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PubMed1984

Glycogenosis type VIII.

Glycogenosis Type VIII, characterized ultrastructurally by an accumulation of rosettes (alpha-particles) of glycogen in the central nervous system, is an extremely rare condition; only two sporadic cases are on record. The first complete autopsy on a patient with cerebral alpha-particle glycogenosis, a 20-year-old American-Indian female, is the subject of this report. The case was clinically unique because of long survival and presumable familial incidence. The gross pathology was characterized by severe brain atrophy but preserved thickness of the cortical mantle. Vacuolation of the neuropil was the main histological abnormality and was most extensive in the striatum and less so in the cerebral cortex and some brain stem nuclei. Biochemical analysis showed glycogen levels elevated fiftyfold in the striatum and eightfold in the cerebral cortex in comparison with control tissue. Ultrastructural observations and evidence obtained from the Golgi method suggest that the distal axon was the principal site of storage. Two prominent additional abnormalities, spheroids, not previously observed in this disease, and massive accumulation of lipofuscin, were probably both related to the prolonged course of illness. The viscera, including the liver were morphologically free of storage.

Adult↗
PubMedDate not supplied

The effect of age on biochemical and morphological changes in the semitendinosus muscle of cattle with generalized glycogenosis type II.

Progressive changes in acid alpha-glucosidase activity, glycogen content and light microscopical and ultrastructural features in skeletal muscle of calves affected by generalized glycogenosis type II were assessed in biopsies from semitendinosus muscle of nine affected, twenty-six carrier and fifteen normal calves taken at varying times between birth and 17 months of age. Affected animals could be identified by using the PAS technique on paraffin and epon embedded material or by electron microscopy. However, estimation of acid alpha-glucosidase activity was required for precise diagnosis of generalized glycogenosis type II or to distinguish between normal and carrier animals. The glycogen content of the semitendinosus muscle of affected animals was approximately three times that in non-affected animals and although storage of glycogen reached a plateau soon after birth, the muscle fibre damage seen in very young calves increased with age. Morphological evidence of glycogen accumulation, both within the cytoplasm and within membrane bound structures, was present at birth. In some animals evidence of muscle fibre regeneration and damage was seen in the same sections.

Age Factors↗
PubMed1980

Type III glycogenosis with deposition of urate and amyloid.

A case of a 44-year-old man with hepatic form of glycogenosis was presented. The patient had abdominal distension and muscular weakness. The glucose tolerance test showed a diabetic pattern, though he had hypoglycemia in fasting state. The fructose tolerance test showed an ability of conversion from fructose to glucose. The double glucagon test showed no rise of blood glucose in fasting state but a rise 2 hours after meal. These symptoms and laboratory data supported the clinical diagnosis of type III glycogenosis. At autopsy, glycogen was markedly deposited in the liver, and slightly in the kidneys and heart. The glycogen pooled in the hepatic cells histochemically showed a normal reaction to several glycogen stainings. Electron microscopy by using Thiéry's method revealed that the pooled glycogen particles were clearly arranged as rosettes measuring 1,000A in largest diameter composed of clustered monoparticulates. There were marked hyalinization of the islets of Langerhans containing amyloid. As to its pathogenesis, this change can be interpreted as a morphological expression of the hypofunction of beta-cells ascribed to long-standing hypoglycemia.

Adult↗
PubMed1989

An investigation of the possible influence of neutral alpha-glucosidases on the clinical heterogeneity of glycogenosis type II.

The lysosomal storage disorder glycogenosis type II, caused by a deficiency of lysosomal alpha-glucosidase, is very heterogeneous in its clinical presentation. It has been suggested that this heterogeneity may be due to differential expression of neutral alpha-glucosidases. We have therefore analysed the activity of the major neutral alpha-glucosidases in cultured fibroblasts or muscle cells from 26 patients with glycogenosis type II. The results indicate that there is no correlation between the expression of neutral alpha-glucosidase isoenzymes and the clinical phenotype of this disease.

