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At least 775 records · Page 43Linked to original sources
PubMed1981

Lysosomal glycogen storage mimicking the cytological picture of Pompe's disease as induced in rats by injection of an alpha-glucosidase inhibitor. I. Alterations in liver.

The present paper describes an animal model of lysosomal glycogenosis as induced by a competitive inhibitor of alpha-glucosidase. Rats received intraperitoneal injections of the inhibitor, a pseudotetrasaccharide (Acarbose, Bay g 5421); liver tissue was examined by light and electron microscopy. Substrate-histochemical and enzyme-cytochemical methods were used to demonstrate intralysosomal glycogen storage within hepatocytes and Kupffer cells. The cytological picture closely resembled that occurring in glycogenosis type II (Pompe's disease) of humans. After cessation of drug treatment, the glycogen storage was slowly reversible. The present results point to the physiological role of the lysosomal apparatus for intracellular glycogen turnover. On the cellular level, this experimentally induced glycogenosis may be useful as a model of Pompe's disease.

Acarbose↗
PubMed1988

Receptor-mediated uptake of acid alpha-glucosidase corrects lysosomal glycogen storage in cultured skeletal muscle.

Attempts at treatment of glycogenosis type II and other lysosomal storage disorders by enzyme replacement have been reported. Parenteral enzyme administration has been ineffectual. Treatment by bone marrow transplantation is currently under investigation. We have used cultured skeletal muscle cells from a patient with infantile glycogenosis type II to study fundamental aspects of enzyme replacement therapy. Efficient uptake of acid alpha-glucosidase was achieved by using the mannose-6-phosphate receptor on the cell surface as a target for an enzyme precursor with phosphorylated high-mannose types carbohydrate chains purified from human urine. We found that the enzyme was channeled to the lysosomes and converted to mature acid alpha-glucosidase. Glycogen storage was reversed. The results are discussed in relation to treatment of glycogenosis type II.

Carrier Proteins↗
PubMed1987

Juvenile polysaccharidosis with cardioskeletal myopathy.

Polysaccharidoses with ultrastructural features reminiscent of glycogenosis type IV, but without enzymatic correlation, have been observed in several adolescent and adult patients. Little is known of the clinical, pathologic, or biochemical nature of these disorders. We describe a patient with ultrastructural characteristics consistent with glycogenosis type IV, but with normal brancher enzyme activity in dermal fibroblasts and cardiac muscle. During life and at autopsy, electron microscopy revealed amylopectin-like polysaccharide deposits present in a wide variety of tissues. The polysaccharidosis of our patient and similar patients may be a variant of glycogenosis type IV with a yet to be defined enzymatic defect.

Biopsy↗
PubMed1980

[Glycogen storage disease type I with normal in vitro activity of glucose-6-phosphatase (author's transl)].

A 4.5 months old girl was suspected to have Glycogenosis type I because of hepatomegalie and recurrent hypoglycemia. Liverbiopsy revealed a normal glycogen content and a normal in vitro activity of glucose-6-phosphatase. We then examined the carbohydrate metabolism and could demonstrate that in vitro the transfer of glucose-6-phosphate to glucose was blocked. We therefore conclude that a normal in vitro activity of glucose-6-phosphatase does not rule out the diagnosis of Glycogenosis type I. Evaluation of carbohydrate metabolism is an important tool in marking the diagnosis. We suggest to use the term Glycogenosis type I B, which some institutions already use for this disorder.

Biopsy↗
PubMed1993

Acid maltase deficiency in childhood. Early diagnosis and clinical follow-up of late-onset glycogen storage disease type II.

A case is described of late-onset glycogenosis type II presenting with an isolated rise in serum transaminase levels. Histological, histochemical, ultrastructural and biochemical examinations performed on muscle biopsy showed the typical laboratory features of late-onset glycogenosis type II, which was diagnosed more than four years before the first appearance of disease-related signs and symptoms. A heterozygote status for the same defect was also demonstrated by enzyme assays in both parents, thus confirming the autosomal recessive mode of inheritance of the disorder. Even though an elevation in transaminases and other serum enzymes of possible muscle origin has been previously described as a diagnostic clue in some unsuspected muscular diseases in childhood, as far as we know no other patient with a sporadic form of glycogenosis type II has been identified when still completely asymptomatic. The possibility of silent primary metabolic diseases and myopathies should be carefully considered when evaluating children with persistently elevated serum transaminases, even in the absence of suggestive anamnestic, familial and physical findings, in order to obtain an early diagnosis and to provide an appropriate genetic counselling.

Age of Onset↗
PubMed1977

Glycogen storage disease: new approaches to therapy.

