Glykogenspeicherkrankheiten

What is glycogen?

Glycogen is a branched-chain polymer of glucose and serves as a dynamic but limited reservoir of glucose, mainly in liver, skeletal muscle, heart, and sometimes the central nervous system and the kidneys.¹ There are a number of different enzymes involved in glycogen synthesis, utilisation and breakdown within the body.

Glycogen storage disorders (GSDs) are a group of inherited inborn errors of metabolism caused by deficiency or dysfunction of these enzymes.²

• Glycogen synthesis errors result in decreased production of normal glycogen ± deposition of abnormally branched glycogen chains.

• Degradation errors block formation of glucose from glycogen, leading to hypoglycaemia and pathological accumulation of glycogen in the tissues.

These metabolic errors can be confined to just liver and muscle but some cause more generalised pathology and affect tissues such as the kidney, heart and bowel. The GSD classification is based on the enzyme deficiency and the affected tissue.³

• The overall GSD incidence is estimated at 1 case per 20,000-43,000 live births.⁴

• Type I is the most common (25% of all GSDs).

• Suspect in infants and children with growth restriction, hypoglycaemia and hepatomegaly.

• In juveniles and adults, GSD tends to present with fatigue and weakness on exercising, and either myositis or myopathy.

• Autosomal recessive (I, II, III, IV, V, VI, VII, some IX, Xl, 0). Both parents are carriers. The chance of a sibling being affected is 1 in 4.

• X-linked (some IX).

See the separate article on Von Gierke's Glycogen Storage Disease.

• Affected enzymes: glucose-6-phosphatase translocase deficiencies.

• Klinische Merkmale:
  

  • As in Von Gierke's disease with variable clinical expression but also immunosuppression (altered neutrophil functions) leading to infection. Pneumonia and oral infections are often seen.

  • May suffer from severe diarrhoea due to granulomatous infiltration of colonic mucosa.

• Behandlung: as in Von Gierke's disease but avoid infection. May need prophylactic antibiotics.

• Affected enzymes: caused by mutations in the gene coding for acid alpha-glucosidase (GAA), the enzyme that breaks down glycogen in lysosomes. Once in the lysosome, glycogen can escape following complete degradation by GAA in the form of glucose. A deficiency of the enzyme leads to lysosomal accumulation of glycogen in multiple tissues, but cardiac and skeletal muscles are most severely affected.

• Klinische Merkmale: Pompe's disease affects people of all ages with varying degrees of severity. Two broad types are recognised based on the onset of symptoms and the presence or absence of cardiomyopathy:

  • The most severe form, referred to as classic infantile onset Pompe's disease is characterised by the age of onset at up to 12 months, rapidly progressive hypertrophic cardiomyopathy, left ventricular outflow obstruction, hypotonia and muscle weakness, respiratory distress, and progressive loss of independent ventilation. Breathing difficulties, feeding problems, and macroglossia are common. Motor development is significantly delayed, and major developmental milestones are often not achieved. Only a small percentage of untreated patients survive beyond 1 year of age and the main cause of death is cardiac and respiratory failure.

  • Less devastating late-onset Pompe disease manifests any time after 12 months of age, usually without significant cardiac involvement. Late-onset patients commonly present with the symptoms of proximal limb-girdle myopathy. The progression of the symptoms is relatively slow but ultimately leads to profound muscle weakness and wasting, wheelchair dependency, and respiratory failure due to the involvement of the diaphragm. Additional symptoms include dysarthria and dysphagia, osteoporosis, scoliosis, sleep apnoea, small fibre neuropathy, hearing loss, impaired gastric function, urinary tract and anal sphincter involvement, and pain and fatigue, as well as a risk of cardiac arrhythmia and cerebral and intracranial aneurysms.

• Behandlung: the mainstay of treatment is now enzyme replacement therapy.

Synonyms: Forbes' disease, Forbes-Cori disease

• Affected enzyme: glycogen debranching enzyme. Deposition of abnormal glycogen structure.

• Affected tissues: liver and muscle.

• Klinische Merkmale:
  

  • Seizures in infancy, hypoglycaemia, poor growth, hepatomegaly, moderate progressive myopathy.

  • Symptoms can regress with age.

  • A few cases of liver cirrhosis and hepatocellular carcinoma have been reported.⁸

• Specific biochemical features: Hyperlipidämie.

• Behandlung: as with type I; also protein supplements for muscle disorder.

• Affected enzyme: transglucosidase (glycogen branching enzyme). Abnormally structured glycogen forms.

• Affected tissues: many, including liver. Rare variant affects peripheral nerves.

• Klinische Merkmale:
  

  • Hepatomegaly, failure to thrive, cirrhosis, splenomegaly, jaundice, hypotonia, waddling gait, lumbar lordosis.

• Behandlung: adherence to a dietary regimen may reduce liver size, prevent hypoglycaemia and improve growth and development. Management of organ failure as required.

• Komplikationen: include hepatocellular carcinoma, Leberversagen, heart failure, nerve dysfunction and ventricular arrhythmia.

• Prognose: mostly death by age 4, due to cirrhosis and portal hypertension.

See the separate article on McArdle's Glycogen Storage Disease.

In the past, types VIII and X were considered distinct conditions but they are now classified with type VI.

• Affected enzyme: liver phosphorylase.

• Affected tissues: liver; there is a rare cardiac form.

• Klinische Merkmale:
  

  • The most common variant is X-linked and therefore usually affects only males.

  • Hepatomegaly, hypoglycaemia, growth restriction, hyperlipidaemia.

• Specific biochemical features: mild ketosis, hyperlipidaemia.

• Behandlung: cardiac transplantation for the rare cardiac form. May need frequent feeding to avoid hypoglycaemia.

• Prognose: usually, a normal lifespan.

See the separate article on Phosphofructokinase Deficiency.

• Affected enzyme: hepatic phosphorylase kinase.¹²

• Affected tissues: liver.

• Clinical features:: divided into types IXa and IXb; both are relatively benign. Clinical symptoms in IXa include hepatomegaly, growth restriction, hyperlipidaemia and fasting ketosis. The clinical and biochemical abnormalities gradually disappear by adulthood.¹²

• Affected enzyme: glucose transporter 2 (GLUT2).

• Klinische Merkmale: hepatomegaly, glucose and galactose intolerance, fasting hypoglycaemia, proximal tubular nephropathy and severe short stature. Symptoms persist into adulthood.

• Behandlung: there is no specific therapy available. Symptomatic treatment to provide stable glucose homeostasis and compensate for renal losses of various solutes.

GSD type 0 is a rare form, representing less than 1% of all cases.

• Affected enzyme: hepatic glycogen synthase.

• Affected tissues: liver.

• Klinische Merkmale: fasting, ketotic hypoglycaemia when ceasing night-time feeds in infants or between meals in older children. Seizures can occur. Postprandial hyperglycaemia. Fatigue and muscle cramps after exertion. Mild growth restriction in some cases.

• Specific biochemical features:
  

  • Hypoglycaemia, ketosis, raised fasting lactate.

  • Glycosuria and ketonuria occur after breakfast and therefore may be confused with diabetes mellitus.

• Behandlung: adequate diet and avoidance of fasting hypoglycaemia.

• Prognose: normal growth and intellectual development if diagnosed early and episodes of hypoglycaemia are prevented.

• Blutuntersuchungen:
  

  • Blood glucose: hypoglycaemia is likely.

  • LFTs: monitoring for hepatic failure.

  • Anion gap calculation: if glucose is low, this may indicate lactic acidaemia.

  • Urate: there may be high urate levels and even associated gout.

  • Renal function tests.

  • Kreatinkinase.

  • FBC: there may (rarely) be anaemia, neutropenia.

  • Coagulation studies: increased bleeding tendency may occur.

  • Lipids: hyperlipidaemia occurs in some types of GSD.

• Urine tests: myoglobinuria after exercise - found in 50% of people with McArdle's disease.

• Bildgebung:
  

  • Abdominal ultrasound scan: hepatomegaly.

  • Echocardiography: cardiac involvement in certain types of GSD.

• Biopsy of liver, muscle or other tissues gives definitive diagnosis. However, biopsy has now largely been replaced by genetic testing.

• Direct biochemical assay of tissues for glycogen and fat content and enzyme analysis.

• Other tests:
  

  • Glucagon stimulation test: in GSD there is not the normal rise in blood glucose.

  • DNA analysis from peripheral lymphocytes for McArdle's disease.

Pränatale Diagnose

• Genetic counselling.

• Referral to a geneticist for possible prenatal investigation and diagnosis.

• In GSD affecting muscle, exclude the muscular dystrophies (including Duchenne-Muskeldystrophie) and secondary disorders of muscle, including Polymyositis.