Defects in glucose-6-transporter/glucose-6-phosphatase complex leading to glycogen

storage disease type Ia (von Gierke disease)

Elyce Gamble

Professor Bowden

NDFS 434: Nutritional Bio-Organic Chemistry

February 13, 2020

 This paper aims to review the current literature surrounding von Gierke disease (GSD Ia),

the first glycogen storage disease identified, which is related to defects in the glucose-6

transporter/glucose-6-phosphatase (G6Pase) complex found in the liver. The etiology and

metabolic pathophysiology, range of symptoms, long-term complications, and the current

available treatments for GSD Ia will be discussed, as well as potential future interventions that

could help increase the quality of life in the affected population.

Von Gierke disease is a rare autosomal recessive trait that occurs in about one out of

every 100,000 people (1). Of all the glycogen storage diseases, GSD Ia is more likely to present

with symptoms. It typically appears during infancy around the age of 3-4 months, and poses a

high risk of mortality in the early years if proper treatment is not given (2). In patients with von

Gierke disease, their body’s metabolism of glycogen is inhibited due to a lack of the G6Pase

enzyme, which regulates the hydrolysis of glucose-6-phosphate (G6P) into glucose and inorganic

phosphate when the body needs to utilize glucose. With type Ia, this enzyme dysfunction

originates in the endoplasmic reticulum, in the catalytic subunit of the enzyme (3). The specific

defect is related to a deficit of the catalytic subunit G6P-alpha, which is only expressed in the

liver, kidney, and intestine (2, 3). This defect results in abnormal glycolysis, leading to increased

production of pyruvate, which is then converted to lactate or triglycerides, thus resulting in lactic

acidemia and hypertriglyceridemia. In addition, an abnormal amount of accumulated glycogen in

the liver, coupled with a limited production of free glucose, leads to chronic hypoglycemia (4).

Hyperlipidemia also results, due to an excess buildup of the acetyl-coenzyme, since high levels

of this substrate promote lipid synthesis (2).

Short- and long-term symptoms often vary according to the patient’s age, and range

broadly in their severity. The characteristic symptoms of this disease include the accumulation of
both glycogen and fat in the liver and kidneys, most often resulting in hepatomegaly and

renomegaly, poor tolerance to fasting, and severe fatigue. Around 3 months of age, the affected

patient may present with a protruded abdomen, indicating splenomegaly and/or hepatomegaly

from the buildup of glycogen (2, 5). Clinical manifestations of von Gierke disease range from

full-cheeked faces and stunted growth, and often times ovarian cysts are present. Other reported

symptoms, include tremors, irritability, cyanosis, paleness, cerebral edema, coma, and cerebral

dysfunction (3). Another problem in patients with GSD Ia is severe microcytic anemia associated

with low iron levels. The anemia is generally linked to the presence of hepatic adenomas, which

irregularly express hepcidin (6). However, researchers of one study showed that the anemia was

asymptomatic in most patients (7).

Although highly undesirable, many of the long-term complications of disrupted glucose

homeostasis can be delayed if good metabolic control is practiced. Long-term complications

include hepatocellular adenomas, renal complications, hyperuricemia, and severe

hypertriglyceridemia (2, 4). Low bone mineral density leading to osteoporosis is also a long-term

symptom of these patients. Although the etiology of the osteoporosis seems multifactorial, it is

probably an effect of the overall metabolic disturbances (5). However, most patients remain

asymptomatic as long as they receive continuous, and adequate dietary treatments. For example,

GSD Ia most commonly presents as hepatomegaly in infants, but the hepatomegaly generally

decreases as the patient ages and receives continuous glucose support (5). Among the

complications addressed above, one of the most severe and life-threatening complications for

these patients is the development of hepatocellular adenomas (HCAs), and potentially,

hepatocellular carcinoma. HCAs are present in most patients with GSD I by the second or third

decade of life, and can become life-threatening when they become malignant and cause profuse
bleeding. Proposed mechanisms for the genesis of HCAs in these patients includes a high

glucagon/insulin ratio, glycogen accumulation in cells, and oncogene activation/mutation (8).

