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PubMed1975

Glycogen phosphorylase and its converter enzymes in haemolysates of normal human subjects and of patients with type VI glycogen-storage disease. A study of phosphorylase kinase deficiency.

1. The properties of phosphorylase a, phosphorylase b, phosphorylase kinase and phosphorylase phosphatase present in a human haemolysate were investigated. The two forms of phosphorylase have the same affinity for glucose 1-phosphate but greatly differ in Vmax. Phosphorylase b is only partially stimulated by AMP, since, in the presence of the nucleotide, it is about tenfold less active than phosphorylase a. In a fresh human haemolysate phosphorylase is mostly in the b form; it is converted into phosphorylase a by incubation at 20degreesC, and this reaction is stimulated by glycogen and cyclic AMP. Once activated, the enzyme can be inactivated after filtration of the haemolysate on Sephadex G-25. This inactivation is stimulated by caffeine and glucose and inhibited by AMP and fluoride. The phosphorylase kinase present in the haemolysate can also be measured by the rate of activation of added muscle phosphorylase b, on addition of ATP and Mg2+. 2. The activity of phosphorylase kinase was measured in haemolysates obtained from a series of patients who had been classified as suffering from type VI glycogenosis. In nine patients, all boys, an almost complete deficiency of phosphorylase kinase was observed in the haemolysate and, when it could be assayed, in the liver. A residual activity, about 20% of normal, was found in the leucocyte fraction, whereas the enzyme activity was normal in the muscle. These patients suffer from the sex-linked phosphorylase kinase deficiency previously described by others. Two pairs of siblings, each time brother and sister, displayed a partial deficiency of phosphorylase kinase in the haemolysate and leucocytes and an almost complete deficiency in the liver. This is considered as being the autosomal form of phosphorylase kinase deficiency. Other patients were characterized by a low activity of total (a+b) phosphorylase and a normal or high activity of phosphorylase kinase in their haemolysate.

Adenosine Monophosphate↗

PubMed1983

Disturbance of lysosomal glycogen metabolism by liposomal anti-alpha-glucosidase and some anti-inflammatory drugs.

The size-distribution of liver glycogen was shown to be distinctly affected by the anti-inflammatory drugs salicylate and indomethacin. By measurement of the incorporation of radioactive glucose into glycogen, salicylate was shown to have a depressing effect on overall liver glycogen metabolism. These effects appear to arise from the stabilizing of the lysosome by the drugs. The incorporation, via liposomes, of purified anti-1,4-alpha-glucosidase activity and in the content of high-molecular-weight glycogen. These changes are increased by prolonged liposomal antibody treatment and suggest that a possible feedback control mechanism operates in the incorporation of glycogen into lysosomes. These experiments may be useful as a model of glycogen turnover and its failure in glycogenosis type II (Pompe's disease).

Acarbose↗

PubMed1985

Lysosomal glycogen storage induced by Acarbose, a 1,4-alpha-glucosidase inhibitor.

The 1,4-alpha-glucosidase inhibitor. Acarbose, when injected intraperitoneally disturbs liver lysosome metabolism, causing distinct and persistent inhibition of the enzymes and acute disturbances of lysosomal glycogen metabolism. A feedback control mechanism appears to operate, affecting cytosolic carbohydrate metabolism. A model is suggested for the adult form of lysosomal storage disease. The biochemical effects closely resemble those occurring in glycogenosis type II (Pompe's disease), and these have been confirmed by electron microscopy.

Acarbose↗

PubMed1990

Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalian cells.

