A new variant of type IV glycogenosis: Deficiency of branching enzyme activity without apparent progressive liver disease

Abstract

Type IV glycogenosis is due to branching enzyme deficiency and is usually manifested clinically by progressive liver disease with cirrhosis and hepatic failure between the second and fourth years of life. We describe a 5-year-old boy who, following an acute febrile illness at 2 years of age, was first noted to have hepatomegaly with mildly elevated serum transaminase levels. Liver biopsy revealed hepatic fibrosis with periodic-acid Schiff-positive, diastase-resistant inclusions in hepatocytes and fibrillar inclusions characteristic of amylopectin by electron microscopy. Enzymatic assay revealed deficient hepatic branching enzyme activity with normal activity of glucose-6-phosphatase, debranching enzyme and phosphorylase activities. During the succeeding 3 years, he grew and developed normally with apparent resolution of any clinical evidence of liver disease and only intermittent elevation in serum transaminase levels associated with fever and prolonged fasting. Repeat liver biopsy at 4 years of age showed persistence of scattered hepatocellular periodic-acid Schiff-positive, diastase-resistant inclusions, but no progression of hepatic fibrosis in spite of persistent deficiency of hepatic branching enzyme activity. Skeletal muscle and skin fibroblasts from the patient also showed deficient enzyme activity. Skin fibroblasts from both parents exhibited half the normal control activity, suggesting a heterozygote state. This is the first documented patient with deficiency of branching enzyme but without evidence of progressive hepatic disease. This patient, coupled with reports of other patients with late onset hepatic or muscle disease with branching enzyme deficiency, suggests that the defect resulting in Type IV glycogen storage disease is more heterogenous and possibly more common than previously suspected.

Early-onset fetal hydrops and muscle degeneration in siblings due to a novel variant of type IV glycogenosis

“…Type IV GSD, due to deficiency of glycogen brancher enzyme, usually presents in one of 4 ways: infantile hepatosplenomegaly with cirrhosis with or without neonatal hypotonia; childhood cardiomyopathy; childhood hepatomegaly; or muscular weakness in adulthood [Andersen, 1956;Levin, 1968;Greene et al, 1988;Tang et al, 1994;Ferguson et al, 1983]. In addition, in a few reports type IV GSD presented as congenital arthrogryposis late in the 3rd trimester or at birth [van Noort et al, 1993;DiRocco et al, 1998;Martins et al, 1998] associated with pulmonary hypoplasia or hydrops.…”

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

“…This is followed by progressive liver cirrhosis with portal hypertension, ascites, esophageal varices, and liver failure, leading to death by 5 yr of age. There are, though less frequently, patients with liver dysfunction who have survived without evidence of progressive liver disease (4)(5)(6)(7). In addition to the hepatic form, a neuromuscular form of the disease has been reported.…”

Glycogen Storage Disease Type IV: Inherited Deficiency of Branching Enzyme Activity in Cats

“…Most affected children fail to thrive before 1 y of age and die from cirrhosis and the sequelae of hepatic failure between 1 and 4 y of age. Some children exhibit signs of cardiac failure or neuromuscular involvement, with or without signs of hepatic disease (8, 10, 1 I), and a few patients with later onset of signs and longer survival have been reported (10,12,13). Orthotopic liver transplantation has been life-saving in a few patients (14).…”

“…Orthotopic liver transplantation has been life-saving in a few patients (14). Biochemical evidence and family pedigrees indicate that type IV glycogen storage disease is inherited as an autosomal recessive trait; heterozygote detection and successful prenatal diagnosis have been reported (12,15,16,17). This report describes the clinical, pathologic, biochemical, and genetic characteristics of glycogen storage disease type IV in a family of purebred domestic cats.…”