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PubMedDate not supplied

An adult case of Andersen's disease--Type IV glycogenosis. A clinical, histochemical, ultrastructural and biochemical study.

A middle-aged man presented with a thirty-year history of progressive, asymmetrical limb-girdle weakness. The muscle biopsy revealed a vacuolar myopathy. The vacuoles which did not disrupt the fibre outline, lay in a subsarcolemmal position. They were PAS-positive and the material was partially resistant to diastase digestion. Electron microscopy showed the vacuoles to contain free unbound glycogen with filamentous material. Leucocyte brancher enzyme activity was normal but the muscle activity was less than half the control value. Histochemical and ultrastructural characteristics of the storage material resemble the amylopectin polysaccharide deposits seen in childhood Type IV glycogenosis.

Glycogen Storage Disease↗
PubMed1987

Breakdown of lysosomal glycogen in cultured fibroblasts from glycogenosis type II patients after uptake of acid alpha-glucosidase.

Fibroblast cultures from patients with different clinical subtypes of glycogenosis type II were compared with respect to residual acid alpha-glucosidase activity and lysosomal glycogen content. Lysosomal glycogen storage was most pronounced in fibroblasts from patients with the rapidly progressive infantile form of the disease, and the most severe enzyme deficiency. In fibroblasts from adult patients with more than 10% of the control activity storage did not occur, and 15% of the total cellular glycogen was found in the lysosomes as in control cells. The strict correlation between residual acid alpha-glucosidase activity and lysosomal glycogen accumulation was further illustrated in two adult Pompe patients with an unusually low enzyme activity. The mild clinical course is unexplained in these particular cases. The enzyme deficiency in all the different mutant cell lines was corrected by the uptake of bovine testis acid alpha-glucosidase from the culture medium. As a result of this, the lysosomal glycogen storage disappeared, and the balance between lysosomal and cytoplasmic glycogen was restored to normal. The implications of this study as a model for enzyme replacement therapy are discussed.

Cell Fractionation↗
PubMed1984

Hepatocellular glycogenosis and related pattern of enzymatic changes during hepatocarcinogenesis.

Systematic studies of the sequence of cellular changes during hepatocarcinogenesis induced predominantly in rats by stop experiments with N-nitrosomorpholine (NNM) led to the following main results and conclusions: The development of hepatocellular tumors is preceded by a multifocal hepatic glycogen storage disease (glycogenosis). Cytomorphological and cytochemical findings suggest a sequence of focal changes leading from clear and acidophilic glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. The clear and acidophilic glycogen storage cells persisting after withdrawal of the carcinogen apparently represent a preneoplastic cell population, the neoplastic transformation of which is accompanied by a gradual reduction of glycogen and a concomitant increase in ribosomes (basophilia). The first appearance and frequency of the different liver lesions investigated was shown to depend on the dose of carcinogen administered. With increasing dose of NNM, the number of focal lesions considerably increased, and this was accompanied by an earlier development of mixed and basophilic cell populations. There was no indication of any reversibility of pronounced focal lesions under the experimental conditions chosen. On the contrary, the foci became larger and acquired phenotypic markers closer to neoplasia independent of further action of the carcinogen. Enzyme histochemically, the majority of the pronounced glycogen storage foci showed a reduction in the activities of glycogen phosphorylase and glucose-6-phosphatase while the activity of glucose-6-phosphate dehydrogenase, a key enzyme for the pentose phosphate pathway, was increased. The mixed cell foci, neoplastic nodules and carcinomas which emerged at later stages were characterized by a progressive shift away from glycogen metabolism towards glycolysis and the pentose phosphate pathway. as indicated by an increase in glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase activities. These changes in enzyme pattern are in keeping with a developmental sequence leading from glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. Biochemical microanalysis of dissected glycogen storage foci and mixed cell foci revealed that the foci composed exclusively of storage cells contained on an average 100% more glycogen than the normal liver tissue. The overall glycogen content of the mixed cell foci, which were composed of both glycogenotic and glycogen-poor basophilic cells, was not distinguishable from that of normal tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Cell-free translation of human lysosomal alpha-glucosidase: evidence for reduced precursor synthesis in an adult patient with glycogenosis type II.

Early events in the biosynthesis of alpha-glucosidase (EC 3.2.1.20) were studied in a wheat-germ cell-free translation system, using control and mutant RNA. In vitro, the primary translation product of the alpha-glucosidase mRNA is a 100 kDa protein. When canine microsomal membranes are added to the translation system, the nascent alpha-glucosidase precursor is cotranslationally transported across the microsomal membranes, yielding a 110 kDa glycosylated form. This protein has the same electrophoretic characteristics as the alpha-glucosidase precursor observed after in vivo labeling of control fibroblasts. Inhibition of glycosylation in vivo by tunicamycin or deglycosylation of the in vivo synthesized alpha-glucosidase precursor by glycopeptidase F reveals a core protein similar in molecular mass to the primary translation product. Total RNA from a patient with the adult form of glycogenosis type II is not able to direct the synthesis of normal amounts of alpha-glucosidase in vitro. Northern blot analysis of the RNA, using cloned alpha-glucosidase cDNA sequences as a probe, demonstrates that in this patient the amount of the 3.4 kb alpha-glucosidase mRNA is highly reduced. The results indicate that the synthesis or stability of the mRNA is affected.