Cells, Cultured↗
PubMed1978

Studies on a patient with in vivo evidence of type I glycogenosis and normal enzyme activities in vitro.

Biochemical and clinical studies on a patient with hepatic glycogen storage disease are reported. The patient showed many of the clinical and biochemical features of type I glycogenosis (glucose-6-phosphatase deficiency), but had normal activities of the following enzymes in liver tissue: glucose-6-phosphatase (EC3.1.3.9); amylo-1,6-glucosidase (EC3.2.1.33); glycogen phosphorylase (EC2.4.1.1); fructose-1,6-diphosphatase (EC3.1.3.11). The urinary excretion of 2-oxoglutaric acid was greatly increased in this patient and in a case of enzymologically proven type I glycogenosis. Abnormal 2-oxoglutaric aciduria has not been previously reported in the glycogen storage diseases. The results are discussed in relation to the possible nature of the underlying biochemical defect in patients of this type.

Fructose-Bisphosphatase↗
PubMed1993

Clinical, diagnostic and biochemical features of generalised glycogenosis type II in Brahman cattle.

Clinical, diagnostic and biochemical features of generalised glycogenosis are described in 96 Brahman-type calves. Typically the calves were presented when about 6 months of age, with ill-thrift and muscular weakness as the most common signs. Acidic alpha-glucosidase activity was reduced in peripheral blood lymphocytes and skeletal muscle. Muscle glycogen concentration was consistently higher in affected animals than in clinically normal cattle. Other observations in affected calves included elevation of serum aspartate aminotransferase and creatine kinase activities and excessive amounts of high molecular weight oligosaccharides in urine. Fine cytoplasmic vacuolation of neurones in the brain and spinal cord, skeletal muscle, myocardium and of Purkinje fibres were consistent histological observations. Periodic acid-Schiff staining revealed the presence of glycogen-like material in peripheral blood lymphocytes of all affected calves, indicating that this is a useful aid for the diagnosis of glycogenosis. While 3 of the 96 calves showed somewhat different clinical signs, the similarity of pathology and the biochemical and clinical evidence in the remainder suggested that, in these animals, the disease was expressed as a single syndrome.

Animals↗
PubMed1995

Evidence of molecular heterogeneity for generalised glycogenosis between and within breeds of cattle.

Northern analyses revealed normal levels of acidic alpha-glucosidase mRNA in cultured fibroblasts from a Shorthorn calf affected with glycogenosis but a gross deficiency in an affected Brahman calf. Analyses of acidic alpha-glucosidase activity, relative to that of other lysosomal enzymes, in blood mononuclear cells revealed greater variation within and between Brahman herds than Shorthorn herds. A Msp1 restriction fragment length polymorphism associated with glycogenosis in Brahmans was not found in Shorthorns. These results are considered in relation to molecular heterogeneity for AAG deficiency in cattle and its implications for disease control programs.

Animals↗
PubMed2001

Genotyping shorthorn cattle for generalised glycogenosis.

OBJECTIVE: To develop a procedure for routine genotyping of Shorthorn cattle for the generalised glycogenosis allele in exon 18 of the acidic alpha-glucosidase gene. PROCEDURE: Allele-specific amplification and double mismatch amplification procedures for the discrimination of the exon 18 alleles were evaluated using leucocytes and hair roots as sources of target DNA. RESULTS: Allele-specific amplification was effective for genotyping Shorthorn cattle at the 2454 site when purified DNA was used as target for the polymerase chain reaction. However, when the target DNA was derived from hair roots, differences in the relative yield of wild-type and mutant amplicons were observed. The double mismatch amplification procedure was effective in genotyping all subjects, independent of the source of DNA. The unique cleavage sites for Drd I and PshA I within exon 18 are present and absent respectively in the wildtype amplicon, and are lost and acquired, respectively, in the mutant amplicon. In addition, the Drd I and PshA I mismatching cleavage sites incorporated into the primers serve as internal controls for Drd I and PshA I cleavage. CONCLUSION: The double Drd I/PshA I mismatch amplification procedure using hair root samples as the source of DNA is a robust method for genotyping Shorthorns for generalised glycogenosis.

