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PubMedDate not supplied

Type Ib glycogenosis.

Type Ib glycogenosis is a rare glycogen storage disorder resulting from a defect in the enzyme, glucose-6-phosphatase microsomal translocase. We report a case of Type Ib glycogenosis in an 18 month-old male child who presented with a history of hypoglycemic seizures and recurrent infections and had a massive hepatomegaly, recurrent hypoglycemia, hyperuricemia, hypertriglyceridemia, neutropenia and fasting lactacidemia which decreased sharply on glucose administration.

Glycogen Storage Disease Type I↗

PubMed1989

A female case of type VIII glycogenosis who developed cirrhosis of the liver and hepatocellular tumor.

The case of a 17-year-old female with a rare form of type VIII glycogenosis who developed cirrhosis of the liver and hepatocellular tumor is reported. Laparoscopy showed a tumor 50 mm in diameter in the lower portion of the right lobe of the liver. The tumor was biopsied under ultrasonic guidance, and tentatively diagnosed as adenomatous hyperplasia. The patient was also diagnosed as having type VIII glycogenosis (phosphorylase kinase deficiency).

Adolescent↗

PubMed1998

Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years.

UNLABELLED: Phosphorylase kinase (PHK) is a regulatory enzyme in glycogen metabolism. Mutations in the gene encoding the alpha subunit of PHK (PHKA2) have been shown to be responsible for X-linked liver glycogenosis (XLG). XLG, a frequent type of glycogen storage disease, is characterised by hepatomegaly and growth retardation. Two subtypes of XLG have been described: XLG type I patients have a clear-cut PHK deficiency in liver and blood cells, whereas XLG type II patients have a normal or residual activity. Here, we present clinical, biochemical and molecular findings on a liver glycogenosis patient in whom the diagnosis XLG II only became clear after enzyme assays in the liver and identification of the disease-causing mutation. A missense mutation replacing arginine at amino acid position 186 by histidine (R186H) was identified in the PHKA2 gene. Mutations of the same arginine residue have been previously found in at least four other unrelated XLG II patients. CONCLUSION: Arginine at position 186 of the alpha subunit seems to play an important role in the structure or the regulation of PHK. In patients with XLG having normal or residual PHK activity where XLG II is suspected, the identification of mutations in PHKA2 leads to the final classification.

Adult↗

PubMed1991

Identification of a point mutation in the human lysosomal alpha-glucosidase gene causing infantile glycogenosis type II.

Two patients in a consanguineous Indian family with infantile glycogenosis type II were found to have a G to A transition in exon 11 of the human lysosomal alpha-glucosidase gene. Both patients were homozygous and both parents were heterozygous for the mutant allele. The mutation causes a Glu to Lys substitution at amino acid position 521, just three amino acids downstream from the catalytic site at Asp-518. The mutation was introduced in wild type lysosomal alpha-glucosidase cDNA and the mutant construct was expressed in vitro and in vivo. The Glu to Lys substitution is proven to account for the abnormal physical properties of the patients lysosomal alpha-glucosidase precursor and to prevent the formation of catalytically active enzyme. In homozygous form it leads to the severe infantile phenotype of glycogenosis type II.

Alleles↗

PubMed1984

Uptake and stability of human and bovine acid alpha-glucosidase in cultured fibroblasts and skeletal muscle cells from glycogenosis type II patients.

Acid alpha-glucosidase (EC 3.2.1.20) was purified from human placenta and bovine testis by affinity chromatography using concanavalin A (conA) and Sephadex G 200. When added to the culture medium of human fibroblasts, the enzyme purified from bovine testis is taken up with a 200-fold higher efficiency than the enzyme from human placenta. Uptake of acid alpha-glucosidase from bovine testis is mediated by the mannose-6-phosphate receptor, whereas only a minor fraction of placental enzyme appears to be equipped with the mannose-6-phosphate recognition marker. Once internalized, both human and bovine acid alpha-glucosidase demonstrate a half-life of about 10 days in fibroblasts from control individuals and patients with different clinical forms of glycogenosis type II (Pompe's disease, acid alpha-glucosidase deficiency). Evidence is presented that the mannose-6-phosphate receptor is also present on the plasma membrane of the clonal myogenic skeletal muscle cell lines G8-1 and L6J1 (respectively from mouse and rat origin) and on cultured human skeletal muscle cells derived from a muscle biopsy. Addition of bovine testis acid alpha-glucosidase to skeletal muscle cell cultures from an adult patient with glycogenosis type II leads to complete correction of the enzyme deficiency.