Cell-Free System↗
PubMedDate not supplied

Quantitative histological study of the sural nerve in a child with acid maltase deficiency (glycogenosis type II).

A boy diagnosed as having glycogenosis type II at three years of age, underwent a sural nerve biopsy at the age of seven years. The distribution of the diameters of myelinated nerve fibers did not clearly demonstrate a bimodal pattern. However, larger fibers of 8 microns or more in diameter were more abundant. This finding correlated with the motor conduction velocity which was within normal limits for his age. A striking feature was the accumulation of glycogen particles in Schwann cells of both myelinated and unmyelinated nerve fibers. The accumulation of glycogen particles was more prominent in Schwann cells of myelinated nerve fibers than in those of unmyelinated ones. The reason for this finding is unclear. The accumulation of glycogen particles in nerve fibers was less than that found in muscle fibers. These morphologic differences between muscle and peripheral nerve fibers may represent an intrinsic difference between the two tissues; glycogen turnover may be faster in muscle than in nerve cells.

Biopsy↗
PubMed2004

Glycogenosis type II: identification and expression of three novel mutations in the acid alpha-glucosidase gene causing the infantile form of the disease.

Glycogenosis type II (GSDII) is an autosomal recessive disorder due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). We identified three novel point mutations, C399A, T1064C, and C2104T, in three unrelated Italian patients with the infantile form of the disease. The C399A mutation was present in homozygosity in proband 1. The C >A transition introduces a premature stop signal in exon 2 resulting in no enzyme production that is correlated with the severe clinical phenotype in this patient. The other two nucleotide changes were missense mutations. The T1064C mutation, which changes Leu in position 355 into Pro, was carried in homozygosity by proband 2. The C2104T nucleotide change, which substitutes Arg 702 into Cys, was present in proband 3 in combination with a known severe mutation DeltaI17-18. The in vitro expression in COS-1 cells of T1064C and C2104T constructs demonstrated no enzymatic activity with respect to the negative control cells. Western blot analysis revealed that both T1064C and C2104T mutant proteins produced in COS-1 cells migrated in SDS-PAGE as the GAA inactive precursor of 110kDa. Immunofluorescence detection of mutant alpha-glucosidases showed enzyme localization primarily in the ER-Golgi compartment, suggesting that T1064C and C2104T mutations could affect the normal processing and stability of the enzyme. In vitro studies demonstrated that the same degree of deficiency in T1064C and C2104T mutations, which is in contrast with patient phenotype. A better correlation was observed with the in vivo studies since proband 2, with a less severe phenotype, presented with low residual enzyme activity while in proband 3, with a classic severe infantile onset GSDII, fibroblast enzyme activity was completely absent.

Animals↗
PubMed1976

Portacaval shunt in siblings for type I glycogenosis.

The paper reports two siblings with type I glycogenosis, presenting supportive laboratory data before and after 1 mo of central venous nutrition and later after surgical portal diversion. Both children dramatically improved with central venous nutrition, allowing safe and technically easy portacaval shunts to be constructed. Their smooth postoperative courses are documented. Currently, both patients are at home pursuing relatively normal lives.

Child↗
PubMed1995

Phosphorylase b kinase deficiency glycogenosis with cirrhosis of the liver.

We describe an Arab girl with complete absence of phosphorylase b kinase activity in the liver, symptomatic hypoglycemia, and persistently elevated serum aminotransferase values whose symptoms did not lessen with age; sequential liver biopsies showed progression to cirrhosis. Cirrhosis could not be ascribed to any other known cause. We conclude that type IX glycogenosis is not always associated with a benign outcome.

Child, Preschool↗
PubMed1980

Glycogenosis type I (glucose 6-phosphatase deficiency): I. Ultrastructural morphometric analysis of juvenile liver cells.

The essential biochemical characteristic of von Gierke's disease is an inborn glucose-6-phosphatase deficiency and glycogen storage in the liver and kidney. This expresses itself morphometrically as an increased volume of glycogen per unit volume of the hepatocellular cytoplasm. Since glucose-6-phosphatase activity in patients studied is practically at the zero level, and the endoplasmic reticulum loses a large part of its membrane values, we conclude that the remaining endoplasmic reticulum represents glucose-6-phosphatase free membranes. A typical structural feature of the endoplasmic reticulum in von Gieke's disease is the appearance of "double contoured vesicles" (= pockets). These vesicles comprise approximately 3,5% of the total membrane system. The mitochondria play an important role in glycolysis and glycogen synthesis. It is thus to be expected that these organelles change in terms of their morphometric parameters in the course of glycogenosis type I. An important point in this direction is numerical mitochondrion reduction in combination with an unchanged mitochondrial volume.

