not cause premature atherosclerotic lesions in affected individuals. Recent evidence suggests that sera from patients with glycogen-storage disease Ia are able to more efficiently promote scavenger receptor class B type I–mediated cellular cholesterol efflux and that an increased antioxidant effect of these sera is directly related to the increased urate concentration.[4]

Notwithstanding these data, the results of a 2015 prospective multisite clinical study suggest a statistical correlation between progression of renal disease and serum lipid levels over time.[5] In addition, a 2009 report suggests that affected individuals may sustain an increase in carotid artery intimal thickness and arterial dysfunction.[6]  

Nosebleeds experienced by the patients in von Gierke's report probably resulted from the bleeding tendency characteristic of glycogen-storage disease Ia and Ib. This tendency resembles von Willebrand disease and suggests alterations in membrane glycoprotein synthesis. Although such changes have been found, no definitive explanation addresses how these alterations actually cause defective platelet aggregation.

Patients with glycogen-storage disease Ib are susceptible to gram-positive infections. Neutrophils from patients with glycogen-storage disease Ib have a significantly impaired respiratory-burst response to stimuli compared with type Ia neutrophils. Because the respiratory burst generates superoxide, which is a major defense against gram-positive organisms, a defect in this response would be expected to render the neutrophils susceptible, causing neutropenia and diminishing the individual's resistance to infection. Evidence suggests that microsomal transport of glucose-6-phosphate has a role in antioxidant protection of the neutrophil; therefore, a genetic defect in the transporter could impair cellular function and lead to apoptosis, as shown in the image below.

Growth is generally impaired in patients with glycogen-storage disease I, although growth can be improved with good dietary therapy in most patients. However, growth remains unimproved by treatment in some patients; the endocrine parameters of growth in this group are not measurably different from the larger number of patients.

Several studies have also documented a decreased bone mineral density in some patients with glycogen-storage disease I. One such investigation reported no correlation between bone mineral density and turnover markers, indicating an uncoupling of bone turnover in patients with glycogen-storage disease.[7, 8]  

The cause of severe anemia in the absence of renal function compromise in children with glycogen-storage disease I has remained unclear. Some have recently proposed that hepcidin production by hepatic adenomas plays a central role in patients with glycogen-storage disease I. Hepcidin is a peptide hormone that is also a key regulator of the egress of cellular iron; in excess, it may interfere with intestinal iron transport as well as iron release from macrophages.

Although extremely rare, glycogen-storage disease subtypes Ic and Id have occurred. Individuals with these forms probably have unusual mutations in the translocase gene (11q23).

Frequency

United States

The lack of newborn screening precludes reliable estimates of the incidence. The only estimates are for glycogen-storage diseases as a group, which suggest an incidence of 1 case per 20,000-25,000 births. Glycogen-storage disease I is unlikely to occur more frequently than 1 case in 50,000 infants.

In an odd quirk, clinical symptoms of biotinidase deficiency in patients with underlying glycogen-storage disease Ia have been associated with marked elevations in biotinidase levels on serum assay. However, mass screening for biotinidase deficiency does not reveal elevated activity.

Mortality/Morbidity

Affected newborns are at risk for all neonatal hypoglycemic complications of glycogen-storage disease type I. (Older children under treatment may experience symptoms identical to those listed below with impending hypoglycemia.)

Hypoglycemic complications are entirely nonspecific and include the following:

• Twitching
• Cyanosis
• Seizures
• Irritability
• Apathy
• Hypotonia
• Hypothermia
• Apnea
• Coma (may be secondary to cerebral edema from combined hypoglycemia and hypoxia secondary to hypoglycemic seizures)

Long-term consequences of glycogen storage include the following:

• Hepatic adenomas
• Hepatocellular carcinoma
• Progressive renal insufficiency
• Hyperuricemic nephrocalcinosis
• Hyperlipidemic xanthomas
• Short stature
• Hypoglycemic brain damage

In glycogen-storage disease Ib, secondary consequences of neutrophilic abnormalities include multiple and recurrent infections, brain abscess, and pseudocolitis.

Sex

Glycogen-storage disease Ia and Ib occur with equal frequency in both sexes.

Age

As genetic disorders, both types are present at conception, with clinical onset at birth.

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.

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.

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]

The initial laboratory workup of glycogen-storage disease type I (GSD I) should include measuring blood glucose levels with electrolytes. If the blood glucose concentration is low, measurement of electrolyte levels may permit calculation of an increased anion gap, which suggests lactic acidemia.

Measurement of liver function, plasma uric acid levels, and urinary creatinine clearance are essential.

Perform a CBC count and differential. In patients with glycogen-storage disease type Ia, the WBC count is usually within reference ranges because the defect does not affect leukocyte function. In contrast, glycogen-storage disease Ib causes chronic granulocytopenia due to the impaired function of the neutrophils, particularly in relation to gram-positive organisms.

Perform a coagulation profile to include bleeding time tests.

Ultrasonography of liver and kidneys may be useful. Abdominal ultrasonography can enable reasonable estimates of liver and kidney size. These estimates are especially useful during treatment of patients with chronic glycogen-storage disease because the relative size of the liver is expected to diminish with growth of the child. Ultrasonography may also be useful late in the clinical course to provide a baseline for evaluating nodules.

Bone-density studies may be useful in middle childhood to identify patients who may have diminished bone density in adolescence.

Glucagon administration produces no hyperglycemic response, although it markedly increases the plasma lactic acid level.

Oral (PO) administration of galactose (1.75 g/kg) causes no change in blood glucose levels, although plasma lactic acid levels markedly increase.

