Disorder Of Glycogen Metabolism Research Articles

Glycogen storage disease type Ia: Molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells

Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of glucose-6-phosphatase (G6Pase) that is expressed in the liver, kidney, and intestinal mucosa. Clinical manifestations include short stature, hepatomegaly, hypoglycemia, hyperuricemia, and lactic acidemia. To elucidate a spectrum of the G6Pase gene mutations and their frequencies, we analyzed mutations in 51 unrelated Japanese patients with GSD-Ia. The most prevalent mutation was g727t, accounting for 88 of 102 mutant alleles examined, followed by R170X mutation, which accounted for 6 mutant alleles, and R83H mutation which was observed in 3 mutant alleles. In addition, 3 different, novel mutations, IVS1-1g<a, Gly122-to-Asp (G122D) and His179-to-Pro (H179P), were identified. We were able to detect "ectopically" transcribed G6Pase-mRNA in Epstein-Barr virus-transformed lymphoblastoid cells and observed aberrant mRNA splicing associated with the g727t and IVS1-1g<a mutations. To our knowledge, this is the first report that ectopic expression can be utilized for the characterization of GSD-Ia mutations. Our findings suggest that a screening for the g727t, R170X, and R83H mutations by simple DNA-based diagnostic methods can detect 95% of the G6Pase mutant alleles in Japanese patients with GSD-Ia, and remaining mutations can be identified and characterized by the direct sequencing of genomic DNA and/or the analysis of ectopically expressed mRNA. The noninvasive molecular diagnosis for GSD-Ia may ultimately replace the conventional means of enzymatic diagnosis that requires liver biopsy.

A man with type III glycogenosis associated with cirrhosis and portal hypertension

Type III glycogenosis, an inherited disorder of glycogen metabolism that results from reduced or absent activity of the enzyme amylo-1,6-glycosidase (debranching enzyme), has not been frequently associated with cirrhosis and portal hypertension in adults. An adult Caucasian man with well-documented type IIIa glycogenosis, who presented with a variceal hemorrhage secondary to hepatic cirrhosis, is described here. No other cause of cirrhosis was found.

Phosphorus magnetic resonance spectroscopy (31P MRS) in neuromuscular disorders

Phosphorus magnetic resonance spectroscopy monitors muscle energy metabolism by recording the ratio of phosphocreatine to inorganic phosphate at rest, during exercise, and during recovery from exercise. In mitochondrial diseases, abnormalities may appear during some or all these phases. Low phosphocreatine-inorganic phosphate ratios at rest are not disease-specific, but can be increased by drug therapy in several myopathies. Phosphorus magnetic resonance spectroscopy can also record intracellular pH and thus identify disorders of glycogen metabolism in which the production of lactic acid is blocked during ischemic exercise. The measurements of accumulated sugar phosphate intermediates further delineate glycolytic muscle defects. Myophosphorylase deficiency responds to intravenous glucose administration with improved exercise bioenergetics, but no such response is seen in phosphofructokinase deficiency. The muscular dystrophies show no specific bioenergetic abnormality; however, elevation of phospholipids metabolites and phosphodiesters was detected in some cases. While phosphorus magnetic resonance spectroscopy remains primarily a research tool in metabolic myopathies, it will be clinically useful in identifying new therapies and monitoring their effects in a variety of neuromuscular disorders.

Disorders of Glycogen Metabolism of Muscle

Glycogen is a crucial source of energy in the initial stages of muscle activity and during exercise of high intensity. There are 10 well-defined biochemical defects of glycogen metabolism expressed in muscle and affecting the following enzymes: alpha 1,4 glucosidase (glycogenesis type II), debrancher enzyme (III), brancher enzyme (IV), phosphorylase (V), phosphofructokinase (VII), phosphorylase b kinase (VIII), phosphoglycerate kinase (IX), phosphoglycerate mutase (X), lactate dehydrogenase (XI). These disorders cause two main syndromes: one characterized by exercise intolerance with cramps and myoglobinuria, the other by fixed weakness. However, there are examples of clinical and biochemical heterogeneity for each disease, and molecular genetic analysis is already showing evidence of genetic heterogeneity. Although our understanding of the biochemical errors has progressed considerably, the pathogenesis of symptoms and signs remains incomplete.

Electron Microscopy of Ocular Muscle in Type Ii Glycogenosis (Pompe's Disease)

In 1928, von Gierke described a small group of young patients who showed mas­ sive deposition of glycogen in their liver and kidneys at autopsy. A few years later, Pompe reported the case of a child who died with glycogen deposits in many organs as well as in skeletal muscle. Subsequently, Cori, Hers, and others have identified the inherited enzyme deficiency responsible for these and other disorders of glycogen metabolism. Pompe's disease (type II glycogenosis) results from absence of the enzyme alpha 1-4 glucosidase (acid maltase). Abnormal depo­ sition of glycogen is found in cardiac and skeletal muscle, liver, kidney, thyroid, and spleen. Because of the wide distribution of abnormal glycogen deposits, Pompe's disease is also referred to as generalized glycogeno­ sis. The light and electron microscopic changes in Pompe's disease have been thor­ oughly studied in skeletal and cardiac muscle and in other organs. Cogan was the first to observe deposits of glycogen in the mural cells of the retinal vessels in patients with Pompe's disease. Toussaint described the light microscopic ocular changes in a fivemonth-old infant with type II glycogenosis. He found deposits of glycogen in retinal ganglion cells, in mural cells of the retinal vessels, and in the smooth and striated mus­ cle fibers of the eye. Their illustrations of the rectus muscle showed a complete disap-