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PubMed1998

Overexpression of insulin receptor substrate-1 emerges early in hepatocarcinogenesis and elicits preneoplastic hepatic glycogenosis.

Insulin receptor substrate-1 (IRS-1) is a multisite docking protein occupying a central position in signaling cascades stimulated by a number of growth factors including insulin. Using Western blotting and immunohistochemistry, we investigated the expression of IRS-1 in more than 400 preneoplastic foci of altered hepatocytes and in 12 hepatocellular carcinomas induced in rats by oral administration of N-nitrosomorpholine. In both N-nitrosomorpholine-treated and untreated rat livers, IRS-1 was demonstrable by Western blotting, but with the exception of a few single hepatocytes it was not detectable in the normal parenchyma by immunohistochemistry. In contrast, immunohistochemistry revealed that IRS-1 was strongly expressed in the majority of foci of altered hepatocytes particularly in approximately 97% of the clear/acidophilic and mixed cell foci showing excessive storage of glycogen (glycogenosis). In glycogen-poor basophilic foci of altered hepatocytes and hepatocellular carcinomas, IRS-1 was not detected by immunohistochemistry, but a weak expression was observed in small subpopulations of three hepatocellular carcinomas containing remnants of glycogen. These results indicate that the focal overexpression of IRS-1 is an early event in hepatocarcinogenesis, which is closely correlated with preneoplastic hepatic glycogenosis. During progression from glycogenotic foci to hepatocellular carcinomas, IRS-1-overexpression is gradually down-regulated, and this late event is associated with a fundamental metabolic shift leading to the malignant neoplastic phenotype.

Animals↗
PubMed1989

Lymphocyte alpha-glucosidase in late-onset glycogenosis type II.

We describe the biochemical characterization of lymphocyte alpha-glucosidase in a 23-year-old man with intermediate clinical features between the childhood and adult forms of glycogenosis type II (Pompe's disease). Acid alpha-glucosidase activity was markedly reduced, but immunologic cross-reactive material against human liver acid alpha-glucosidase protein could be detected, and its amount was normal. In this patient, the disorder was induced by the catalytically inactive enzyme with a normal amount of enzyme protein.

Adult↗
PubMed1985

Infectious and bleeding complications in patients with glycogenosis Ib.

Clinical, hematologic, and immunologic findings were reviewed in 21 patients with glycogenosis Ib. Fifteen of the patients suffered from moderate to severe bacterial infections. Ten patients had excessive epistaxis or bleeding from surgical sites, and eight suffered oral and anal mucosal ulceration. Sixteen of 21 patients exhibited chronic neutropenia associated with abnormalities in myeloid maturation and decreases in the bone marrow storage and peripheral marginating pools. Diminished neutrophil motility was documented in 14 of 15 patients tested, and adherence was decreased in three patients studied. Neutrophil microbicidal activity, reduction of nitroblue tetrazolium, and ingestion were normal in all patients tested. Bleeding times were prolonged in five of eight patients, and results of platelet function studies were abnormal in five individuals. Excessive bleeding in patients with glycogenoses Ia and Ib are similar and may be secondary to the functional deficiency of glucose-6-phosphatase. However, neutropenia, neutrophil dysfunction, and the resulting infectious complications are specific for Ib disease and may be related to abnormal glucose-6-phosphate transport.

Adolescent↗
PubMed1993

Fanconi's syndrome with hepatorenal glycogenosis associated with phosphorylase b kinase deficiency.

OBJECTIVE: To describe two patients with Fanconi's nephropathy secondary to glycogen storage disease and speculate on the possible etiology. DESIGN: Convenience sample. SETTING: Tertiary care, referral center. PATIENTS: Two related children referred for failure to thrive, rickets, and hepatomegaly. INTERVENTION: Dietary and therapeutic measures for rickets and renal tubular acidosis. MEASUREMENTS AND RESULTS: The main laboratory findings were fasting hypoglycemia and massive glucosuria, with evidence of multiple renal tubular dysfunction characteristic of the Fanconi syndrome. Liver and kidney biopsy specimens were consistent with glycogen storage disease. Enzymatic assay of liver homogenates revealed marked deficiency of phosphorylase b kinase in one patient and absent activity in the other. CONCLUSION: Phosphorylase b kinase deficiency may be causally related to hepatorenal glycogenosis with the Fanconi syndrome. More patients with this syndrome need to be studied before a definitive causal role is implicated.

