Pathogenetic Considerations

Type IV glycogen storage disease is a rare autosomal recessive disorder representing 0.3% of all cases of glycogenosis of any type. The disease is caused by a deficiency of the glycogen branching enzyme. Glycogen branching enzyme is encoded by the gene GBE, which is located on chromosome 3p14. There is evidence for the existence of different isoenzymes, probably generated by alternative splicing. The enzyme is involved in glycogen synthesis. Deficiency leads to accumulation of polysaccharides, which are resistant to amylase digestion and have longer outer chains and shorter branch points than normal glyco-gen.

Glycogen storage disease type IV is highly heterogeneous as to clinical symptoms and age of onset. The latter varies between the early neonatal period through childhood to late adulthood. The classical type is characterized by early onset and rapidly progressive hepatosplenomegaly, progressive cirrhosis with portal hypertension, ascites, esophageal varices, and death between 3 and 5 years due to liver failure, unless liver transplantation is performed. Nonprogressive hepatic variants have also been described. Patients with neuromuscular involvement have a my-opathy with or without cardiomyopathy, neuropathy, and liver cirrhosis. The age at onset varies from neonatal to adulthood. Neonatal variants presenting with pronounced hypotonia are extremely rare. They resemble patients with the Werdnig-Hoffmann type of spinal muscular atrophy. They may have additional cardiomyopathy or hepatosplenomegaly. Presentation with hydrops fetalis is also very rare. APBD characterized by late onset and slowly progressive severe neurological symptoms can also be an expression of glycogen branching enzyme deficiency.

The phenotypic variability and tissue specificity described above may be due to particular mutations resulting in selective tissue-based expression or deficiency of isoenzymes. This hypothesis does not,how-ever, explain the differences in phenotypic expression between patients with identical genotype.

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