Previously isolated lysosomal alpha-glucosidase cDNA clones were ligated to full-length constructs for expression in vitro and in mammalian cells. One of these constructs (pSHAG1) did not code for functional enzyme, due to an arginine residue instead of a tryptophan residue at amino acid position 402. The mutation does not affect the rate of enzyme synthesis, but interferes with post-translational modification and intracellular transport of the acid alpha-glucosidase precursor. Using immunocytochemistry it is demonstrated that the mutant precursor traverses the endoplasmic reticulum and the Golgi complex, but does not reach the lysosomes. Pulse-chase experiments suggest premature degradation. The Trp-402-containing enzyme (encoded by construct pSHAG2) is processed properly, and has catalytic activity. A fraction of the enzyme is localized at the plasma membrane. It is hypothesized that membrane association of the acid alpha-glucosidase precursor, as demonstrated by Triton X-114 phase separation, is responsible for transport to this location. Transiently expressed acid alpha-glucosidase also enters the secretory pathway, since a catalytically active precursor is found in the culture medium. This precursor has the appropriate characteristics for use in enzyme replacement therapy. Efficient uptake via the mannose 6-phosphate receptor results in degradation of lysosomal glycogen in cultured fibroblasts and muscle cells from patients with glycogenosis type II.

Animals↗

PubMed1998

Decreased activity of acid alpha-glucosidase in a patient with persistent periocular swelling after infusions of hydroxyethyl starch.

After infusion therapy with hydroxyethyl starch (HES) on account of sudden hearing loss, a 68-year-old woman developed a marked and persistent periocular swelling. This extraordinary adverse effect caused us to search for an explanation by means of histopathology, immunohistochemistry, immunoelectron microscopy and biochemistry. In lesional periocular skin and in normal-appearing skin, lysosomal storage of HES could be detected with a specific HES antibody in histiocytes, endothelial cells, basal keratinocytes and small nerves. In the periocular skin, a stronger deposition of HES was found in addition to distinct xanthomatous changes as well as features of lymphoedema. In view of lysosomal HES storage we measured the pH-dependent activity of the lysosomal alpha-glucosidase (GAA) in cultured fibroblasts. We found a 50% decreased activity of the acid GAA, which is consistent with a heterozygous state of glycogenosis type II (Pompe's disease) and potentially of pathogenetic relevance for the intralysosomal accumulation of HES. Xanthomatous changes and lymphoedema are likely to be secondary effects, but contribute considerably to the clinical manifestation of persistent visible swelling. This observation could point to a role for GAA in the elimination of tissue-stored HES. Patients with decreased activities of GAA may be at risk of unusual adverse effects following extraordinary and prolonged tissue storage of HES, especially if it is infused in large quantities.

Aged↗

PubMed2000

Metabolic cardiomyopathies.

The energy needed by cardiac muscle to maintain proper function is supplied by adenosine Ariphosphate primarily (ATP) production through breakdown of fatty acids. Metabolic cardiomyopathies can be caused by disturbances in metabolism, for example diabetes mellitus, hypertrophy and heart failure or alcoholic cardiomyopathy. Deficiency in enzymes of the mitochondrial beta-oxidation show a varying degree of cardiac manifestation. Aberrations of mitochondrial DNA lead to a wide variety of cardiac disorders, without any obvious correlation between genotype and phenotype. A completely different pathogenetic model comprises cardiac manifestation of systemic metabolic diseases caused by deficiencies of various enzymes in a variety of metabolic pathways. Examples of these disorders are glycogen storage diseases (e.g. glycogenosis type II and III), lysosomal storage diseases (e.g. Niemann-Pick disease, Gaucher disease, I-cell disease, various types of mucopolysaccharidoses, GM1 gangliosidosis, galactosialidosis, carbohydrate-deficient glycoprotein syndromes and Sandhoff's disease). There are some systemic diseases which can also affect the heart, for example triosephosphate isomerase deficiency, hereditary haemochromatosis, CD 36 defect or propionic acidaemia.

Adult↗

PubMed2006

Ground-glass, polyglucosan-like hepatocellular inclusions: A "new" diagnostic entity.