Detailed studies of the effect of 32 days of intravenous alimentation on the metabolic, hormonal and clinical status of a 4-year-old boy with Type I glycogenosis revealed that the biochemical abnormalities and growth failure in this disorder are a consequence of glucose lack after brief periods of fasting which results from the inborn enzyme deficiency. Long-term (1.5-5.7 years) observations of the therapeutic effects of portacaval shunt without and with continuous overnight intragastic glucose by gastrostomy in two brothers, and of continuous overnight intragastric glucose alone in five other patients with this disorder, on metabolic status and physical growth and development suggest that adequate glucose can be provided by the intragastric route without hepatic portal circulatory by-pass. The introduction of this therapy in the first year of life should prevent the serious risk to life and long-term failure in growth and development previously observed in patients with Types I and III glycogenosis.

Child↗
PubMed1988

Primary structure and processing of lysosomal alpha-glucosidase; homology with the intestinal sucrase-isomaltase complex.

Lysosomal alpha-glucosidase (acid maltase) is essential for degradation of glycogen in lysosomes. Enzyme deficiency results in glycogenosis type II. The amino acid sequence of the entire enzyme was derived from the nucleotide sequence of cloned cDNA. The cDNA comprises 3636 nt, and hybridizes with a messenger RNA of approximately 3.6 kb, which is absent in fibroblasts of two patients with glycogenosis type II. The encoded protein has a molecular mass of 104.645 kd and starts with a signal peptide. Sites of proteolytic processing are established by identification of N-terminal amino acid sequences of the 110-kd precursor, and the 76-kd and 70-kd mature forms of the enzyme encoded by the cDNA. Interestingly, both amino-terminal and carboxy-terminal processing occurs. Sites of sugar-chain attachment are proposed. A remarkable homology is observed between this soluble lysosomal alpha-glucosidase and the membrane-bound intestinal brush border sucrase-isomaltase enzyme complex. It is proposed that these enzymes are derived from the same ancestral gene. Around the putative active site of sucrase and isomaltase, 10 out of 13 amino acids are identical to the corresponding amino acids of lysosomal alpha-glucosidase. This strongly suggests that the aspartic acid residue at this position is essential for catalytic function of lysosomal alpha-glucosidase.

Amino Acid Sequence↗
PubMed1985

Myopathies due to enzyme deficiencies.

After the discovery in 1959 of myophosphorylase deficiency, at least 15 myopathies due to deficiency of enzymes involved in energy substrate utilization have been described. In this review two main categories of enzymopathies, glycogenosis and mitochondrial disorders, are discussed. Clinically, the patients with these categories of enzyme defects present two major syndromes: acute recurrent muscle impairment, generally related to exercise, associated with cramps and/or myoglobinuria; progressive muscular weakness and wasting eventually associated with signs of affected organs other than skeletal muscle. Defects of glycogen breakdown and of the first step of glycolysis are more frequently associated with acute exercise intolerance, such as in myophosphorylase and phosphofructokinase deficiencies, but may be associated with progressive muscle weakness and wasting, such as in acid maltase and debrancher enzyme deficiency. Clinical heterogeneity is common in these disorders, but a biochemical explanation for their different clinical expression is still lacking. Defects of the second step of glycolysis, phosphoglycerate kinase, phosphoglycerate mutase and lactate dehydrogenase deficiencies, have been discovered recently and are associated with exercise intolerance. The reason for muscle weakness and atrophy in glycogenosis is still unclear, although it has been suggested that excessive protein catabolism occurs in myophosphorylase, debrancher and acid maltase deficiencies. Myopathies due to deficiencies of mitochondrial enzymes are less well defined, as a group, than the glycogenoses. They are currently considered to fall into three main groups: defects of substrate utilization, such as carnitine palmitoyltransferase deficiency; defects of respiratory chain complexes, such as cytochrome-c-oxidase deficiency and defects of phosphorylation-respiration coupling, such as Luft's disease. Again, severe and benign exercise intolerance or progressive life-threatening myopathic syndromes may be the clinical expression of these disorders. Detailed biochemical and morphological studies of muscle biopsies are needed in these patients to obtain a definite diagnosis and prognosis, and to decide on eventual treatment.

Adult↗
PubMed1989

Debrancher deficiency neuromuscular disorder with pseudohypertrophy in two brothers.

A neuromuscular disorder is reported in two brothers, aged 28 and 38 years, with glycogenosis type III. Both patients had proximal weakness, pseudohypertrophy of sternocleidomastoid, trapezius and quadriceps muscles, mild distal wasting and myopathic EMG changes. Pseudohypertrophy was more evident in the younger brother, whereas weakness was prominent in the older one. In the former, muscle biopsy revealed vacuolar myopathy and virtual absence of amylo-1,6-glucosidase enzyme. Few familial cases of debrancher deficiency neuromuscular disorder have been reported. Distal wasting has been considered a quite characteristic manifestation of the disease. It is also suggested that this particular kind of pseudohypertrophy may represent a distinctive feature of glycogenosis type III.