Child, Preschool↗
PubMed2003

Efficacy of multidisciplinary approach in the treatment of two cases of nonclassical infantile glycogenosis type II.

Glycogenosis type II (GSD II) is a lysosomal storage disorder due to acid alpha-glucosidase deficiency. We report the results of a clinical multidisciplinary approach in two cases of nonclassical infantile GSD II. The patients received a high-protein diet by percutaneous enteral gastrostomy (PEG), mechanical ventilatory support by tracheostomy and a physiotherapy programme. After 12 months of treatment, the patients showed significant improvement in muscular strength, nutritional state and respiratory function. Electrocardiography (ECG) and echocardiography improved in both patients. They maintained good clinical conditions for a period of 18 and 20 months, respectively; thereafter they presented with an elevated and persistent fever that was not correlated to a septic status and was not responsive to any antipyretic treatment. They deteriorated progressively and died. This study shows how a multidisciplinary approach may be useful to improve, even if temporarily, the clinical course of nonclassical infantile GSD II.

Child, Preschool↗
PubMed1981

Skeletal-muscle alpha-glucosidases in bovine generalized glycogenosis type II.

The skeletal muscle of cattle suffering from generalized glycogenosis type II was shown to lack acid alpha-glucosidase (EC 3.2.1.3) activity. Furthermore, there was no evidence of enzymically inactive proteins that cross-reacted with antibodies raised against acid alpha-glucosidase from the muscle of normal animals.

Animals↗
PubMed2001

Liver transplantation for type Ib glycogenosis with reversal of cyclic neutropenia.

We describe a case of glycogen storage disease type Ib in 32-year old male patient with poor metabolic control in spite of medical and nutritional management and the use of recombinant granulocyte stimulating factor. Because of this, liver transplantation was considered as a definitive treatment. We comment on the metabolic results of liver transplantation performed, with reversal of hypoglycemia, hyperuricemia, hypertriglyceridemia and cyclic neutropenia, all of which persist 4 years post-transplant. In view of this case, we believe that liver transplantation is a feasible option to consider in patients with type Ib glycogenosis as a definitive therapeutic procedure.

Adult↗
PubMedDate not supplied

Hydropericardium causing sudden infant death in glycogenosis type I: osmotic injury due to percutaneous silastic catheterization.

BACKGROUND: The aim of this case report and the review of the literature is to demonstrate dangers when using peripherial silastic catheters in preterm and term newborns or infants. PATIENT, METHODS AND RESULTS: We report on a female infant with glycogenosis type I a (MIM 232200) due to glucose 6-phosphatase deficiency (homozygosity for R170X) and sudden infant death at the age of 9 months due to a rare catheter complication (hydropericardium with tamponade without perforation). CONCLUSION: We believe that this fatal complication was caused by local osmotic dysbalance due to direct contacts between atrial wall and the catheter tip. There is no relation known between patients with inborn errors of metabolism complicated by metabolic derangement and higher incidences of mechanical or non-mechanical catheter complications.

Cardiac Catheterization↗
PubMed1979

Genetics of type II glycogenosis: assignment of the human gene for acid alpha-glucosidase to chromosome 17.

We have studied somatic cell hybrids between thymidine kinase (EC 2.7.1.75) deficient mouse cells and human diploid fibroblasts for the expression of human acid alpha-glucosidase (EC 3.2.1.20). A deficiency in this enzyme is associated with the type II glycogenosis or Pompe disease. All 30 somatic cell hybrids selected in hypoxanthine/aminopterin/thymidine medium expressed human acid alpha-glucosidase and galactokinase (EC 2.7.1.6) and retained human chromosome 17; counterselection of the same hybrids in medium containing 5-bromodeoxyuridine resulted in the growth of hybrids that concordantly lost the expression of human acid alpha-glucosidase and galactokinase as well as human chromosome 17. Hybrids between thymidine kinase-deficient mouse cells and fibroblasts from a patient with Pompe disease that contained human chromosome 17 were found not to express human acid alpha-glucosidase. Because we have already shown that hybrids between mouse peritoneal macrophages and GM54VA simian virus 40-transformed human cells selectively retain human chromosome 17 and lose all other human chromosomes, we tested 13 independent mouse macrophage x GM54VA hybrid clones, including two that retained human chromosome 17 and no other human chromosomes, for the expression of human acid alpha-glucosidase and galactokinase. All 13 hybrid clones were found to express these human enzymes. Thus, we conclude that the gene coding for human acid alpha-glucosidase is located on human chromosome 17.

Animals↗
PubMed1999

Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II.

X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutations in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning >/=65 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.

Base Sequence↗