Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene.

Abstract

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-IV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of GBE activity, whereas the Y329S resulted in loss of ‫ف‬ 50% of GBE activity. The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3 Ј acceptor splicing site mutation ( ag to aa ). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease.

Increased Laforin and Laforin Binding to Glycogen Underlie Lafora Body Formation in Malin-deficient Lafora Disease

“…Polyglucosans are poorly soluble and precipitate, aggregate, resist digestion, and accumulate in many tissues (e.g. liver, muscle, heart, and brain); replace cell cytoplasm; and lead to type IV glycogenosis (Andersen disease) characterized by death in infancy from hepatic failure (7)(8)(9)(10).…”

Hepatic disease as the first manifestation of progressive myoclonus epilepsy of Lafora

“…8 Glycogen storage disease or glycogenosis type IV, also known as amylopectinosis or Andersen disease (MIN23250), is an autosomal recessive disorder caused by a deficiency of glycogen-branching enzyme (GBE) activity due to mutations in the GBE1 gene. 9 A diagnosis can be made on the basis of the study of branching enzyme activity in erythrocytes. 10 Glycogenosis type IV is highly heterogeneous in terms of tissue involvement, clinical manifestations, and age at onset.…”

“…The classic form of glycogenosis type IV is characterized by rapidly progressive hepatosplenomegaly and liver failure leading to either liver transplantation or death by the age of 5 years. 9 In addition to the classic form, variants such as a milder nonprogressive hepatic disease, 11 neuromuscular forms varying in onset and severity (from a fatal neonatal disease 12 to a mild adult myopathy 13 ), a cardiopathic form of childhood, 14 or a variant with multisystem involvement including liver and muscle 15 have been reported. GBE belongs to the alpha-amylase family and is required for glycogen synthesis.…”

Living Donor Liver Transplantation in a Korean Child with Glycogen Storage Disease Type IV and a GBE1 Mutation

“…GSD-IV has been diagnosed histologically and biochemically, by measuring glycogen branching enzymes in individual tissues. 3 GSD-IV is associated with mutations in GBE1, which encodes the glycogen branching enzyme, 4 and several types of GBE1 mutation have been identified. 5,6 We describe here a 20 month-old girl with progressive liver cirrhosis associated with GSD-IV, as confirmed by GBE1 gene analysis, who was successfully treated by liver transplantation.…”