Von Gierke's Syndrome (Type I Glycogen StorageDisease)
Synonyms: GSD1
Background
Von Gierke described the disease that bears his name in 1929.
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There are 7 variations of glycogen storagedisease (GSD) of which his is designated type I as it represents the largest group at about 25% of all GSD. Hecalled it hepatonephromegalia glycogenica but in 1952 the association with glucose-6-phosphatase wasdescribed by Cori and Cori.
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They had type III GSD named after them.The disease has been further divided as the biochemistry has been elucidated. Glucose-6-phosphatasedeficiency is the cause of type Ia and it should not be confused withglucose-6-phosphate dehydrogenasedeficiency. There is a specific translocase deficiency in type Ib but they also have altered neutrophil functionspredisposing them to gram-positive bacterial infections. Two other translocase deficiencies have beendescribed to give types Ic and Id.For practical purposes, there are 2 major forms. Type Ia has deficient glucose-6-phosphatase in the liver andtype Ib has normal activity.The abnormality has been located on gene map locus 17q21 for type Ia and 11q23 for type Ib. Type Ic hasbeen mapped to 11q23-q24.2 and type Id to 11q23-q24.
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Epidemiology
The condition is inherited as an autosomal recessive which means that both parents are carriers and thechance of a sibling being affected is 1 in 4. There is equal sex distribution and no racial difference in frequency.
Biochemistry
There is an enzyme defect in glucose-6-phosphatase so that glucose-6-phosphate cannot be converted intofree glucose but is metabolised to lactic acid or incorporated into glycogen. The liver and kidney are involvedand hypoglycaemia is a major feature. Large quantities of glycogen are formed and stored in hepatocytes, renaland intestinal mucosa cells. Enlarged liver and kidneys are an important feature. Abnormalities of lipids maylead to xanthoma formation. Uric acid is often elevated and may cause clinicalgout. Endogenous glucoseproduction is not fully inhibited but in young people, production of free glucose reaches half that of healthyindividuals, whilst adult patients may produce as much as two thirds of the normal amount of free glucose.Galactose, fructose, and glycerol are metabolised to lactate which is used in the brain as an alternative sourceof energy. The elevated blood lactate levels cause metabolic acidosis. Uric acid production is increased asglucagon levels are raised and there is competition with lactate for renal excretion.
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Presentation
Presentation is usually soon after birth but can be a little later.Shortly after birth hypoglycaemia andlactic acidosisoften cause convulsions.•
More moderate hypoglycaemia can cause irritability, pallor, cyanosis, hypotonia, tremors, loss ofconsciousness and apnoea.•Some children have diarrhoea due to pseudocolitis.•There is a characteristic rounded "doll's face" due to deposition of fat.•During the first weeks of life the liver is normal in size but it enlarges, sometimes very considerably,and the mother may note abdominal enlargement.•Growth is retarded and height is usually below the 3rd centile. Puberty is delayed but mentaldevelopment is normal.•Skin and mucous membranes may show eruptive xanthomas or gouty tophi on the extensor surfacesof the extremities. Uric acid arthropathy can develop.•Altered platelet function can cause bleeding, especially epistaxis and this may result iniron deficiencyanaemia.•
Page 1 of 3Von Gierke's Syndrome (Type I Glycogen Storage Disease)
Basic Tests
Blood glucose and pH are usually low with elevated lactate, uric acid, triglyceride and cholesterol.•Creatinine and urea may be raised if renal function is impaired.•Lactic acidosis may simply be suggested by a high anion gap when electrolytes are measured.•Older patients may show anaemia, neutropenia and proteinuria or at leastmicroalbuminuria.•
Special Tests
Ultrasound should be used to assess and monitor the size of liver and kidneys and to detectpossible hepatic adenomas and nephrocalcinosis.•Glucagon does not cause a rise in glucose levels, but it does raise lactic acid levels.•Oral galactose and fructose fail to increase glucose levels but plasma lactic acid levels increase.•Glucose tolerance test progressively lowers lactic acid levels over several hours.•
Tissue Diagnosis
Definitive diagnosis involves assessment of glucose-6-phosphatase activity in fresh and frozen livertissue specimens. To assess translocases, an open surgical liver biopsy is needed to obtain anadequate specimen.•Histology shows increased amounts of normal glycogen, as well as fatty infiltration of the liver.•Kidneys show glomerular hypertrophy. There is glomerulosclerosis and renal failure is a significantcause of morbidity and mortality.
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Management
Diet and Lifestyle
The main aim of treatment is to correct hypoglycaemia and maintain normoglycaemia. Younginfants require a nasogastric tube overnight to deliver glucose. Older infants and children eat rawcornstarch to give slow release of glucose by day but nasogastric feeding by night is still required toprevent hypoglycaemia and associated metabolic problems. It is thought likely that preventinghypoglycaemia, that is especially a problem at night, will reduce complications.
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•Intake of fructose and galactose should be restricted as they do not increase glucose levels but itdoes increase lactic acid.•Restriction of lipids is advised but statins are not used.•Physical activity does not have to be restricted but rough games and contact sports should beavoided because of the bleeding tendency and the risk of rupture to an enlarged liver.•
Drugs and Surgery
Blood loss may require oral iron and uric acid levels may necessitateallopurinol. Treatment ofhyperuricaemia and pyelonephritis protect renal function.•Diazoxideto maintain blood glucose has been disappointing.•Liver transplantationfor primary disease or forhepatocellular carcinomaseems effective although
the immunosuppresion may cause deterioration of renal function.
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Transplantation of hepatocytesappears to have had only temporary benefit.
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Complications
Acute hypoglycaemia may be fatal or cause brain damage.•Frequent infections in type Ib require intravenous therapy to correct hypoglycaemia and intravenousantibiotics to control infections.•Bacterial infections and cerebral oedema are caused by prolonged hypoglycaemia and metabolicacidosis. Patients with type Ib are susceptible to bacterial infections including those of the CNS.•Chronic metabolic lactic acidosis and changes in the proximal renal tubule cells can cause osteopeniaand rickets with severe skeletal deformities or fractures. These impair mobility.•Elevated uric acid causes a decrease in the glomerular function with proteinuria, haematuria,hypertension andchronic renal failure. Incomplete distal tubular acidosis sometimes causeshypercalciuria, nephrocalcinosis and renal stones.•Older children and young adults require ultrasound assessment of the liver at least once a year.•Hepatic adenomas usually develop in late teens and require careful follow-up in case of transformationto hepatocellular carcinoma although some tumours are embryonic hepatoblastomas. There is male tofemale ratio of 2:1 compared with a female preponderance that is usual in hepatocellular carcinoma. Itis thouht that adeuate lucose feedin will reduce the risk of malinant chane and ma even•
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Von Gierke's Syndrome
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