Type Ib Glycogen Storage Disease

Glycogen storage diseases (GSD) are a group of inherited autosomal recessive disorders caused by genetic mutations that lead to the inability to breakdown and metabolize glycogen into glucose. The resultant inability to breakdown glycogen results in excessive buildup of glycogen in organs responsible for gluconeogensis and glycogenolysis, most importantly the liver and kidneys. In most cases, the defect has systemic consequences; however, in others the defect is limited to specific organs. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

The image below illustrates the metabolic pathways for carbohydrates.

Although at least 14 unique GSDs are discussed in the literature, the 5 that cause clinically significant symptomology are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), Tarui disease (GSD type VII, phosphofructokinase deficiency), and Von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency or type Ib, glucose-6-phosphate transporter mutation). The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, there also is a GSD type 0, which is due to defective glycogen synthase.

Von Gierke disease (GSD type Ia and Ib) was first reported in 1929 based on the autopsy findings in 2 children who had excessive hepatic and renal glycogen accumulation. Although 4 other cases were reported of excess glycogen storage in the livers of autopsy patients, it was not until 1978 when Narisawa et al were able to differentiate GSD type Ia and type Ib, recognizing type Ia was due to a deficiency in the G6Pase enzyme, and type Ib was due to deficiency in the G6P transporter.[4] GSD Ib, like other GSDs, is also an autosomal recessive disorder and causes significant end-organ disease with significant morbidity, and typically presents in infancy (by age 3-4 months).  

GSD type Ib is an autosomal recessive condition caused by a mutation in the glucose-6-phosphate transporter gene (G6PT1, also known as SLC37A4).[1]  Normally, in the terminal steps of both glyogenolysis and gluconeogensis, glucose-6-phosphate transporter (G6PT) permits movement of G6P from the cytoplasm into the lumen of the endoplasmic reticulum, presenting it to a G6Pase for breakdown to glucose and phosphate and release into the cytoplasm. Mutation of SLC37A4 results in deficiency of the G6P transporter (G6PT), which then prevents transport of G6P from the cytoplasm to the endoplasmic reticulum. This leads to hypoglycemia, glycogen accumulation, and dysfunction in the liver, kidneys, and intestinal mucosa.  Of those individuals with GSD type I, 80% have genetic mutation of the G6Pase (type Ia) and 20% have mutation of the G6PT (type Ib). 

Impaired gluconeogensis and glycogenolysis then leads to increased metabolites such as lactic acid, uric acid, lipids, and triglyceride. Like GSD type Ia, type Ib presents with hypoglycemia and lactic acidemia in infancy but more commonly at 3-6 months of age, along with growth retardation, hyperlipidemia, hyperuricemia, and lactic acidemia. Unlike type Ia, GSD type Ib results in neutropenia and myeloid dysfunction, causing recurrent bacterial infections. The underlying mechanisms for neutropenia and myeloid dysfunction are not completely understood. Patients with GSD-I (both type Ia and type Ib) do not generally have skeletal abnormalities or myopathy.  

 

International data

GSD I is a disorder with genetic mutations found in multiple ethnic groups and has an overall incidence of ~1/100,000.  Among the Ashkenazi Jews, there is a relatively high prevalence (1/20,000).[5]  Newer epidemiological studies found the Serbian population had an incidence of ~1/60,000 live births, which is the highest incidence of GSD Ib worldwide.[6]

Morbidity/mortality

Long-term outcomes have improved with appropriate dietary therapy, but due to ongoing complications, morbidity and mortality still exists and depends on age and duration of disease. Early in life, morbidity is due to hypoglycemia, which can lead to life-threatening seizures. With advancing age, hepatic and renal dysfunction due to glycogen accumulation may lead to hepatic and renal failure and hepatocellular adenoma. Individuals with GSD type Ib (unlikely GSD type Ia) also develop recurrent bacterial infections due to neutropenia and inflammatory bowel disease along with complications of liver adenomas. Other complications of GSD type Ib include the following:

• Hepatic adenoma with potential malignant transformation

• Inflammatory bowel disease 

• Recurrent pulmonary and skin infections

• Secondary diabetes mellitus (may be a late complication)

• Acute myelogenous leukemia (Pinsk et al suggest surveillance for acute myelogenous leukemia as a potential complication of GSD type Ib[7] )

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.

