Glycogen storage disease type I overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]
Overview
Glycogen storage disease type 1 also known as Von Gierke's disease is an enzymopathy. The most common defect is deficiency of glucose-6-phosphatase enzyme. Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis. The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Glycogen storage disease type 1 is an autosomal recessive disorder. Glycogen storage disease type 1a is caused by the deficiency of the glucose-6-phosphatase enzyme. Glycogen storage disease type 1b is caused by a defect in the microsomal glucose-6-phosphate transporter. The incidence of glycogen storage disease type 1 (GSD 1) is approximately 1 per 100,000 individuals worldwide. Glycogen storage disease type 1 (GSD 1) presents first as an average age of 6 months (1 - 12 months). If left untreated, glycogen storage disease type 1 develop complications including protruding abdomen due to marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, rounded doll-like face, and wasted muscles. Glycogen storage disease type 1 is diagnosed by identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in G6PC for patients with GSD type 1a and biallelic pathogenic variants in SLC37A4 for patients with GSD type 1b. Liver transplantation is the final treatment for patients with metabolic disease associated associated with GSD type 1. The medical management of GSD type 1 is divided into nutritional therapy and medical management of systemic complications. The primary concern in infants and young children with GSD type 1 is hypoglycemia. There is resolution of metabolic derangements (correction of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia) after liver transplantation in patients with GSD type 1. Effective measures for primary prevention of glycogen storage disease type 1 include genetic counseling, prenatal diagnosis, and screening. Effective measures for secondary prevention of glycogen storage disease type 1 (GSD type 1) include blood glucose (BG) monitoring, prevent overtreatment, growth tracking as well as several system wise recommendations including general medical care, gastrointestinal or nutritional, hepatic and hepatic transplantation, nephrology, hematology, cardiovascular, surgery/anesthesia, and gynecological/obstetrical recommendations.
Historical Perspective
Glucose-6-phosphatase deficiency in glycogen storage disease (GSD 1) is identified as first specific enzymopathy in a hereditary disorder. In 1952, Gerty T. Cori and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type I (GSD 1). In 1952, Gerty T. Cori and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type Ia (GSD-1a). In 1978, Narisawa et al. suggested that a defect in the microsomal transport system of glucose-6-phosphate (T1 deficiency) may cause a new variant known as glycogen storage disease type Ib (GSD-1b). In 1982, the first liver transplantation for GSD type 1 was performed.
Classification
Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit consist of calcium binding protein and three transport proteins (T1, T2, and T3). The movement of glucose-6-phosphate, phosphate, and glucose into and out of the enzyme is facilitated by T1, T2, and T3 respectively. Glycogen storage disease type 1 (GSD1) is divided on the basis of defect/deficiency of either enzyme or transporter into four types including glycogen storage disease type 1a, type 1b, type 1c, and 1d.
Pathophysiology
Glycogen storage disease type 1 (GSD 1) results due to defects in either hydrolysis or transport of glucose-6-phosphate. Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis. The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Glycogen also deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques. Hematologic disorders in GSD type 1 include anemia, bleeding diathesis, and neutropenia. Neutropenia and neutrophil dysfunction is specific of GSD type 1b. Abnormal expression of hepcidin in GSD type 1 leads to refractory iron deficiency anemia. GSD type 1 follows an autosomal recessive pattern. On gross pathology analysis, the features of glycogen storage disease type 1 include hepatomegaly. Hepatomegaly decreases as age increases. On microscopic histopathological analysis, the features of glycogen storage disease type 1 include distended liver cells by glycogen and fat, PAS positive and diastase sensitive glycogen distributed uniformly within the cytoplasm, and numerous large lipid vacuoles.
Causes
Glycogen storage disease type 1 is an autosomal recessive disorder. Glycogen storage disease type 1a is caused by the deficiency of the glucose-6-phosphatase enzyme. The gene for the glucose-6-phosphatase enzyme is located on chromosome 17q21. Glycogen storage disease type 1b is caused by a defect in the microsomal glucose-6-phosphate transporter. The gene for the microsomal glucose-6-phosphate transporter is located on chromosome 11q23.
Differentiating Glycogen Storage Disease type I from Other Diseases
Epidemiology and Demographics
The incidence of glycogen storage disease type 1 (GSD 1) is approximately 1 per 100,000 individuals worldwide. The prevalence of glycogen storage disease type 1 is approximately 5 per 100,000 individuals in Ashkenazi Jewish population. Glycogen storage disease type 1 is usually first diagnosed among infants.
Risk Factors
The most potent risk factor in the development of glycogen storage disease type 1 is a sibling with glycogen storage disease type 1.
Screening
Glycogen storage disease type 1 is an autosomal recessive disease so carrier screening of at-risk relatives may be done. Screening requires prior identification of G6PC or SLC37A4 pathogenic variants in the family.