BACKGROUND & AIMS: Ground-glass (GG) inclusions within hepatocytes are an important histopathologic marker of chronic hepatitis B virus (HBV) infection but may also be seen in Lafora's disease (myoclonus epilepsy), cyanamide alcohol aversion therapy, and type IV glycogenosis. We have noted a recent increased incidence of liver biopsy and postmortem specimens with GG inclusions associated with none of these etiologic factors. This study was undertaken to further delineate the clinical and liver pathologic features in such cases and their possible pathogenesis. METHODS: Ten cases with GG inclusions (8 biopsy, 2 postmortem) were examined by light and electron microscopy, and the patients' clinical records were reviewed. RESULTS: Light microscopy demonstrated pale pink, oval to crescentic intracytoplasmic inclusions with a predilection for periportal hepatocytes but sometimes present throughout the lobules. The inclusions were intensely positive on periodic acid-Schiff stain and digested with diastase. Transmission electron microscopy of two cases showed non-membrane-bound cytoplasmic collections of granules with mild-to-moderate electron density, consistent with abnormal glycogen granules. The patients included 7 transplant recipients (liver, hematopoietic stem cell), 3 with type 2 diabetes and a child on chronic parenteral nutrition for short bowel syndrome. Medications included immunosuppressive agents, antibiotics, and insulin. CONCLUSIONS: GG hepatocellular inclusions may be seen in individuals without HBV infection or other recognized etiologies, appear to be composed of abnormal glycogen and closely resemble polyglucosan bodies described in humans, animals, and experimental models. The possible pathogenetic roles of disturbed glycogen metabolism and polypharmacotherapy are stressed.

Adolescent↗

PubMed1977

Neuropathy in a patient with McArdle's syndrome and diabetes mellitus.

A juvenile-type diabetic patient of five years standing presented with a mononeuritis and gave a history of painful muscle swelling induced by exertion. Failure of the blood lactate to rise during ischaemic exercise and a normal blood glucose rise following intravenous glucagon confirmed the clinical diagnosis of muscle glycogenosis. The association of diabetes and McArdle's Syndrome has not previously been documented. An ulnar nerve palsy, which persisted for many months, followed the ischaemic exercise test possibly due to compression by muscular swelling, but may have been exacerbated by the co-existing diabetes.

Adult↗

PubMed2002

[26-year-old female patient with elevated liver enzymes].

A 26-year-old woman presented with elevated liver enzymes, which were diagnosed two months ago. Examination revealed mild proximal muscle weakness, though the patient herself did not realise any impairment. The abdominal ultrasound and the histology of the liver remained unsuspicious. Muscle biopsy showed vacuolar degeneration, which could be ultrastructurally identified as large deposits of membrane-bound glycogen. The morphological findings prompted biochemical investigations which showed an excess of muscle glycogen. Acid maltase activity was reduced to < 10 % of normal, leading together with the clinical findings to the diagnosis of glycogenosis type II (Pompe's disease) of the adult type. Because of the modest impairment of the patient and the limited therapeutic possibilities, the patient remained thus untreated for.

Adult↗

PubMed1995

[The value of in-vivo 31-phosphorus spectroscopy in the diagnosis of generalized muscular diseases. The clinical results and the differential diagnostic aspects].

PURPOSE: In a prospective study, characteristics and the diagnostic potential of in vivo 31-phosphorus spectroscopy in cases of generalised muscle diseases were analysed. METHOD: 41 patients with myogenic and neurogenic muscle diseases and 11 healthy volunteers were examined using MRI and in vivo 31-phosphorus spectroscopy by means of a 50 mm double-tuned surface coil. RESULTS: The spectra showed significant changes of the metabolite ratios depending on the degree of the disease. Inflammatory muscle diseases were characterised by increased PME and PDE peaks, which indicates that there is a higher conversion of the cell membrane. The spectra of muscular dystrophy showed a slight increase of PDE and Pi. A strongly reduced PCr and an increased Pi peak were demonstrated in cases of muscle atrophy depending on their degree of markedness. The pH values were minimally increased in comparison to the volunteers. In other muscle diseases, such as glycogenosis or myotonia, no significant changes were detected. CONCLUSION: Standardised in vivo 31-phosphorus spectroscopy of generalised muscle diseases provides noninvasive prognostic information on the type and behaviour of the disease and is complementary to clinical and histological findings.