Animals↗

PubMed1993

A man with type III glycogenosis associated with cirrhosis and portal hypertension.

Type III glycogenosis, an inherited disorder of glycogen metabolism that results from reduced or absent activity of the enzyme amylo-1,6-glycosidase (debranching enzyme), has not been frequently associated with cirrhosis and portal hypertension in adults. An adult Caucasian man with well-document type IIIa glycogenosis, who presented with a variceal hemorrhage secondary to hepatic cirrhosis, is described here. No other cause of cirrhosis was found.

Adult↗

PubMed1991

Diagnosis of muscular glycogenosis by in vivo natural abundance 13C NMR spectroscopy.

Natural abundance 13C NMR (nuclear magnetic resonance) spectroscopy was used to distinguish patients suffering from muscle glycogenosis type V (McArdle's disease) from normal subjects by measuring their muscle glycogen content at rest. Proton-decoupled 13C spectra were obtained in 10-15 min from calf muscles at rest. The ratio of the glycogen/creatine signal areas was 12.9 +/- 1.7 in four McArdle's disease patients and 2.0 +/- 0.7 in seven normal subjects. This technique thus allows the non-invasive diagnosis of muscle glycogenosis.

Adult↗

PubMed1994

Bovine glycogenosis type II: the molecular defect in Shorthorn cattle.

The molecular defect in Shorthorn cattle affected with glycogenosis type II was studied. Polyclonal and monoclonal antibodies specific for bovine skeletal muscle acid alpha-glucosidase were raised and used to study the molecular and biochemical defect in seven affected animals. Cultured normal bovine fibroblasts pulsed and chased with [3H] leucine produced a 130 kDa precursor form of acid alpha-glucosidase which was processed via several 100 kDa intermediate forms to the 65 kDa mature form within 26 h. Fibroblasts from affected animals were labelled in vitro and were shown to produce a cross-reactive protein which was identified as the precursor form of the enzyme. The mature form of the enzyme was not found. The precursor form of the enzyme was demonstrated in Western blots of muscle tissue extracts from affected animals. Glycogenosis type II in Shorthorn and Brahman cattle must be caused by a different, independent maturation, since Brahman cattle lack the cross-reactive protein for acid alpha-glucosidase.

Animals↗

PubMed1996

A mild adult myopathic variant of type IV glycogenosis.

Type IV glycogenosis is usually a rapidly progressive disease of early childhood, causing death before 4 years of age. It is characterized by hepatosplenomegaly, cirrhosis, and chronic hepatic failure. Muscle involvement is generally overshadowed by liver disease. A mild non-infantile variant of type IV glycogenosis has been described in a few patients. In some of them, the patients suffered foremost from chronic progressive myopathy. We here report on a female patient aged 51 years who had experienced difficulties in climbing stairs for 2 years due to leg weakness. EMG revealed a myopathic pattern. The muscle biopsy findings revealed polyglycosan bodies. Biochemical investigation showed absence of branching enzyme in muscle but not in leukocytes and fibroblasts.

Adult↗

PubMed2006

A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis.

Mutations in the gene encoding the gamma2 subunit of AMP-activated protein kinase (PRKAG2) cause familial cardiac hypertrophy and electrophysiological abnormalities, with glycogen accumulation in the heart of affected patients. The authors describe a 38-year-old man with a new heterozygous PRKAG2 mutation (Ser548Pro) manifesting by hypertrophic cardiomyopathy, severe conduction system abnormalities, and skeletal muscle glycogenosis. Considering those results, PRKAG2 gene could be a potential candidate for unexplained muscle glycogenosis associated with cardiac abnormalities.

AMP-Activated Protein Kinases↗

PubMed1975

Studies in type I glycogenosis: the paradoxical effect of ethanol on lactate.