Researchers have discovered the mechanism by which the pathophysiology proceeds in

this disease, and how to best diagnose it. The research has widely shown that it is mutations in

the G6PC (17q21) gene in the G6Pase complex that lead to this disease (2, 9). The most

important clinical point for these patients is that they are promptly and accurately diagnosed, as

immediate treatment is crucial. One method of diagnosis is conducting a glucagon stimulation

test, and evaluating the glycemic response, which will be null for the affected populations since

they can’t break down glycogen stores (6). Although biochemical and clinical findings can be

used for unofficial diagnosis of GSD, various molecular methods have been used throughout the

years to diagnose GSD I types a and b, and most of these methods have been based on detecting

a mutation. In 1993, the gene of G6Pase was identified, and was found to play a crucial role in

glycogenolysis and gluconeogenesis. Now, this previously identified gene that spans 12.5 kb on

chromosome 17q21 is used for diagnosing purposes in DNA sequence analysis (1, 9). The gold

standard for the diagnosis of GSD type Ia is an evaluation of G6Pase activity and a liver biopsy

indicating glycogen and fat-induced hepatocytic distension, absent liver G6Pase enzyme activity,

and possible fibrosis (2, 6, 10).

Since GSD Ia is relatively rare, it is difficult to conduct a study on large numbers of

patients. However, to develop guidelines for the management of this disease, the collaborative

European Study on GSD I was initiated, and 231 GSD Ia patients were assessed for various

measures (11). In 2002, these guidelines were published and disseminated to the public. Some of

the most significant findings for these GSD Ia patients included: 56% had delay in their pubertal

development, 89% of the patients under the age of 15 were unable to follow normal general
education, patients who presented with GSD Ia after infancy had fewer symptoms of acute

metabolic derangement and presented more with growth retardation, and life expectancy is

increasing for these patients due to improved dietary therapy (11). In addition, guidelines for

clinicians were published in 2014 by the American College of Medical Genetics and Genomics

to help them provide exceptional medical services with other members of the interdisciplinary

team (5). These findings suggest that although life expectancy is increasing, more needs to be

done to help facilitate prompt diagnosis, and better medical and nutrition education for these

patients so that they can grow at a more normal rate.

The treatment for this disease is the frequent administration of exogenous cornstarch,

which helps diminish the excess production of lactate, triglycerides, uric acid, and glycogen by

providing a slow-releasing glucose source. The primary goal of treatment is to maintain a normal

blood glucose concentration and prevent hypoglycemic attacks (3). The preferred current therapy

during infancy and early childhood consists of a continuous supply of dextrose to the GI tract via

continuous nasogastric drip feedings to prevent hypoglycemia, ensure normal growth, and delay

long-term organ complications (1, 2, 6). Fasting must be avoided at all costs for these infants (5).

After one year, symptoms tend to improve, and dietary glucose treatments can be provided less

frequently, while still providing the same beneficial effect of keeping blood glucose levels in a

normal range. The most common treatment for adults is frequent meals coupled with uncooked

cornstarch therapy, since it is a slow-absorbed carbohydrate, and is provided every 3-4 hours to

these patients with the age-appropriate dosage (2). General guidelines for appropriate dosing of

the cornstarch include 1.6 g of cornstarch per kg of body weight every 3-4 hours for young

children, and 1.7-2.5 g cornstarch per kg of body weight every 4-6 hours for older children,

adolescents and adults (5). Nocturnal intragastric feedings may be recommended for these
patients so that they do not have to wake up in the night to ingest cornstarch (3). It is also

recommended that these patients restrict their intakes of both fructose, sucrose, and galactose,

since those sugars can further aggravate hyperlacticaemia. It is important for patients to monitor

daily caloric intake to ensure adequate, but not excessive caloric intake, as this can lead to other

unwanted complications such as hyperglycemia and weight gain (2). Total parental nutrition is

only indicated for those patients unable to curb symptoms with oral intake and cornstarch

therapy alone (8). Other dietary precautions used to prevent periods of severe hypoglycemia

include a dietary prescription of limited amounts of fruits, vegetables, and milk to limit sugar

intake, and the administration of vitamins and minerals to prevent any micronutrient deficiencies

(3).