Biopsy↗
PubMed1999

Early-onset fetal hydrops and muscle degeneration in siblings due to a novel variant of type IV glycogenosis.

We report on 3 consecutive sib fetuses, presenting at 13, 12, and 13 weeks of gestation, respectively, with fetal hydrops, limb contractures, and akinesia. Autopsy of the first fetus showed subcutaneous fluid collections and severe degeneration of skeletal muscle. Histologic studies demonstrated massive accumulation of diastase-resistant periodic acid-Schiff-positive material in the skeletal muscle cells and epidermal keratinocytes of all 3 fetuses. Enzyme studies of fibroblasts from the 3rd fetus showed deficient activity of glycogen brancher enzyme, indicating that this is a new, severe form of glycogenosis type IV with onset in the early second trimester.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1997

Glycogenosis type II: a juvenile-specific mutation with an unusual splicing pattern and a shared mutation in African Americans.

The recessively inherited deficiency of acid alpha-glucosidase (GAA) called Glycogenosis Type II is expressed as three different phenotypes: infantile, juvenile, and adult. At the molecular level, infantile and adult forms of the disease have been extensively studied, but little is known regarding the genetic defects associated with the juvenile form. We describe a novel mutation that defines the intermediate juvenile phenotype in a compound heterozygous patient. A transversion of t to g in intron 6 at position -22 creates a cryptic acceptor site and results in unusual splicing abnormality: insertion of 21 nucleotides of the intronic sequence into mRNA and removal of exon 6 without disruption of the reading frame. The second mutation, Arg854Stop in exon 18, had been previously identified in another African-American patient (Hermans et al., 1993a). Family study indicates that a silent allele harboring the Arg854Stop mutation in our patient is inherited from the patient's father, who is also African-American, thus suggesting a common mutation in this population.

Base Sequence↗
PubMed1992

Type Ia glycogenosis associated with hepatocellular carcinoma.

The predisposition of preexisting cirrhotic metabolic liver disease to the development of hepatocellular carcinoma is well established. However, the association between glycogenoses (a form of noncirrhotic metabolic liver disease) and the formation of benign and malignant liver tumors is less well known. The sixth case of simultaneous occurrence of glycogenosis type Ia and hepatocellular carcinoma, which occurred in a 34-year-old man referred for advice on therapy for his malignant neoplasm, is reported. Cases previously described in the literature are reviewed and management of this entity in light of the current knowledge in the diagnosis and treatment of hepatocellular carcinoma is discussed.

Adult↗
PubMedDate not supplied

A new variant of type IV glycogenosis: deficiency of branching enzyme activity without apparent progressive liver disease.

Type IV glycogenosis is due to branching enzyme deficiency and is usually manifested clinically by progressive liver disease with cirrhosis and hepatic failure between the second and fourth years of life. We describe a 5-year-old boy who, following an acute febrile illness at 2 years of age, was first noted to have hepatomegaly with mildly elevated serum transaminase levels. Liver biopsy revealed hepatic fibrosis with periodic-acid Schiff-positive, diastase-resistant inclusions in hepatocytes and fibrillar inclusions characteristic of amylopectin by electron microscopy. Enzymatic assay revealed deficient hepatic branching enzyme activity with normal activity of glucose-6-phosphatase, debranching enzyme and phosphorylase activities. During the succeeding 3 years, he grew and developed normally with apparent resolution of any clinical evidence of liver disease and only intermittent elevation in serum transaminase levels associated with fever and prolonged fasting. Repeat liver biopsy at 4 years of age showed persistence of scattered hepatocellular periodic-acid Schiff-positive, diastase-resistant inclusions, but no progression of hepatic fibrosis in spite of persistent deficiency of hepatic branching enzyme activity. Skeletal muscle and skin fibroblasts from the patient also showed deficient enzyme activity. Skin fibroblasts from both parents exhibited half the normal control activity, suggesting a heterozygote state. This is the first documented patient with deficiency of branching enzyme but without evidence of progressive hepatic disease. This patient, coupled with reports of other patients with late onset hepatic or muscle disease with branching enzyme deficiency, suggests that the defect resulting in Type IV glycogen storage disease is more heterogenous and possibly more common than previously suspected.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2006

Hepatic and neuromuscular forms of glycogenosis type III: nine mutations in AGL.

