Glycogen Storage Disorder (Type 1a)

Also known as: Von Gierke’s glycogen storage disease

Glycogen storage disorder type 1a (GSD type 1a) is an autosomal recessive condition characterised by growth retardation and accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and renomegaly.

Glycogen storage disorder type 1a (GSD type 1a) is the most common glycogen storage disorder.

Presentation

  • May present in the neonatal period with convulsions caused by hypoglycaemia and lactic acidosis.
  • More commonly presents in infants of 3-4 months with hepatomegaly, lactic acidosis, failure to thrive, hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia and / or hypoglycaemic seizures.
  • More moderate hypoglycaemia can cause irritability, pallor, cyanosis, hypotonia, tremors, loss of consciousness and apnoea.
  • There is a characteristic rounded ‘doll’s face’ due to deposition of fat.
  • The liver is usually normal in size during the first weeks of life, but then enlarges, sometimes considerably, to cause marked abdominal distension.
  • Growth is retarded and height is usually below the third centile.
  • Skin and mucous membranes may show eruptive xanthomas or gouty tophi on the extensor surfaces of the extremities.
  • Uric acid arthropathy can develop.
  • Altered platelet function can cause bleeding, especially epistaxis, which can result in iron-deficiency anaemia.

Please click on the titles to open and close the following information sections.

  • GSD type 1a is caused by mutations in the G6PC gene located at 17q21.31
  • These mutations cause a deficiency of Glucose-6-phosphatase (G6Pase) catalytic activity in the liver.
  • G6Pase deficiency leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycaemia, a
  • major feature of the disorder.
  • Large quantities of glycogen are formed and stored in hepatocytes, renal and intestinal mucosa cells. The liver and kidneys become enlarged.
  • Galactose, fructose and glycerol are metabolized to lactate. The elevated blood lactate levels cause metabolic acidosis.
  • In Ashkenazi Jews the carrier frequency of the most common mutation is approximately 1:70 with a disease prevalence is 1:20,000.
  • The disease incidence of GSD type 1a in the general population is approximately 1:100,000-200,000.

Gene Specific:

  • Clinical diagnosis can also be confirmed by genetic testing for mutations in the G6PC gene.

Other supporting evidence:

  • Histology shows increased amounts of normal glycogen, and fatty infiltration of the liver.
  • Kidneys may show glomerular hypertrophy and glomerulosclerosis.
  • Blood glucose and pH are usually low with elevated lactate, uric acid, triglyceride and cholesterol.
  • Lactic acidosis may be suggested by a high anion gap when electrolytes are measured.
  • Older patients may show anaemia, neutropenia and proteinuria.
  • Ultrasound is used to assess and monitor the size of the liver and kidneys and to detect possible hepatic adenomas and nephrocalcinosis.
  • Glucagon does not cause a rise in glucose levels, but a raised lactic acid level; as do oral galactose and fructose.
  • Glucose tolerance test progressively lowers lactic acid levels over several hours.

Diet and lifestyle:

  • Mainstay of treatment is the correction of hypoglycaemia and maintenance of normoglycaemia.
  • Young infants require frequent feeding (usually 2-3 hourly) during the day with continuous gastronomy feeding at night. Hypoglycaemia and lactic acidosis can develop after a short fast.
  • Older children use uncooked corn flour to provide slow release of glucose by day, but often continue to require nasogastric or gastrostomy feeding at night to prevent hypoglycaemia and associated metabolic problems.
  • Restricted intake of fructose and galactose, as they do not increase glucose levels, but do increase lactic acid.
  • Restriction of lipids.
  • Physical activity should not be restricted, but contact sport should be avoided due to the bleeding tendency and the risk of rupture to an enlarged liver.

Drugs and surgery:

  • Blood loss may require oral iron.
  • Raised uric acid levels may require allopurinol.
  • Treatment of hyperuricaemia and pyelonephritis protects renal function.
  • Liver transplantation for primary disease or for hepatocellular carcinoma improves metabolic control.

Family members should be offered genetic counselling and testing. Carrier testing and pre-natal testing is available for this condition.

  • Early diagnosis and treatment have significantly improved prognosis. Normal growth and puberty may be expected in treated children, and affected individuals live into adulthood.
  • It is not known if all long-term secondary complications can be avoided by good metabolic control.
  • Early death is usually caused by acute metabolic complications of hypoglycaemia or acidosis, or bleeding.
  • Chronic kidney disease, hypertension or malignant change of hepatic adenomas may cause mortality in adolescents and young adults.

Potential complications:

  • Acute hypoglycaemia may be fatal or cause brain damage.
  • Prolonged hypoglycaemia and metabolic acidosis may cause cerebral oedema.
  • Elevated uric acid causes a decrease in the glomerular filtration with proteinuria, haematuria, hypertension and chronic kidney disease.
  • Incomplete distal tubular acidosis sometimes causes hypercalciuria, nephrocalcinosis and renal stones.
  • Chronic metabolic lactic acidosis and changes in the proximal renal tubule cells can cause osteopenia and rickets with severe skeletal deformities or fractures.
  • Children with GSD1 have poor growth and short stature, however with strict dietary regimens and control, growth and final adult stature have improved.
  • Hyperlipidaemia.
  • Hepatic adenomas usually develop in the second or third decade of life, a complication of which is intrahepatic haemorrhage.  The adenomas may also undergo malignant transformation into hepatocellular carcinoma.
  • Liver transplantation can improve quality of life with metabolic control, but does not prevent renal disease.
  • For children exhibiting features of GSD, suggested initial referral would be to a paediatrician. For Jewish patients, it is important to note the child’s ancestry and higher prevalence of GSD1a in the Jewish population.
  • For patients that have received a positive GSD diagnosis :
    • On-going management is usually under the care of a specialist metabolic paediatrician with other specialist input as appropriate.
    • Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.

There is currently no UK-based patient group dedicated to Bloom Syndrome, however, the international resources below provide further information and support for those affected.

Association For Glycogen Storage Disease UK

The AGSD is a parent and patient oriented support group that covers all different types of GSD. Advised by a group of experienced medical professionals, the organisation raises awareness and educates others, as well as publishing a quarterly newsletter – The Ray.

University Of Florida Glycogen Storage Disease Program

This is a USA based research program designed to improve treatment of GSDs. The website provides information for parents and patients, and reports on current research into potential gene therapy for GSDs

GeneReviews: www.ncbi.nlm.nih.gov/books/NBK1312

OMIM: #232200

Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by: Professor John Walter MD FRCPCH, Honorary Clinical Professor of Inherited Metabolic Medicine, University of Manchester, Manchester Centre for Genomic Medicine.
Last review: 03.05.2016

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