Natural History, Complications, and Prognosis
Glycogen storage disease type 1 (GSD 1) presents first as an average age of 6 months (1 - 12 months). If left untreated, glycogen storage disease type 1 develop complications including protruding abdomen due to marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, rounded doll-like face, and wasted muscles. Common complications of glycogen storage disease type I include bleeding diathesis, chronic renal failure, hepatic adenoma, anemia, and inflammatory bowel disease (specifically in GSD type 1b).
Diagnosis
Diagnostic Study of Choice
Glycogen storage disease type 1 is diagnosed by identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in G6PC for patients with GSD type 1a and biallelic pathogenic variants in SLC37A4 for patients with GSD type 1b. Enzyme activity assay performed are glucose-6-phosphatase (G6Pase) catalytic activity and glucose-6-phosphate exchanger SLC37A4 (transporter) activity.
History and Symptoms
The presentation of GSD type 1 may vary depending on the age of the patients. Glycogen storage disease type 1 commonly presents in infancy period (particularly age 3 - 6 months) with protruded abdomen due to hepatomegaly. Neonates presents rarely with hypoglycemia and lactic acidosis.
Physical Examination
Physical examination of patients with glycogen storage disease type 1 is usually remarkable for protruding abdomen due to marked hepatomegaly, short stature, doll-like facial appearance, truncal obesity, and wasted muscles.
Laboratory Findings
Laboratory findings consistent with the diagnosis of glycogen storage disease include hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia.
Electrocardiogram
There is no ECG finding associated with glycogen storage disease type 1.
X-ray
There is no X-ray finding associated with glycogen storage disease type 1.
CT Scan
Abdominal computed tomography or magnetic resonance imaging with contrast is performed to screen for hepatocellular carcinoma and should be repeated every 6 - 12 months or earlier on the basis of laboratory and clinical findings.
MRI
Recurrent hypoglycemia causes brain damage in patients with glycogen storage disease type 1. MRI findings in glycogen storage disease type 1 due to brain damage include dilatation of occipital horns and/or hyperintensity of subcortical white matter in the occipital lobes. Abdominal magnetic resonance imaging or computed tomography with contrast is performed to screen for hepatocellular carcinoma and repeated every 6 - 12 months or earlier on the basis of laboratory and clinical findings.
Ultrasound
Ultrasound may be helpful in the diagnosis of glycogen storage disease type 1. Findings on an ultrasound suggestive of glycogen storage disease type 1 include hepatomegaly, increased hepatic echogenicity, and enlarged kidneys. Abdominal ultrasound should be performed at baseline and every 12-24 months to detect transformation of hepatocellular adenoma to hepatocellular carcinoma.
Imaging Findings
Dual energy X-ray absorptiometry (DXA) may be helpful in the diagnosis of osteoporosis and/or osteopenia due to poor metabolic control in patients with glycogen storage disease type 1. Findings on an dual energy X-ray absorptiometry suggestive of osteoporosis and/or osteopenia in patients with glycogen storage disease type 1 include low bone mineral density (BMD).
Other Diagnostic Studies
Other studies used for diasnosis of glycogen storage disease type 1 include identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in G6PC for patients with GSD type 1a and biallelic pathogenic variants in SLC37A4 for patients with GSD type 1b. Enzyme activity assay performed are glucose-6-phosphatase (G6Pase) catalytic activity and glucose-6-phosphate exchanger SLC37A4 (transporter) activity.
Treatment
Medical Therapy
The medical management of GSD type 1 is divided into nutritional therapy and medical management of systemic complications. The primary concern in infants and young children with GSD type 1 is hypoglycemia. Small frequent feeds high in complex carbohydrates (preferably those high in fiber) are distributed evenly throughout 24 hours for the prevention of hypoglycemia. Sucrose (fructose and glucose) and lactose (galactose and glucose) may be limited or avoided. Solis food is introduced at the time of 4 - 6 months. Infant cereals are started followed by vegetables and then by meat. Preferred treatment for young child is cornstarch (CS) which may be used alone or by mixing it with sucrose-free, fructose-free, lactose-free infant formula, sugar-free soy milk, sugar-free drinks, and/or water. Other treatment strategy are directed towards management of hypocitraturia, hypercalcemia, proteinuria, platelet dysfunction, and neutropenia.
Surgery
Liver transplantation is the final treatment for patients with metabolic disease associated associated with GSD type 1. Indications for liver transplantation include patients with multifocal lesions, growing lesions that do not regress with improved dietary regimens, and patients who do not have evidence of distant metastatic disease. There is resolution of metabolic derangements (correction of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia) after liver transplantation in patients with GSD type 1 after Liver transplantation.
Primary Prevention
Effective measures for primary prevention of glycogen storage disease type 1 include genetic counseling, prenatal diagnosis, and screening.
Secondary Prevention
Effective measures for secondary prevention of glycogen storage disease type 1 (GSD type 1) include blood glucose (BG) monitoring, prevent overtreatment, growth tracking as well as several system wise recommendations including general medical care, gastrointestinal or nutritional, hepatic and hepatic transplantation, nephrology, hematology, cardiovascular, surgery/anesthesia, and gynecological/obstetrical recommendations.