Always directly measure glucose-6-phosphatase activity in the liver before and after detergent treatment of the homogenate, especially when activity appears to be within the reference ranges before treatment.

Open biopsy was usually needed to obtain sufficient tissue for this assay; however, complete sequencing of the gene now permits molecular diagnosis without the need for invasive procedures.

Although histology should be routinely performed on liver samples obtained during surgery, neither light nor electron microscopy permit differentiation of the underlying reasons for glycogen storage.

Clinically significant lipid storage occurs with both types of glycogen-storage disease type I, which does little to clarify the picture.

Diagnostic evaluation of glycogen-storage disease type I (GSD I) is most safely performed in a hospital, especially in infants, because of the potential for severe hypoglycemia. Many untreated children are admitted by a hematologist or gastroenterologist for the diagnosis of massive hepatomegaly.

Young infants require continuous nasogastric (NG) tube feedings to sustain blood sugar levels. Older children can usually be switched to raw cornstarch feedings, which sustain blood glucose values for 4-6 hours. Trials using chemically-altered cornstarch that resulted in longer-term blood sugar support have been reported; these products are not yet widely available.[11]  Large quantities of raw cornstarch may be necessary, because overall use of this material is impaired in patients compared with healthy control subjects.

Pay scrupulous attention to the dental and oral health of patients with glycogen-storage disease type Ib to reduce incidence of infection.

Any intercurrent infection that causes decreased intake requires intravenous (IV) glucose support until resolution.

Currently, efforts are underway in animal models to develop gene therapy in patients with both forms of glycogen-storage disease type I.[12]

Surgery is usually unnecessary after initial diagnosis.

Promptly attend to any skin infection in patients with glycogen-storage disease type Ib because deep-tissue extension requiring surgical debridement and plastic reconstruction may develop.

In older children with glycogen-storage disease type Ib, cautiously evaluate abdominal pain for pseudocolitis.

Perform ultrasonography annually to evaluate for hepatic adenomas, which may require surgical removal.

Hepatic transplantation has been attempted in a few cases with modified success.

Consider the following consultations:

• Biochemical genetics specialist

• Nephrologist

Diet, the mainstay of therapy for both types of glycogen-storage disease type I, requires close monitoring and adjustment by a highly specialized nutritionist.

The fundamental principle of diet management for these patients is maintenance of a steady-state balance between circulating glucose and existing glycogen stores. Consequently, a chief aim is to avoid excessive carbohydrates and calories while supplying adequate calories and protein for growth.

Because of the triglyceridemia characteristic in this disorder, counsel the patient to avoid high lipid intake.[13]

Most biochemical parameters can be substantially normalized and liver size can be reduced by approaching glucose homeostasis by means of overnight feeding.

Overnight NG feedings should be administered only by a pump equipped with an alarm in case of flow interruption.

When pancreatic amylase reaches sufficient activity in children older than 2-3 years, overnight feeding is usually replaced by raw cornstarch at bedtime and early morning hours.

Instruct the patient to avoid all contact sports because of the propensity for infection and bleeding, as well as the potential for liver damage.

Encourage the patient to engage in all other physical activities up to individual limits. Personal limitations should be the basis for participation in school activities.

Glycogen-storage disease type Ia (GSD Ia) has no specific medication requirement beyond prophylactic PO iron and prompt treatment of intercurrent infections (which may interrupt PO intake).

Weekly administration of granulocyte colony–stimulating factor (GCSF), in addition to prophylactic PO iron and prompt treatment of intercurrent infections, is critical in patients with glycogen-storage disease type Ib. GCSF administration is now standard therapy to prevent or reduce incidences of serious infection. GCSF may also delay or prevent pseudocolitis symptoms. A 2014 multicenter study indicated that bone mineralization status correlated positively with initial age and duration of GCSF administration.[14]

Class Summary

These are inorganic substances found in small amounts in the tissues and required for various metabolic processes.

Iron sulfate (Feosol)

Nutritionally essential inorganic substance.

Class Summary

These agents act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia when patients are receiving myelosuppressive cancer chemotherapy and to reduce neutropenia associated with bone marrow transplantation. These drugs are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and to manage chronic neutropenia.

Filgrastim (G-CSF, Neupogen)

GCSF that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.

Close nutritional and biochemical genetic follow-up is critical, especially during initial and pubertal growth periods.

Patients should be seen by subspecialists at least every 6 months.

Conditions that reduce oral (PO) intake, such as in glycogen-storage disease type I (GSD I) require intravenous (IV) glucose to maintain blood sugar and to avoid complications of severe hypoglycemia.

No medications are required for glycogen-storage disease type Ia.

Patients with glycogen-storage disease type Ib require granulocyte colony-stimulating factor (GCSF) on a weekly basis.

Consider transferring any patient who is admitted for any reason other than routine IV fluid administration for blood glucose support.

See the list below:

• Severe hypoglycemia, cerebral edema, coma, death

• Hepatic adenoma, adenocarcinoma, or both

• Glomerular hyperfiltration and glomerulosclerosis

• Brain damage

• Severe anemia

• Growth failure

Patients receiving proper treatment should have a reasonable life span.

Teach parents of infants how to insert a nasogastric (NG) feeding tube.

Teach family members how to test blood glucose levels.

Teach family members and older children how to recognize signs of impending hypoglycemia.

Provide intensive nutritional education to patients so they can assist in their own dietary control as early as possible.

For excellent patient education resources, visit eMedicineHealth's Ear, Nose, and Throat Center. Also, see eMedicineHealth's patient education article Nosebleeds.