Adolescent↗

PubMedDate not supplied

[Fanconi-Bickel syndrome].

The Fanconi-Bickel syndrome is characterized by tubular dysfunction, impaired metabolism of glucose and galactose and glycogenosis. Up to now the data of nineteen patients have been reported. In the following case firstly an abnormal body composition is described measuring the concentration of Potassium-40 with a Whole Body Radiation Counter. Before therapy an increased value of total body cell mass but no value of total body fat is measured. After therapy body weight increased while cell mass decreased and a value of fat had been observed. Concerning renal parameters a 60 fold elevation of the beta 2-microglobulin-clearance is noted.

Body Constitution↗

PubMed2002

Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey.

OBJECTIVE: To estimate at the national level the overall and disease-specific incidence of inborn errors of metabolism not mass screened at birth. STUDY DESIGN: Prospective nonconcurrent study (1985-1997) on patients 0 to 17 years of age, diagnosed in 23 Italian pediatric reference centers. RESULTS: Cases (n = 1935) were recruited representing an incidence of 1:3707 live births for approximately 200 diseases. In the last 5 years the incidence was 1:2758, reflecting improved diagnostic facilities, better coverage, increased medical awareness, and newly discovered diseases. In this period, the most frequent classes of diseases were lysosomal storage disease, 1:8275; disorders of carbohydrate metabolism, 1:19,532; organic acidopathies, 1:21,422; and primary lactic acidemias, 1:27,106. The most frequent individual diseases were Gaucher type I, 1:40,247; glycogenosis type 1a, 1:57,746; methylmalonic acidurias, 1:61,775; and ornithine transcarbamylase deficiency, 1:69,904. The incidence of diseases potentially identifiable with the use of a new neonatal mass screening technique is 1:6200. Of surviving patients, 11% reached adulthood by the end of the study. CONCLUSIONS: Inborn errors of metabolism constitute a highly heterogeneous category of rare diseases, representing a relevant cause of morbidity and mortality in childhood. This study quantifies the minimum size of the disease burden, providing useful tools for public health and health policy planning.

Adolescent↗

PubMed1995

Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenazi Jewish patients with Tarui disease.

Mutations in the human phosphofructokinase muscle subunit gene (PFKM) are known to cause myopathy classified as glycogenosis type VII (Tarui disease). Previously described molecular defects include base substitutions altering encoded amino acids or resulting in abnormal splicing. We report a mutation resulting in phosphofructokinase deficiency in three patients from an Ashkenazi Jewish family. Using a reverse transcription PCR assay, PFKM subunit transcripts differing by length were detected in skeletal muscle tissue of all three affected subjects. In the longer transcript, an insertion of 252 nucleotides totally homologous to the structure of the 10th intron of the PFKM gene was found separating exon 10 from exon 11. In addition, two single base transitions were identified by direct sequencing: [exon 6; codon 95; CGA (Arg) to TGA (stop)] and [exon 7; codon 172; ACC (Thr) to ACT (Thr)] in either transcript. Single-stranded conformational polymorphism and restriction enzyme analyses confirmed the presence of these point substitutions in genomic DNA and strongly suggested homozygosity for the pathogenic allele. The nonsense mutation at codon 95 appeared solely responsible for the phenotype in these patients, further expanding genetic heterogeneity of Tarui disease. Transcripts with and without intron 10 arising from identical mutant alleles probably resulted from differential pre-mRNA processing and may represent a novel message from the PFKM gene.

Aged↗

PubMed2002

The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway.

