Type Ia Glycogen Storage Disease

Updated: Jul 07, 2021
  • Author: Kathleen R Ruddiman, DO; Chief Editor: George T Griffing, MD  more...
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Practice Essentials

glycogen storage disease (GSD) is the result of an enzymatic defect among various reactions that produce glucose, either by glycogenolysis or gluconeogenesis. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly. [1]

The diagram below illustrates metabolic pathways of carbohydrates.

Metabolic pathways of carbohydrates Metabolic pathways of carbohydrates

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. 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, GSD type 0, which is due to defective glycogen synthase, also is recognized.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal-recessive conditions. Several different mutations have been reported for each disorder.


The diagnosis may be suspected based on the patient history, physical examination, and laboratory findings. Biochemical assay for enzyme activity and gene sequencing is the method of definitive diagnosis.  

Specifically, GSD type Ia is characterized by deficiency in the glucose-6-phosphatase (G6Pase) enzyme. GSD type Ib is a similar condition that has active G6Pase enzyme activity but with a defect in the glucose-6-phosphate transporter protein. A newly described form, GSD type Ic, does not appear to be related to mutations within the transporter protein.


Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities, and active research continues to investigate the possibility of genetic therapy in the future.



With GSDs, carbohydrate metabolic pathways are blocked at various levels and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect. As noted above, G6Pase, which is found mainly in the liver and kidneys, is affected in GSD-Ia. G6Pase hydrolyzes glucose-6-phosphate (G6P), an end-product of both glycogenolysis and gluconeogenesis, into glucose before it can be released into circulation. G6Pase is present in the lumen of the endoplasmic reticulum (ER) in the aforementioned tissues and requires G6P transport into the ER in order to function. In GSD Ib, G6P transport into the ER is defective and prevents normal G6Pase from converting G6P into glucose. In GSD Ia, the transport complex is functional, but the G6Pase enzyme activity is decreased or absent.

GSD type I, also known as Von Gierke disease, is an autosomal-recessive condition and has several subtypes. GSD Ia may be explained by mutations of the catalytic unit gene of the G6Pase complex, unlike GSD type Ib and GSD type Ic.  The G6PC gene that codes for G6Pase is located on chromosome 17q21, and various mutations have been identified that lead to its abnormal function in GSD Ia. [2]

Direct metabolic effects

GSD Ia leads to fasting hypoglycemia owing to the inability to convert G6P into glucose. If undiagnosed or untreated, this condition can cause hypoglycemic seizures, with significant risk for morbidity and mortality. Accumulation of G6P substrate leads to increased utilization of the glycolysis pathway for energy production, resulting in lactic acidosis. [3]  Increased use of the glycolytic pathway also increases lipogenesis, leading to hypercholesterolemia and hypertriglyceridemia, which can result in hepatic steatosis and pancreatitis. [4]  Atherosclerotic risk in relation to the hyperlipidemia of GSD Ia is still unclear. [5] Additional excesses of G6P are shunted down the pentose phosphate pathway, leading to excess production of purines. The purines are then broken down into uric acid, resulting in hyperuricemia, which can cause gout and kidney stones

Indirect/chronic effects 

Often, GSD Ia is diagnosed early and can be managed with dietary interventions.  In this case, immediate mortality from hypoglycemic seizures becomes less common, and patients more often deal with long-term effects of the disease. For example, chronic hypoglycemia and resulting chronic hypo-insulinemia result in growth defects and delayed puberty. Accumulation of glycogen in the liver and kidneys causes hepatomegaly and nephromegaly, and may lead to chronic kidney disease and hepatic adenomas, with some patients developing hepatocellular carcinoma. [6]   Chronic kidney disease can in turn result in anemia of chronic disease and hypertension. [7]



GSD Ia is seen in 1/100,000 births, with notably increased prevalence in the Ashkenazi Jewish population (1/20,000).  [8]

Sex- and age-related demographics

GSDs are autosomal-recessive conditions, with an equal number of males and females being affected.

In general, GSDs present in childhood. In a retrospective analysis by Rake et al, median age of presentation for GSD I was 6 months. [9]



Von Gierke disease is not curable.


Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications resulting in morbidity and mortality include nephropathy and hepatic adenoma. [6]


Complications include the following:

  • Hypoglycemic seizures

  • Nephropathy with renal failure

  • Hepatic adenoma with potential malignant transformation

  • Osteoporosis 


Patient Education

Educate patients in the recognition of hypoglycemia and its appropriate treatment. For patient education resources on hypoglycemia, see the following: