Glycogen storage disease type I (GSD I) is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary in maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. There are also possibly rarer subtypes, the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id); however, a recent study suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable, and are therefore GSD Ib.
GSD Ia is caused by a deficiency in the enzyme glucose-6-phosphatase; GSD Ib, a deficiency in the transport protein glucose-6-phosphate translocase. Because glycogenolysis is the principal metabolic mechanism by which the liver supplies glucose to the body during fasting, both deficiencies cause severe hypoglycemia and, over time, excess glycogen storage in the liver and (in some cases) in the kidneys.
Because of the glycogen buildup, GSD I patients typically present with enlarged livers from non-alcoholic fatty liver disease. Other functions of the liver and kidneys are initially intact in GSD I, but are susceptible to other problems. Without proper treatment, GSD I causes chronic low blood sugar, which can lead to excessive lactic acid, and abnormally high lipids in the blood, and other problems. Frequent feedings of cornstarch or other carbohydrates are the principal treatment for all forms of GSD I.
GSD Ib also features chronic neutropenia due to a dysfunction in the production of neutrophils in the bone marrow. This immunodeficiency, if untreated, makes GSD Ib patients susceptible to infection. The principal treatment for this feature of GSD Ib is filgrastim; however, patients often still require treatment for frequent infections, and a chronically enlarged spleen is a common side effect. GSD Ib patients often present with inflammatory bowel disease.
It is the most common of the glycogen storage diseases. GSD I has an incidence of approximately 1 in 100,000 births in the American population, and approximately 1 in 20,000 births among Ashkenazi Jews. The disease was named after German doctor Edgar von Gierke, who first described it in 1929.
Signs and symptoms
Early research into GSD I identified numerous clinical manifestations falsely thought to be primary features of the genetic disorder. However, continuing research has revealed that these clinical features are the consequences of only one (in GSD Ia) or two (in GSD Ib) fundamental abnormalities: impairment in the liver's ability to convert stored glycogen into glucose through glycogenolysis in GSD Ib, impairment of the neutrophil's ability to take up glucose, resulting in neutrophil dysfunction and neutropenia
These fundamental abnormalities give rise to a small number of primary clinical manifestations, which are the features considered in diagnosis of GSD I: Low blood sugar (hypoglycemia), due to impairment of glycogen breakdown (glycogenolysis) causing insufficient fasting blood glucose hepatomegaly of non-alcoholic fatty liver disease, due to impairment of glycogenolysis causing glycogen accumulation in the liver in GSD Ib, increased infection risk, due to neutropenia and neutrophil dysfunction
Affected people commonly present with secondary clinical manifestations, linked to one or more of the primary clinical manifestations: High levels of uric acid in the blood and attendant risk of gout or kidney damage, caused by low serum insulin levels in prolonged hypoglycemia High levels of lactic acid in the blood, in extreme cases leading to lactic acidosis, caused by prolonged hypoglycemia hepatic adenomas developing in adulthood and attendant risk of anemia, suspected to be caused by blood glucose dysregulation in the presence of non-alcoholic fatty liver disease in GSD Ib, inflammatory bowel disease and attendant risk of anemia, caused by neutrophil dysfunction and exacerbated by the increased carbohydrate intake required to prevent hypoglycemia