Glycogen storage diseases

• Type 1 - von Gierke's disease

  • deficiency in glucose 6-phosphatase that results in large increase in glucose 6-phosphate (gluconeogenesis)
  • results in large accumulation of glycogen in the liver (and the kidney)
  • causes inability to increase blood sugar levels in response to glucagon and adrenaline release - can't release free glucose into the bloodstream

  Symptoms

  • hepatomegaly
  • hypoglycaemia

  Treatments

  • drug-induced inhibition of glucose uptake by the liver
  • continuous intra-gastric feeding of glucose overnight

  Severe cases

  • transposition of portal vein - diverts glucose rich blood from liver to peripheral tissues
  • remove liver
• Type 2 - alpha 1,4-glucosidase deficiency (Pompe's)

  • most severe
  • causes accumulation of glycogen within lysosomes due to inability to process glycogen granules
  • patients die of cardio respiratory failure - normally before 1
  • can be detected via blood testing
  • 1 in 85-100 carry a mutation in a single copy of the gene (double copy needed for disease)
  • mutations that destroy the enzyme cause infant onset Pompe's
  • mutations that leave a bit of the enzyme intact cause juvenile onset or adult onset

  Treatment

  • enzyme replacement therapy - addition of alpha 1,4 glucosidase into the blood stream enters the cell and converts the overabundant glycogen to glucose (glycolysis)
• Type 3 - Amylo-(alpha) 1,6-glucosidase deficiency (Cori's disease)

  • enzyme used in glycogenolysis
  • branch point on glycogen can't be removed
  • short outer chains accumulate in the liver and muscle - glycogen cannot be completely degraded
  • symptoms usually present during puberty

  Symptoms

  • muscle weakness
  • liver problems similar to von Gierke's

  Treatment

  • frequent feeding
  • high protein diet - counteracts loss of amino acids via gluconeogenesis
• Type 4 - Amylo-(alpha)-1,4-1,6-transglycosylase (Anderson's disease)

  • leads to inability to store glucose residues as glycogen - no new branch points
  • glycogen is present but has an abnormal structure - long unbranched chains
  • sufferers rarely survive beyond 4 years
  • main symptom is liver dysfunction - possibly due to immune response
  • Liver transplantation is one of the only treatments
• Type 5 - Muscle Phosphorylase deficiency (McArdle's disease)

  • lack of muscle glycogen phosphorylase leads to a lack of glucose for glycolysis to produce ATP
  • Causes painful muscle cramps after exertion
  • characterised by an absense of blood lactate as muscle cells cannot convert glycogen to glucose and then to lactate
  • causes muscle breakdown due to lack of ATP - causes general weakness
• Type 6 - Liver phosphorylase deficiency (Her's disease)

  • lack of glycogen phosphorylase in the liver - glycogen not broken down
  • similar symptomatic profile to those who have mild von Gierke's - less severe than type 5
  • sufferers have hepatomegaly, mild hypoglycaemia - can't increase blood glucose levels, mild ketosis - non functioning TCA cycle, acetyl CoA converted to ketones instead and retarded growth
• Type 7 - Muscle PFK 1 deficiency (Tarui's disease)

  • PFK 1 is the main regulator of glycolytic pathway
  • deficiency leads to build up of G6P and F6P
  • Build up of G6P leads to increased activity of glycogen synthase as well as UDP glucose pyrophosphorylase
  • causes build up of glycogen in the muscle stopping glucose breakdown to give ATP
• Type 8 - X-linked Phosphorylase Kinase deficiency

  • defective phosphorylase kinase cannot add a phosphate group to convert glycogen phosphorylase b (inactive) to glycogen phosphorylase a (active)
  • glycogen is not broken down so glucose is not released
  • symptomatically similar to Her's
  • Type 6 (Her's) is autosomal recessive but Type 8 is X-linked
• Type 9 - Phosphorylase kinase deficiency

  • autosomal recessive disease
  • caused by mutations in one of the genes that encodes the phosphorylase kinase sub-units (b,g or d)
  • symptoms and severity variable - different tissues contain different isoenzymes of phosphorylase kinase
  • symptomatically similar to type 6 and type 8
• Type 0 - Liver Glycogen Synthase deficiency

  • inability to synthesise glycogen
  • autosomal recessive
  • some sufferers are asymptomatic
  • others suffer from hypoglycaemia after meals or other times