Findings

Physical examination findings are common between GSD type Ia and type Ib, and they include the following:

• Hypotonia (from hypoglycemia in infancy)
• Short for age
• Round face with full cheeks (Cushingoid appearance)
• Hepatomegaly with abdominal protuberance 
• Hyperpnea due to lactic acidosis
• Cognitive delay due to recurrent hypoglycemic episodes causing cerebral injury
• Nephromegaly (along with other biochemical abnormalities, is specific to GSD Ia/Ib)

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.

Laboratory studies

The following laboratory studies are recommended:

• Obtain a creatine kinase level in all cases of suspected glycogen storage disease (GSD).

• Obtain a lipid profile, owing to changes in glucose metabolism.

• Because hypoglycemia may be found in some types of GSD, fasting glucose measurement is indicated. Hypoglycemia is concerning and may lead to hypoglycemic seizures.

• Urine studies are indicated because myoglobinuria may occur in some GSDs.

• Hepatic failure occurs in some GSDs. Liver function studies are indicated.

• Biochemical assay is required for definitive diagnosis.

Imaging studies

Imaging may reveal hepatic adenoma, which may become malignant.

Ischemic forearm test

The ischemic forearm test is an important tool for the diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.

The following steps are included in the ischemic forearm test:

• Instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples in the antecubital vein.

• Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.

• Obtain a urine sample for myoglobin analysis.

• Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.

• Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.

• Collect a final urine sample for myoglobin analysis.

Interpretation of ischemic forearm test results

With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.

Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 µg/dL. Levels will return to baseline. If neither level increases, the exercise was not strenuous enough and the test result is not valid.

Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy. Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all GSDs have a positive ischemic test. Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency. The results of the ischemic forearm test are normal in patients with GSD type Ib.

Electromyelography

Electromyelographic findings may be suggestive of myopathy, although abnormal spontaneous activity may be present. Electrical myotonia without clinical myotonia may be present.

Myotonic discharges may be found in the paraspinal muscles. Fibrillation potentials, positive sharp waves, and complex repetitive discharges may also be found. Myopathic findings of polyphasic responses, decreased duration of potentials, and decreased amplitude usually are present.

Electrocardiography

The electrocardiogram demonstrates a pan-lead, short PR interval and elevated QRS complexes in the infantile form.

Endoscopy

Given the association of inflammatory bowel disease, endoscopic procedures may be necessary.

Liver biopsy

Liver histology is characterized by hepatocytes distended by glycogen and fat. Associated fibrosis is minimal.

Medical care

In general, no specific treatment exists for glycogen storage diseases (GSDs).[13]

In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development. Early diet therapy may help prevent hepatic disease, including hepatocellular carcinoma.

There is ongoing research into emerging gene therapy treatments. Zingone et al demonstrated the abolition of the murine clinical manifestations of Von Gierke disease with a recombinant adenoviral vector.[14]  These findings suggest that corrective gene therapy for GSDs may be possible in humans. An encouraging study by Bijvoet et al provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[15]

Surgical care

Liver transplantation may be indicated for patients with hepatic malignancy. It is not clear whether transplantation prevents further complications, although a study by Matern et al demonstrated post-transplantation correction of metabolic abnormalities.[16]

Shimizu et al reviewed the long-term outcomes of 11 children with GSD type Ib who had undergone living donor liver transplantation. They found that blood glucose levels had stabilized and hospitalizations for infectious complications had decreased in all of the patients. However, platelet function had not improved.[17]

Consultations

Gastroenterology consultation may be necessary to evaluate the presence or absence of inflammatory bowel disease.

A high-protein diet may provide increased muscle function in cases of weakness or exercise intolerance. A high-protein diet also may slow or arrest disease progression. In addition, patients must receive adequate glucose. Adequate administration of starch may avoid hypoglycemia.

In a 2-year study of 7 patients with GSD type Ib, Melis et al examined whether the administration of vitamin E could improve or prevent the clinical manifestations of neutropenia and neutrophil dysfunction.[18] Vitamin E supplementation was provided to patients only during the second year of the study, and neutrophil counts from the first and second years were compared. The investigators found that during the second year, mean neutrophil counts were significantly greater than they were during the first. Reductions in the frequency and severity of infections, mouth ulcers, and perianal lesions also occurred during the second year. However, no changes in neutrophil function were found in association with vitamin E supplementation. Another study by Melis et al reported that during vitamin E supplementation, frequency and severity of infections in a caseload of 18 GSD1b patients were lower and mean value of neutrophil count were higher.[19]