Acid alpha-glucosidase (GAA) is a lysosomal enzyme that degrades glycogen. A deficiency of GAA is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenosis type II. Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells. Hes-1 is a well studied downstream target gene in the Notch signaling pathway. In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling. In co-transfection experiments, Hes-1, up-regulated by over-expressed NICD, enhanced the repressive effect of the DNA element with wild type Hes-1 binding sites but not with mutant Hes-1 binding sites. Conversely, depletion of Notch-1 with phosphorothioated antisense oligonucleotides, corresponding to the fourth ankyrin repeat within NICD, led to reduced Hes-1. Constitutively over-expressed Hes-1 and Notch-1 repressed GAA gene expression. Therefore, our data establish that the human GAA gene, encoding a lysosomal enzyme, is a downstream target of the Notch-1/Hes-1 signaling pathway.

Base Sequence↗

PubMed2003

The myopathology of floppy and hypotonic infants in Singapore.

AIMS: This study attempts to determine the type and relative frequency of muscle diseases contributing to floppy and hypotonic infants in Singapore. METHODS: Eighty consecutive muscle biopsies in the Department of Pathology, National University of Singapore, in the period 1978-2000, in which a clinical diagnosis of floppy or hypotonic infant was made, were reviewed. RESULTS: The commonest cause of severe hypotonia in infancy was spinal muscular atrophy, which accounted for 33% of cases followed by congenital muscular dystrophy (13%). Eight cases (10%) of infantile type II glycogenosis (Pompe's disease) were encountered. There were seven cases of congenital myopathy, of which four were centronuclear myopathy, and one each of central core myopathy, nemaline myopathy and congenital fibre type disproportion. One case of centronuclear myopathy was associated with type I fibre smallness. Type II atrophy, which is generally considered a non-specific change, was encountered in five cases. Of interest is the relatively large number of muscle biopsies (29%) in which no significant pathological features were encountered at the light microscopic, histochemical as well as ultra-structural level. CONCLUSIONS: The study has revealed a great variety of pathology affecting the muscle of children presenting as floppy infants or with hypotonia. The muscle diseases included spinal muscular atrophy, congenital muscular dystrophies, congenital myopathies and metabolic myopathies. However, 23 (29%) cases showed no significant pathology. For this group of floppy and hypotonic infants further studies are needed.

China↗

PubMed1977

Effect of insulin on ultrastructure and glycogenesis in primary cultures of adult rat hepatocytes.

Insulin in the presence of high concentrations of glucose has a beneficial trophic effect on the development of primary cultures of hepatocytes. Compared to the situation observed in hormone-free control cultures, the flattening of the reaggregated hepatocytes is enhanced, and the reconstituted cell trabeculae are enlarged and tend to form a confluent monolayer after 3 days; the survival time is prolonged from 3 to 5 or 6 days. Ultrastructural modifications are also initiated by insulin; numerous glycogen particles appear after 24 h, in between the cisternae of the proliferated smooth endoplasmic reticulum. After 48 h, large amounts of glycogen are stored, and numerous polysomes are present. A small number of cells showed an increased synthesis of lipid droplets in the lumen of the smooth endoplasmic reticulum and form liposomes at the same time. After 72 h, cytolysomes filled with glycogen develop, simulating glycogenosis type II. Simultaneously, microtubules and microfilaments, closely related to numerous polysomes, appear in cytoplasmic extensions constituting undulating membranes. The biochemical data demonstrate that, in the absence of insulin, a high concentration of glucose stimulates glycogenesis and hinders glycogenolysis. This effect of glucose on polysaccharide synthesis is progressively lost. The addition of insulin to the culture induces after 48 and 72 h, a three- to fivefold increase of the glucose incorporation into glycogen, as compared to the controls. The presence of insulin is required to maintain the hepatocyte's capacity to store glycogen. Glycogen synthetase is converted into its active form under the influence of glucose. Insulin increases the rate of activation.