Alleles↗
PubMed1975

Amylo-1,60glucosidase deficiency (glycogenosis type III) in the Faroe Islands.

Seven cases of glycogenosis type III (amylo-1,6-glucosidase deficiency) in two probably related families from the Faroe Islands are presented. The group of patients comprised two pairs of sibs. In a total of 78 members of the two families case histories were obtained and clinical examinations, analyses of amylo-1,6-glycosidase activity in erythrocytes and leucocytes, determinations of red cell, serum and enzyme groups as well as HL-A types were performed. In addition, all patients were subjected to studies of liver function. The distribution patients in these families supports the assumption of autosomal recessive inheritance. Heterozygotes could not be diagnosed with certainty by the methods of enzyme activity analysis employed. The incidence of glycogenosis type III with amylo-1,6-glucosidase deficiency was found to be high in the Faroe Islands.

Adolescent↗
PubMed1981

Immunochemical studies of human acid alpha-1,4-glucosidase in type II glycogenosis.

The results of immunochemical studies performed in 6 cases of type II glycogenosis (1 classical form, Pompe's disease) and 5 atypical forms (2 juvenile, 3 adult) are reported. The use of antiacid alpha-1,4-glucosidase antibodies greatly improved the specificity of the diagnostic tests for type II glycogenosis, particularly in fibroblasts, lymphocytes, and urine. The use of these antibodies permits the precise measurement of lysosomal enzymes and also enables to demonstrate the activating influence of potassium chloride on urinary lysosomal alpha-1,4-glucosidase. The use of such specific antibodies should prove to be an aid in genetic studies and allows a better understanding of the disease mechanism.

Fibroblasts↗
PubMed1987

Clinical diversity in glycogenosis type II. Biosynthesis and in situ localization of acid alpha-glucosidase in mutant fibroblasts.

The molecular basis of clinical diversity in glycogenosis type II (Pompe's disease) was investigated by comparing the nature of acid alpha-glucosidase deficiency in cultured fibroblasts from 30 patients. Biosynthetic forms of acid alpha-glucosidase with different molecular mass were separated electrophoretically and identified by immunoblotting. Immuno-electron microscopy was employed to determine the intracellular localization of mutant enzyme. Our studies illustrate that maturation of acid alpha-glucosidase is associated with transport to the lysosomes. Deficiency of catalytically active mature enzyme in lysosomes is common to all clinical phenotypes but, in the majority of cases, is more profound in early onset than in late onset forms of the disease. Thus, the results suggest that the clinical course of glycogenosis type II is primarily determined by the amount of functional acid alpha-glucosidase. The role of secondary factors can, however, not be excluded because three adult patients were identified with very low activity and little enzyme in the lysosomes.

Adult↗
PubMed1990

Rat heart perfusion as model system for enzyme replacement therapy in glycogenosis type II.

Cardiac failure and skeletal muscle weakness are the main clinical features of glycogenosis type II, a lysosomal storage disorder caused by acid alpha-glucosidase deficiency. In our study, we have investigated in a rat heart perfusion-recirculation system whether acid alpha-glucosidase can be taken up from the vascular system into cardiomyocytes. When rat hearts were perfused with mannose 6-phosphate-containing acid alpha-glucosidase purified from bovine testis, a 3- to 4-fold increase of enzyme activity was obtained. Perfusion with human placental acid alpha-glucosidase not containing the mannose 6-phosphate recognition marker did not have such an effect. The presence of bovine testis acid alpha-glucosidase in heart tissue was demonstrated by immunoblotting. Immunocytochemistry provides evidence for uptake of the exogenous enzyme in lysosomes of the cardiomyocytes. The relevance of these findings for enzyme therapy in glycogenosis type II is discussed.