Glycogenosis type III (Cori disease) is an autosomal recessive disorder caused by the deficiency of the glycogen debranching enzyme, encoded by the AGL gene, and existing in six isoforms alternately spliced in a tissue-specific way. Generally, disease onset occurs early on starting from the first year of life, with hepatomegaly, hypoglycemia, hyperlipidemia, increased CK levels, and, in some cases, short stature and slight mental retardation. Frequently, hepatomegaly tends to resolve spontaneously and inexplicably during childhood, when myopathy, often associated with cardiomyopathy, arises. This disease is known to lack almost invariably clear links between the genotype and clinical phenotype. We describe nine new mutations in Italian patients: four nonsense (p.Arg285X, p.Lys422X, p.Arg910X, p.Arg977X), three frameshift (c.442delA, c.753_756delGACA, c.3963delG), and two missense (p.Ala1120Pro, p.Arg524His). Particularly, the nonsense p.Arg285X is linked to an exonic splicing enhancer and it was found to produce two species of transcripts at the same time. Moreover, we discuss a subgroup of subjects carrying c.2681+1G>A, which has proven to be the most frequent mutation among our patients. The previously described c.664+3A>G was also detected in two patients, both homozygous. The present work is yet another confirmation that the individual genetic background plays a pivotal role in influencing the phenotypes, as occurs in other metabolic diseases.

Adult↗
PubMedDate not supplied

Type III glycogenosis with multicore structures.

A case of an infantile type III glycogenosis (Forbes disease), confirmed by morphologic and biochemical studies, had light-microscopic, histochemical, and electron-microscopic evidence of multicore structures and type 1 fiber predominance with hypotrophy. This association is discussed with relation to the unusual clinical findings. The authors conclude that two distinct disease entities--Forbes disease and multicore myopathy--may coexist.

Adenosine Triphosphatases↗
PubMed1983

Amylo-1,6-glucosidase activity in cultured cells: a deficiency in type III glycogenosis with prenatal studies.

Deficiency of amylo-1,6-glucosidase activity was expressed in parallel in liver and skin fibroblasts from a patient with type III glycogenosis. In crude extracts of control liver and muscle, amylo-1,6-glucosidase (M.W. 164000) was identified by immunoprecipitation; no cross-reacting material was found in the patient's liver. Assay of amylo-1,6-glucosidase activity in cultured skin fibroblasts from the affected family revealed less than 10 per cent of control value in mutant homozygous cells whereas in cells from the parents, activity was reduced to 40-60 per cent of the control value. Activity in cultured amniotic fluid cells was similar to that of control fibroblasts. In cultured amniotic fluid cells obtained during the mother's subsequent pregnancy, the normal amylo-1,6-glucosidase activity measured, predicted correctly the outcome of this pregnancy prior to the 20th week of gestation.

Amniotic Fluid↗
PubMed2000

Approach to gene therapy of glycogenosis type II (Pompe disease).

Pompe disease is a generalized lysosomal glycogenosis affecting essentially the skeletal muscles and the heart. It is due to the deficiency of acid alpha-glucosidase, also called acid maltase, involved in glycogen degradation by the cleavage of alpha-1,4 and alpha-1,6 glycosidic linkages. The severe infantile, milder juvenile, and late-onset or adult forms are associated under the generic name of glycogenoses type II. The clinical picture can differ according to these variants, forming a clinical spectrum from cardiorespiratory failure with early death in the infantile variant to late muscular weakness or respiratory problems in the adult variant. Enzymatic pre- and postnatal diagnoses and mutation characterization are available. Different therapeutic attempts have been conceived and some of them have come to clinical trials. Several pilot studies have demonstrated the feasibility of gene therapy and remarkable advances have been realized. Of particular interest, strategies for gene therapy in a generalized disease like Pompe disease must be accompanied by the secretion and uptake of the corrective enzyme by more distant cells or tissues in order to obtain efficient results. Preliminary positive results have been obtained in animal models, and new approaches with improvements in the access to muscle and heart, in the efficacy and innocuity of vectors, and in the clinical evolution are proposed. Gene therapy is a promising strategy for Pompe disease. However, several steps must be explored before this method becomes clinically successful.