Adult↗
PubMed1982

Ultrastructural pathology of human lymphocytes in lysosomal disorders: a contribution to their morphological diagnosis.

Ultrastructural examination of peripheral lymphocytes was performed in 28 cases of various lysosomal diseases, including infantile, late infantile and juvenile neuronal ceroid-lipofuscinoses (NCL), mucopolysaccharidoses (MPS), juvenile and adult metachromatic leukocystrophies (MLD), GM1-gangliosidosis, one patient with presumed mucolipidosis type IV, mucolipidosis type III, and glycogenosis type II. Based on our own observations on the ultrastructure of lymphocytes in lysosomal disorders, our results may be divided into the following 3 groups: 1. pathological findings with specific inclusions: each type of NCL, presumed mucolipidosis type IV, glycogenosis type II; 2 pathological findings with vacuoles: types I-H, II, III-A and III-B, IV, VI-A and VI-B of MPS, GM1-gangliosidosis; 3. apparently no pathological findings: juvenile and adult MLD, mucolipidosis type III, GM2-gangliosidosis, Gaucher disease. These results led us to conclude that morphological investigations utilizing lymphocytes do not always offer sufficient diagnostic information although easy accessibility favors diagnostic ultrastructural studies of lymphocytes. Such morphological studies should be supplemented by diagnostic biochemical methods.

Ceroid↗
PubMed1987

Fanconi-Bickel syndrome.

Clinical, biochemical, functional and morphological data are presented in nine infants, children and adults, with Fanconi-Bickel syndrome. Long-term follow-up studies show severe growth retardation, partly compensated for by late onset of puberty. Glomerular filtration rate is normal or slightly decreased. Renal tubular dysfunction is characterized by a specific pattern of impaired proximal tubular transport mechanisms, with marked impairment of glucose transport. The utilization of glucose and galactose is defective, whereas fructose metabolism seems to be normal. Glycogenosis of the liver may be an epiphenomenon. Glycogen accumulation in the kidney is limited to the proximal tubule, with maximal levels in the straight part. The Fanconi-Bickel syndrome is a defined clinical entity which is distinguished from other inherited metabolic diseases by complex defects of renal tubular transport and other forms of glycogenosis.

Adolescent↗
PubMed1990

Effects of cornstarch treatment in very young children with type I glycogen storage disease.

Three children aged 1-2 years with glycogenosis type I were treated with 2 g/kg bodyweight oral cornstarch per meal (4-5 times a day) for a period up to 16 months. In comparison to the previous dietary regimen (day and nocturnal feedings every 3 h) the cornstarch diet stabilised serum glucose profiles and dramatically improved secondary hyperlipoproteinaemia. Mean total triglycerides decreased up to one half, consistent with a fall of very low density lipoprotein-triglycerides up to two thirds. Metabolic acidosis and hyperuricaemia did not occur and normal growth rates (0.7-1 cm/month) were achieved. We conclude that the cornstarch regimen even in the age group up to 2 years can be considered as an efficient alternative in the treatment of glycogenosis type I patients with less frequent feedings and without nocturnal infusion.

Blood Glucose↗
PubMed1976

Some cases of Type III glycogen storage disease.

Five patients with glycogen storage disease are described. Hypoglycemia was observed in all patients after an overnight fast, and glycemic and lactatemic curves obtained after oral administration of glucose or galactose were typical of those seen in Type III glycogenosis. An increase of liver glycogen up to 12-16% and complete absence of liver amylo-1,6-glucosidase were found in liver tissue samples obtained by needle biopsy. The patients were diagnosed as having Type III glycogenosis. In two patients the absence of amylo-1,6-glycosidase was accompanied by a sharp decline of liver phosphorylase activity. In one patient a decline of glucose-6-phosphatase activity was observed. The structure of liver glycogen was different in different patients, and so were the types of glycemic and lactatemic curves obtained upon protein tolerance tests. The above phenomena might be explained by some secondary disturbances in the activity of enzymes (phosphorylase, glucose-6-phosphatase) involved in the metabolism of liver glycogen of these patients.

Blood Glucose↗
PubMed1989

Effects of N-hydroxyethyl-1-deoxynojirimycin (BAY m 1099) on the activity of neutral- and acid alpha-glucosidases in human fibroblasts and HepG2 cells.

The effect of the glucose analogue N-hydroxyethyl-1-deoxynojirimycin (BAY m 1099) on the activity of alpha-glucosidases was studied in human fibroblasts and HepG2 cells. BAY m 1099 inhibits neutral and acid alpha-glucosidase activities of both cell types in a dosage-dependent and reversible manner. Inhibition of endoplasmic reticulum glucosidases I and/or II is suggested by delayed processing of lysosomal (acid) alpha-glucosidase. Competitive inhibition of mature acid alpha-glucosidase leads to lysosomal accumulation of glycogen as in glycogenosis type II. There seems to be little risk, however, of inducing this storage disorder when using the drug in a dose of 50 mg per os for treatment of type II diabetes. In high doses, the drug may prove useful for studying the pathogenesis of glycogenosis type II in vitro or in animal models.