Animals↗
PubMed1989

Partial characterization of leucocyte alpha-glucosidase in late onset glycogenosis type II.

We describe partial characterization and properties of leucocyte alpha-glucosidase from a patient with clinical features intermediate of juvenile and adult onset forms of glycogenosis type II. Acid and neutral alpha-glucosidase activities toward 4-methylumbelliferyl glucopyranoside as substrate were studied in total leucocytes, and separately in lymphocytes and granulocytes. Lymphocytes, which showed markedly reduced activities of acid alpha-glucosidase in the patient, are the most reliable peripheral blood cells for the diagnosis of glycogenosis type II. Moreover, the ratio of acid/neutral alpha-glucosidase activities, especially in lymphocytes, is a useful parameter for the diagnosis. In lymphocytes, the Km values of both acid and neutral alpha-glucosidases were essentially the same between the patient and normal controls; the Vmax value of acid alpha-glucosidase from the patient was markedly reduced, and the Vmax value of neutral alpha-glucosidase from the patient was reduced by 36% as compared with that from normal controls. Heat-inactivation experiments revealed that acid alpha-glucosidase activities of lymphocytes were relatively heat-stable, while both acid and neutral alpha-glucosidases of granulocytes were heat-labile. No differences in these properties, however, could be detected between the patient and normal controls.

Adult↗
PubMed1990

Leucocyte alpha-1,4- and alpha-1,6-glucosidase activities towards oligosaccharides in late onset glycogenosis type II.

We describe the partial characterization and some properties of leucocyte alpha-glucosidase towards disaccharides with the alpha-1,4 (maltose) and alpha-1,6-glucosidic linkage (isomaltose) and tetrasaccharides with the alpha-1,4 (maltotetraose) and alpha-1,6-glucosidic linkage (tetrasaccharide, Glc alpha 1----6Glc alpha 1----4Glc alpha 1----4Glc, which was isolated from the urine of a patient with glycogenosis type II). Leucocyte alpha-glucosidase showed optimal activity towards all four oligosaccharides under two conditions, acidic (pH 4.0-4.5) and neutral (pH 6.0-6.5) regions. Our comparative studies on enzyme kinetics showed that leucocyte alpha-glucosidase was able to hydrolyze both the 1----4 isomers and the 1---6 isomers at acidic and neutral pH. Acid alpha-glucosidase could hydrolyze maltose about 10 times faster than isomaltose, and maltotetraose about 5 times faster than tetrasaccharide isolated from urine. In leucocytes of the patient with late onset glycogenosis type II, acid alpha-glucosidase activities towards maltose, isomaltose, maltotetraose and tetrasaccharide isolated from urine showed 75.3%, 67.4%, 76.5% and 41.4% of normal control values, respectively. Neutral alpha-glucosidase activities towards these four oligosaccharides were normal. Tetrasaccharide with alpha-1,6-glucosidic linkage might be accumulated by the impaired hydrolysis in the circulation as well as the leakage of undegraded glycogen to the circulation from the affected muscle.

Adult↗
PubMed2002

Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease).

