Glycogen storage disease type IV: novel mutations and molecular characterization of a heterogeneous disorder.

Abstract

Glycogen storage disease type IV (GSD IV; Andersen disease) is caused by a deficiency of glycogen branching enzyme (GBE), leading to excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues. The accumulated glycogen lacks multiple branch points and thus has longer outer branches and poor solubility, causing irreversible tissue and organ damage. Although classic GSD IV presents with early onset of hepatosplenomegaly with progressive liver cirrhosis, GSD IV exhibits extensive clinical heterogeneity with respect to age at onset and variability in pattern and extent of organ and tissue involvement. With the advent of cloning and determination of the genomic structure of the human GBE gene (GBE1), molecular analysis and characterization of underlying disease-causing mutations is now possible. A variety of disease-causing mutations have been identified in the GBE1 gene in GSD IV patients, many of whom presented with diverse clinical phenotypes. Detailed biochemical and genetic analyses of three unrelated patients suspected to have GSD IV are presented here. Two novel missense mutations (p.Met495Thr and p.Pro552Leu) and a novel 1-bp deletion mutation (c.1999delA) were identified. A variety of mutations in GBE1 have been previously reported, including missense and nonsense mutations, nucleotide deletions and insertions, and donor and acceptor splice-site mutations. Mutation analysis is useful in confirming the diagnosis of GSD IV--especially when higher residual GBE enzyme activity levels are seen and enzyme analysis is not definitive--and allows for further determination of potential genotype/phenotype correlations in this disease.

• Authors: Sing-Chung Li, Chiao-Ming Chen, Jennifer L Goldstein, Jer-Yuarn Wu, Emmanuelle Lemyre, Thomas Andrew Burrow, Peter B Kang, Yuan-Tsong Chen, Deeksha S Bali
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 33 Suppl 3 Pg. S83-90 (Dec 2010) ISSN: 1573-2665 [Electronic] United States
• PMID: 20058079 (Publication Type: Case Reports, Journal Article)

Chemical References

• Glycogen Debranching Enzyme System
• GBE1 protein, human

Topics

• Amino Acid Sequence
• Base Sequence
• DNA Mutational Analysis
• Female
• Genetic Predisposition to Disease
• Genetic Testing (methods)
• Glycogen Debranching Enzyme System (genetics, metabolism)
• Glycogen Storage Disease Type IV (complications, diagnosis, enzymology, genetics)
• Humans
• Infant
• Male
• Molecular Sequence Data
• Mutation, Missense
• Pedigree
• Phenotype
• Prognosis
• Sequence Deletion
• Severity of Illness Index