Animals↗
PubMed1994

Neonatal hypotonia and cardiomyopathy secondary to type IV glycogenosis.

A neonate with deficiency of branching enzyme (glycogenosis type IV) presented symptoms of severe hypotonia pre- and postnatally, and dilated cardiomyopathy in early infancy. The classical clinical manifestation of liver cirrhosis was not present, although amylopectin-like inclusions were found in the hepatocytes. In contrast to a previous report, the neurons in the brain stem and spinal anterior horns contained PAS-positive, diastase-resistant deposits. The combined involvement of the muscles and motor neurones could account for the severity of hypotonia. The muscle biopsy, electromyogram and biochemical and enzyme assays were helpful in establishing the diagnosis.

Biopsy↗
PubMed1988

Prospect for enzyme therapy in glycogenosis II variants: a study on cultured muscle cells.

Impairment of skeletal muscle function is the common feature of distinct clinical forms of glycogenosis type II. In the present study, muscle cultures from different patients were used to investigate the cause of clinical heterogeneity and the feasibility of enzyme replacement therapy. The activity of acid alpha-glucosidase appears to be the primary factor in determining the extent of lysosomal glycogen storage in muscle, and thereby the clinical severity of the disease. Neutral alpha-glucosidases do not seem influential. Correction of the enzymatic defect was achieved in skeletal muscle cultures from patients by administration of a "high-uptake" form of acid alpha-glucosidase, purified from human urine. The enzyme reaches the lysosomes, including the glycogen storage vacuoles, and the lysosomal glycogen content is reduced to control level. In normal muscle cells 20% of the total cellular glycogen pool is segregated in lysosomal compartments. This percentage is higher than in fibroblasts, which may partly explain why muscles are more prone to store glycogen. The relevance of this study for enzyme therapy is discussed.

Cells, Cultured↗
PubMed1993

Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type IV glycogenosis).

Polyglucosan body diseases in adults, contrary to infantile cases (Andersen's disease or type IV glycogenosis or amylopectinosis), are usually not associated with a significant deficiency of the branching enzyme (= amylo-1,4-1,6 transglucosidase). We, therefore, report on a 19-year-old male with complete branching enzyme deficiency presenting with severe myopathy, dilative cardiomyopathy, heart failure, dysmorphic features, and subclinical neuropathy. His 14-year-old brother had similar symptoms and was erroneously classified by a previous muscle biopsy as having central core disease but could later be identified as also having polyglucosan body myopathy. The skeletal muscle, endomyocardiac, and sural nerve biopsies as well as the autopsy revealed extraordinarily severe deposits of polyglucosan bodies not only in striated and smooth muscle fibers, but also in histiocytes, fibroblasts, perineurial cells, axons and astrocytes. Occasional paracrystalline mitochondrial inclusions were also noted. Thus, this patient represents to our knowledge the first juvenile, familial case of polyglucosan body disease with total branching enzyme deficiency and extensive polyglucosan body storage.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1980

The concept of homology in quantitative organelle pathology. Application of symbolic logic to glycogenosis type I in the liver.

The process of quantification has led pathology into an objective and abstract direction to which it is unaccustomed. The introduction of the concept of homology in pathology by Doerr has proven to be very fruitful, since it has helped to clarify otherwise poorly understood relationships. As shown in the foregoing paper, the success of the homology concept applies also to quantitative organelle pathology. Homologies have demonstrated relationships within the ergastoplasmic - mitochondrial - peroxisomal system which are apparent only with the help of symbolic logic. These homologies permit inferences, shown here with the example of glycogenosis type I, regarding the adaptive potential of the cell and the degree of cellular damage. In addition, these homologies, which are described in terms of formal logic, may serve as a model for human pathologic anatomy.

Glycogen Storage Disease Type I↗