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.

Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review

“…This observation is consistent with previous literature reviews that suggest that individuals with 2 missense mutations tend to have a milder form of the disease when compared with those with 2 null mutations [15][16][17], and those with the more severe congenital presentation often have at least 1 protein-truncating mutation and/or large deletion [3,[16][17][18][19][20]. However, considerable overlap exists both between and within subtypes of GSD IV [10].…”

“…It has been postulated that different mutations may lead to variable expressivity of the protein in different cell types, therefore contributing to the clinical, pathologic, and enzymatic variability in organ systems [10]. Genotypephenotype correlations remain unclear yet are beginning to emerge.…”

“…Reduced GBE enzyme activity is observed in all patients with GSD IV [9] and most commonly measured in cultured skin fibroblasts, liver, and skeletal muscle. There is extensive variability in the amount of residual enzyme activity between patients as well as differences in residual activity in different tissues within the same patient [10]. Although there appears to be some correlation between the underlying biochemical abnormality and organ involvement, it is difficult to predict disease progression based on enzyme activity alone [10,11].…”

Adult Polyglucosan Body Disease: Clinical and histological heterogeneity of a large Italian family

“…Neurogenic bladder, spastic paraplegia and axonal polyneuropathy, presenting in the fifth-sixth decade, constitute the most recurrent features [1]. Mutations in GBE1 are also causative of Glycogen Storage Disease type IV (GSDIV), a usually infantile liver disease or skeletal/cardiac myopathy [2], though an intermediate variant between childhood GSDIV and APBD has been recently described [3]. We investigated a large non-Jewish Italian family affected with APBD, and found an unexpected clinical and histological intra-familial heterogeneity at disease onset.…”

Neuromuscular, cognitive and metabolic implications of McArdle Syndrome: a global overview

“…The subdivision of the GSD, in turn, is based on the particular type of carbohydrate metabolism-related enzyme deficiency. On these grounds, 14 distinct diseases have currently been identified:  Type I, or Von Gierke's disease, which develops due to glucose-6-phosphatase deficiency [5];  Type II, or Pompe's disease, which develops due to acid alpha glucosidase deficiency; it exhibits two different forms: early-onset (or the infantile form) and late-onset (or the juvenile/adult form) [6];  Type III, or Cori's disease, which develops due to alteration of a glycogen debranching enzyme (4-alpha glucanotransferase); it is subdivided into subtypes IIIa, IIIb, IIIc and IIId as a function of the degree of enzyme deficiency [7];  Type IV, or Andersen disease, which develops due to alteration of the glycogen branching enzyme [8];  Type V, or McArdle Syndrome (MS), which develops due to myophosphorylase deficiency [9];  Type VI, or Hers' disease, which develops due to liver phosphorylase deficiency [10]. Type VII results from phosphofructokinase deficiency [11], and types VIII and X were included in the latter category;  Type IX, which develops due to deficiency of the liver phosphorylase kinase isoform PHK2 [12];  Type XI, or Fanconi-Bickel Syndrome, which is caused by accumulation of the gene that encodes glucose transporter GLUT 2 [13];  Type XII, or distal glycogenosis, which results from aldolase A deficiency [14];  Type XIII, which develops due to β-enolase deficiency [15];  Type XIV, which develops due to phosphoglucomutase deficiency [16]; and  Type 0, which develops due to glycogen synthase deficiency [17].…”