Across healthcare settings, there remains a large discrepancy in the preferred methods of

dietary and pharmacological treatment of GSD Ia. Dietary treatment has been shown to improve

patient clinical status and mortality, yet not completely reverse the long-term complications that

tend to affect the liver, kidney, and other body systems. Frequently, therapeutic substances such

as vitamin supplements, calcium, and iron are given to further improve patient outcomes (2).

These patients are encouraged to maintain their serum glucose levels greater than 75 mg/dl both

day and night, to help diminish the hypoglycemic symptoms previously discussed. Some trials

have been done to assess the efficacy of continuous subcutaneous glucose monitoring in children

with GSD Ia and GSD Ib. One group of researchers found in 2014 that glucose monitoring could

be used as an safe and important adjuvant treatment to self-monitoring of blood glucose, and

recommend that it be used in those GSD I patients with poor metabolic control and recurrent

severe hypoglycemia. However, more research on the long-term benefits on metabolic control

needs to be done (12). Hypertriglyceridemia can be curbed through fenofibrate therapy and
atorvastatin, which are medications effective at lowing cholesterol and total triglyceride levels.

Oral contraception medications are contraindicated for these patients, due to their potential to

stimulate the growth of liver adenomas (6).

For patients who are experiencing severe symptoms, including hepatocellular adenoma, a

liver transplantation might be warranted. However, it is important to note that these transplant

recipients have a higher risk of developing future malignancies and portal vein thrombosis (4, 8).

One group of researchers state that liver transplantation should only be indicated for patients

with GSD type IV and other progressive hepatic types of GSDs (3). In addition, the shortage of

liver donors is a problem, and there is always a risk of acute rejection after the transplant (8). On

the other side, a group of researches reviewed 80 GSDI patients with liver transplantation in the

literature, and found that all of these patients showed improvements in metabolic control and

fasting tolerance post-liver transplantation (13). In addition, if renal function is compromised, a

combined liver-kidney graft might be discussed with the patient (2). However, dietary control is

currently the preferred, and most successful treatment for the GSD Ia population as a whole.

Based on the literature presented, it is clear that much is known about the

pathophysiology and symptoms of GSD Ia. However, it is also apparent that more research must

be done to ensure that appropriate and effective treatments are available to these patients.

Although the life expectancy is rising for these patients, their quality of life has room for

improvement. A modified starch is currently being tested in GSD patients, with the hope that it

will provide a longer duration of normal glucose levels, and better metabolic control (2). This

would allow these patients more freedom, as they would be able to sleep through the night,

without having to awake periodically to ingest cornstarch. A group of researchers found that a

waxy maize extended release cornstarch therapy appears to improve the quality of life for
patients with GSD I without decreasing metabolic control. However, long-term safety and

efficacy of the product needs to be addressed through more studies (7).

In addition, many questions remain unsolved such as the etiology of most symptomatic

complications and the proper protocol for the management of liver adenomas. Gene therapy has

not been tested on human subjects, although it has proven long-term correction of GSD Ia in

mouse and dog models (2). Finally, many of the studies indicate that it is common for patients

with GSD Ia to have a late onset of appropriate therapy, irregular follow-up, and poor

compliance with dietary management. There is obviously a need for physicians and dietitians to

work more closely and consistently with these patients to help them achieve a higher quality of

life. More research needs to be done to develop more effective and sustainable ways of nutrition

education and disease management.

It is shocking there are currently no cures for any of the twelve subtypes of glycogen

storage disease. Most treatments help manage signs and symptoms, but with the advancement of

medicine in today’s society, it is not unreasonable to expect that a cure be developed to provide

these patients with a better life. It seems that if we have created a way for Type I diabetics to

have a continuous supply of insulin, scientists could create a way to provide patients with GSD

Ia with a continuous supply of glucose therapy. We can also do a better job with initiating

immediate treatment and continuing to develop gene therapy or cell-based therapies for liver

replacement, which would act as life-altering cures for these patients.

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