Glycogenosis type II (GSDII, Pompe disease) is an autosomal recessive lysosomal storage disease caused by a deficiency of acid alpha-glucosidase (acid maltase, GAA). The enzyme degrades alpha -1,4 and alpha -1,6 linkages in glycogen, maltose, and isomaltose. Deficiency of the enzyme results in accumulation of glycogen within lysosomes and in cytoplasm eventually leading to tissue destruction. The discovery of the acid a-glucosidase gene has led to rapid progress in understanding the molecular basis of glycogenosis type II and the biological properties of the GAA protein. The last decade has seen several developments: 1) extensive mutational analysis in patients with different forms of the disease, 2) characterization of the enzyme biosynthesis, processing, and lysosomal targeting, 3) generation of knockout mouse models, 4) development of viral vectors for gene replacement therapy, 5) the production of recombinant human enzyme, and 6) a shift in the enzyme replacement therapy approach from theory to practice. It is anticipated that the enzyme replacement therapy will be widely available for human use in the near future. Several recent reviews (including the most comprehensive one by R. Hirschhorn and A. Reuser [1]), address clinical, biochemical and genetic aspects of the disease, as well as development of new therapies for GSDII [2, 3, 4]. In this article we will review recent findings in the area including rapidly accumulating molecular genetic data (more than 20 mutations need to be added to the list), transcriptional control of gene expression, studies in mouse models, and new approaches to gene therapy. We will also highlight some emerging questions following the introduction of enzyme replacement therapy.

Adult↗
PubMedDate not supplied

A congenital variant of glycogenosis type IV.

Three related patients are described with glycogenosis type IV with an unusual clinical presentation resulting in perinatal death. Stored material showed birefringent Maltese crosses and was present in skeletal muscles, heart, central nervous system, and liver. Muscular dysfunction resulted in a fetal hypokinesia sequence with arthrogryposis and lung hypoplasia. A subdivision of glycogenosis type IV in four subtypes is proposed, based on age of onset. Measurement of the enzyme activities in different tissues does not permit, at the moment, a distinction between the subtypes.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1999

[Pompe disease or type 2 glycogenosis].

We report the case of a rapidly progressing respiratory failure of a three-month old infant, who shows a cardiomyopathy with left ventricule hypertrophy leading to a Pompe's disease diagnosis. This type 2 glycogenosis will be confirmed by the enzymatic study of the hepatocytes. It is a genetic pathology associated with a deficient activity of the acid maltase resulting in a intralysosomial accumulation of glycogen. The most generally responsible mutations are: delta 18 et delta 525. Prognosis is quite bad with a progressive deterioration of the heart, brain and muscular functions causing death at around 4 to 8 months. Type 2 glycogenosis may be diagnosed before birth through enzymatic study of a material collected through an amniocentesis or a biopsy on chorionic villi, and through DNA analysis. Curative treatment is still under study, but two main research orientations are being developed: genic therapy using viral vector and the correction of the enzymatic deficiency thanks to the synthesis of alpha glucosidase modified to specially get affixed to the heart and muscular cells. Both techniques have already show some encouraging results even though the clinical applications are not presently valid yet.

Female↗
PubMed1975

[The fructose induced "glycogenosis". I. Ultrastructural and morphometric analysis of rat hepatocytes 7 days after fructose overload (author's transl)].

INTRODUCTION: Infusion of fructose has been shown to stimulate the SER and to reduce the RER in rat liver cells. After feeding fructose of 7 days a glycogenosis of unknown pathogenesis occurs, which was analysed morphometrically. MATERIAL AND METHODS: 60% fructose in water, was given as drinking water to animals deprived of other food. Controls had free access to Altromin-R-standard diet and drinking water. Liver tissue was analysed morphometrically according to the methods described by Weibel. RESULTS AND DISCUSSION: Rat hepatocytes accumulate a material with histochemical properties of glycogen. The enlargement of hepatic nuclei is probably due to a pathological edema. The SER is decreased suggesting a drop of glycogen catabolizing enzymes. The drastic reduction of the RER and the non-membrane bound ribosomes are signs of inpeeded protein synthesis. According to this, the peroxisomes, which arise from the RER, are decreased in volume and number. The hepatocellular chondrioma is transformed morphometrically in a smaller number of larger, pleomorphic and cup-shaped mitochondria. The ATP level drops while, on the other hand, the cristeal membranes increase. This might be caused by a negative feed back mechanism. The hepatocellular cytoarchitecture described is similar to the one found in glycogenosis type I and in the cerebrohepato-renal syndrom.

Animals↗