Cells, Cultured↗

PubMed1998

Adenovirus-mediated transfer of human acid maltase gene reduces glycogen accumulation in skeletal muscle of Japanese quail with acid maltase deficiency.

Acid maltase deficiency (AMD) causes a lysosomal glycogenosis inherited as an autosomal recessive trait. The infantile type of AMD (Pompe disease) leads to early death due to severe dysfunction of cardiac and respiratory muscles and no effective therapy is available. Replication-defective adenovirus vectors offer a promising tool for in vivo gene delivery and gene therapy. We constructed a recombinant adenovirus containing the human acid maltase (AM) cDNA downstream of the CAG promoter, composed of modified chicken beta-actin promoter and CMV IE enhancer (AxCANAM). Japanese quail with AMD was used for this study as an animal model for human AMD. When cultured fibroblasts from AMD quail were infected with AxCANAM, AM activity in the cells increased in proportion to the multiplicity of infection (MOI). When AxCANAM (4.5 x 10(8) PFU) was injected into unilateral superficial pectoral muscle of AMD quail, PAS staining showed that glycogenosomes disappeared and stainability of acid phosphatase was reduced in the injected area as compared with the contralateral muscle of the same birds. Biochemically, AM activity increased and glycogen content decreased in the injected muscle. Western blot analysis showed that AMD quail muscle injected with AxCANAM expressed human AM protein processed to active forms. These results suggest that the human AM cDNA transferred by an adenovirus vector was sufficiently expressed, leading to a marked reduction of the glycogen accumulation in the skeletal muscle of AMD quail.

Adenoviridae↗

PubMed1994

Cell proliferation and cell death (apoptosis) in hepatic preneoplasia and neoplasia are closely related to phenotypic cellular diversity and instability.

Preneoplastic and neoplastic hepatic lesions were induced in male Sprague-Dawley rats by oral exposure to N-nitrosomorpholine (12 mg/kg body wt/day) for 7 weeks (stop model). Twelve, 23 and 34 weeks after withdrawal of the carcinogen, cell proliferation and cell death (apoptosis) were studied in defined phenotypes of preneoplastic foci of altered hepatocytes (FAH), hepatocellular adenomas (HCA) and carcinomas (HCC) by autoradiographic determination of the labelling index (LI) resulting from continuous administration of [3H]thymidine for 48 h and by simultaneous counting of apoptotic bodies respectively. Compared with the liver parenchyma of untreated controls and the extrafocal parenchyma of treated animals, the mean LI was elevated in all types of FAH, HCA and HCC, but the extent of this increase differed markedly between the diverse phenotypes. The increase in the LI was significant for clear/acidophilic, intermediate and mixed/basophilic cell foci, but remained insignificant for the relatively rare tigroid and amphophilic cell foci. The previously established progression-linked phenotypic instability in the predominant cell lineage leading to HCC was associated with a gradual increase in the mean LI showing four significantly different proliferative stages: (i) clear/acidophilic and intermediate cell foci excessively storing glycogen, (ii) mixed/basophilic cell populations in FAH and glycogen-storing HCA, (iii) glycogen-poor HCA and glycogen-storing HCC and (iv) glycogen-poor HCC. The inverse correlation between glycogen accumulation and cell proliferation during progression from glycogenotic FAH to glycogen-poor HCC indicates that the fundamental metabolic shift associated with the gradual disappearance of the glycogenosis is essential for the evolution of the malignant phenotype. The mean ratio of necrotic cells (RN) was somewhat higher in all types of FAH compared to the normal and extrafocal liver parenchyma, but this was not statistically significant. Only when HCA and HCC appeared was there a significant increase in the mean RN, proceeding with the progression of neoplastic development. Our results do not support the concept that cell death (apoptosis) plays a major role in counterbalancing cell replication in FAH, but rather suggest that cell death occurs more frequently in the course of hepatocarcinogenesis the more neoplastic development advances.

Animals↗