1-Deoxynojirimycin↗
PubMed1996

Muscle phosphofructokinase deficiency in two generations.

Phosphofructokinase (PFK) is the key regulatory enzyme of glycolysis. Patients lacking the muscular isoform of PFK typically present with myopathy and compensated hemolysis (glycogenosis type VII or Tarui's disease). Since 1965 about 30 cases of muscular PFK deficiency have been reported. In most cases family history suggests a recessive inherited trait. We describe a family of Ashkenazi Jewish origin with two members in subsequent generations suffering from muscular PFK deficiency. The propositus, a 19-year-old male patient presented with weakness, myalgias and exercise intolerance since early infancy. His father also had early fatigue on exercise with myalgias; the mother and a 12-year-old brother were asymptomatic. Muscle biopsy of both the propositus and his father showed increased glycogen storage and absent histochemical stain for PFK. Biochemical studies of muscle revealed a markedly decreased PFK activity and DNA analysis of the muscle PFK gene revealed compound heterozygosity in both cases. This is the first description of proven muscle PFK deficiency (glycogenosis type VII) in two subsequent generations.

Adult↗
PubMed2006

Successful staged kidney and liver transplantation for glycogen storage disease type Ib: A case report.

Glycogen storage disease type Ib is a rare metabolic disease caused by a defect of the G6P transporter. Patients suffer from hypoglycemic episodes; growth and developmental delay; osteoporosis; neutropenia; and tendency to infections, ovarian cysts, and liver adenomas. Terminal kidney disease is a rare complication. Liver transplantation has been performed to prevent malignant transformation of hepatic adenomas. We present the case of a female patient with glycogenosis type Ib who had severe hypoglycemic episodes and recurrent infections since early childhood. She became dialysis dependent at the age of 24 years. Kidney transplantation was performed at age 30, and liver transplantation 2 years later. The main indication for liver transplantation were the persistent, therapy-refractory hypoglycemic episodes. The transplanted kidney function is stable. The liver transplantation resulted in the disappearance of hypoglycemic episodes, with the patient leading a normal life and eating a normal diet. The neutropenia did not recover, but there were no more significant infectious episodes after liver transplantation. This is, to the best of our knowledge, the first communication of a dual kidney and liver transplant performed in a patient with glycogenosis type Ib. It confirmed the beneficial effect of liver transplantation on the quality of life of patients with severe hypoglycemia. The transplantation should be attempted earlier in the course of the disease to reduce complications and allow catch-up growth. Hepatocyte transplantation may be considered; however, long-term results seem to be rather poor in the few documented cases.

Adult↗
PubMed1997

Early bioenergetic changes in hepatocarcinogenesis: preneoplastic phenotypes mimic responses to insulin and thyroid hormone.

Biochemical and molecular biological approaches in situ have provided compelling evidence for early bioenergetic changes in hepatocarcinogenesis. Hepatocellular neoplasms regularly develop from preneoplastic foci of altered hepatocytes, irrespective of whether they are caused by chemicals, radiation, viruses, or transgenic oncogenes. Two striking early metabolic aberrations were discovered: (1) a focal excessive storage of glycogen (glycogenosis) leading via various intermediate stages to neoplasms, the malignant phenotype of which is poor in glycogen but rich in ribosomes (basophilic), and (2) an accumulation of mitochondria in so-called oncocytes and amphophilic cells, giving rise to well-differentiated neoplasms. The metabolic pattern of human and experimentally induced focal hepatic glycogenosis mimics the phenotype of hepatocytes exposed to insulin. The conversion of the highly differentiated glycogenotic hepatocytes to the poorly differentiated cancer cells is usually associated with a reduction in gluconeogenesis, an activation of the pentose phosphate pathway and glycolysis, and an ever increasing cell proliferation. The metabolic pattern of preneoplastic amphophilic cell populations has only been studied to a limited extent. The few available data suggest that thyromimetic effects of peroxisomal proliferators and hepadnaviral infection may be responsible for the emergence of the amphophilic cell lineage of hepatocarcinogenesis. The actions of both insulin and thyroid hormone are mediated by intracellular signal transduction. It is, thus, conceivable that the early changes in energy metabolism during hepatocarcinogenesis are the consequence of alterations in the complex network of signal transduction pathways, which may be caused by genetic as well as epigenetic primary lesions, and elicit adaptive metabolic changes eventually resulting in the malignant neoplastic phenotype.

Animals↗