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Glycogen storage disease due to glucose-6-phosphatase deficiency
Glycogenosis due to glucose-6-phosphatase (G6P) deficiency or glycogen storage disease, (GSD), type 1, is a group of inherited metabolic diseases, including types a and b (see these terms), and characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver.
ORPHA:364Classification level: Disorder
- G6P deficiency
- GSD due to G6P deficiency
- GSD type 1
- GSD type I
- Glycogen storage disease due to G6P deficiency
- Glycogen storage disease type 1
- Glycogen storage disease type I
- Glycogenosis type 1
- Glycogenosis type I
- Hepatorenal glycogenosis
- Von Gierke disease
- Prevalence: Unknown
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: E74.0
- OMIM: 232200 232220 232240
- UMLS: C0017920 C2919796
- MeSH: -
- GARD: 7864
- MedDRA: 10018464
Prevalence is unknown. Annual incidence at birth is around 1/100,000. Type a affects 80% of patients.The existence of other types (c, d) has not been confirmed.
The disease may manifest at birth by hepatomegaly or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia. Patients have enlarged liver, growth retardation, osteopenia, sometimes osteoporosis, full-cheeked round face, nephromegaly and frequent epistaxis due to platelet dysfunction. In addition, in type b, infections and inflammatory bowel disease are due to neutropenia and neutrophil dysfunction. Late complications are hepatic (adenomas and more rarely hepatocarcinoma) and renal (proteinuria and sometimes renal insufficiency).
The disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Mutations in the G6PC gene (17q21) cause a deficit of the catalytic subunit G6P-alpha restricted to expression in the liver, kidney and intestine (type a), and mutations in the SLC37A4 gene (11q23) cause a deficit of the ubiquitously expressed G6P transporter (G6PT) or G6P translocase (type b).
Diagnosis is based on clinical presentation, and glycemia and lactacidemia levels, after a meal (hyperglycemia and hypolactacidemia), and after three to four hour fasting (hypoglycemia and hyperlactacidemia). Uric acid, triglycerides, and cholesterol serum levels are increased. There is no glycemic response to glucagon. Molecular genetic testing enables confirmation of diagnosis. Use of liver biopsy to measure G6P activity is becoming increasingly rare.
Differential diagnoses include the other glycogenoses, in particular glycogenosis due to glycogen debranching enzyme deficiency (GDE deficiency) or GSD type III (see this term) but in this case, glycemia and lactacidemia are high after a meal and low in a fasting period. Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but easily ruled out through clinical and ultrasound data.
Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may be discussed.
Transmission is autosomal recessive. Genetic counseling should be offered.
Management and treatment
Management aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch), acidosis (restricted fructose and galactose intake, oral supplementation in bicarbonate), hypertriglyceridemia (diet, cholestyramine, statines), hyperuricemia (allopurinol) and hepatic complications. Renal protection using converting enzyme inhibitors must be started should microalbuminuria be detected. Osteoporosis may require bisphosphonates. Liver transplantation, performed on the basis of poor metabolic control or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type b. Kidney transplantation can be performed in case of severe renal failure. Combined liver-kidney grafts have been performed in a few cases.
With adapted management, prognosis is better: patients have almost normal life span.