Paradoxically, ethanol, which raises lactate in normal individuals, lowers the elevated levels of lactate in patients with Type I glycogenosis. We found that, although lactate levels fell, pyruvate proportionately declined even more, resulting in an increased L/P ratio which indicates that, as in the normal, the oxidation of ethanol had generated NADH. In type I glycogenosis, the increased level of pyruvate-lactate derives from glycogenolysis. We found that, despite continued glycogenolysis, ethanol had caused less pyruvate-lactate to form. The effect of an increased NADH/NAD+ ratio on the flow of carbon through the Embden-Meyerhof pathway could account for the finding, presumably by its effect on the oxidation-reduction couples with diversion of carbon toward formation of triglyceride rather than pyruvate-lactate.

Adolescent↗

PubMed1989

Cerebral glycogenosis, alpha particle type: morphologic and biochemical observations in an infant.

A 3-month-old infant with congenital hypotonia suffering from an unusual form of glycogenosis is reported. The most striking neuropathologic findings were vacuolation of neuropile and glycogen accumulation, especially in the cerebral cortex and cerebellar molecular layer. Ultrastructurally, glycogen accumulation was present mainly in neurites and astrocytic processes, and mostly appeared as rosettes (alpha glycogen particles). Biochemical analysis of glycogen in various regions of the central nervous system showed an increase of up to 100-fold. The cerebral cortex, deep nuclei, and cerebellar cortex had the highest glycogen elevations, while the cerebral white matter glycogen level was normal. Among other tissues, the heart showed a several-fold increase in glycogen content. Muscle, liver, and kidney glycogen levels were not elevated. Findings in this case and in three other reported patients with cerebral glycogenosis of alpha particle type are discussed.

Brain↗

PubMed1999

Adult glycogenosis II with paracrystalline mitochondrial inclusions and Hirano bodies in skeletal muscle.

Hirano bodies constitute eosinophilic intracytoplasmic inclusions, typically seen in the central nervous system, where they are related to senility and certain dementias such as Alzheimer's disease or the Parkinson-dementia complex. They have been found in different tissues of experimental animals and, on rare occasions, in extraocular muscles of elderly individuals. However, to our knowledge they have not been described in skeletal muscle in locations other than extraocular muscles or associated with muscle pathology. Glycogenosis II or Pompe's disease, is a metabolic disorder caused by acid maltase deficiency and is characterized by glycogen accumulation in lysosomes in various tissues, including skeletal muscle. There are three clinical forms depending on age at onset, the most frequent being the childhood form. We present the histopathological and ultrastructural findings of a muscle biopsy performed in a case of the adult form of glycogenosis II which showed, in addition to characteristic lysosomal glycogen storage, paracrystalline mitochondrial inclusions and, as an exceptional finding, intracytoplasmic Hirano bodies in some muscle fibres.

Female↗

PubMed2003

Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases.

Muscle-specific deficiency of phosphorylase kinase (Phk) causes glycogen storage disease, clinically manifesting in exercise intolerance with early fatiguability, pain, cramps and occasionally myoglobinuria. In two patients and in a mouse mutant with muscle Phk deficiency, mutations were previously found in the muscle isoform of the Phk alpha subunit, encoded by the X-chromosomal PHKA1 gene (MIM # 311870). No mutations have been identified in the muscle isoform of the Phk gamma subunit (PHKG1). In the present study, we determined Q1the structure of the PHKG1 gene and characterized its relationship to several pseudogenes. In six patients with adult- or juvenile-onset muscle glycogenosis and low Phk activity, we then searched for mutations in eight candidate genes. The coding sequences of all six genes that contribute to Phk in muscle were analysed: PHKA1, PHKB, PHKG1, CALM1, CALM2 and CALM3. We also analysed the genes of the muscle isoform of glycogen phosphorylase (PYGM), of a muscle-specific regulatory subunit of the AMP-dependent protein kinase (PRKAG3), and the promoter regions of PHKA1, PHKB and PHKG1. Only in one male patient did we find a PHKA1 missense mutation (D299V) that explains the enzyme deficiency. Two patients were heterozygous for single amino-acid replacements in PHKB that are of unclear significance (Q657K and Y770C). No sequence abnormalities were found in the other three patients. If these results can be generalized, only a fraction of cases with muscle glycogenosis and a biochemical diagnosis of low Phk activity are caused by coding, splice-site or promoter mutations in PHKA1, PHKG1 or other Phk subunit genes. Most patients with this diagnosis probably are affected either by elusive mutations of Phk subunit genes or by defects in other, unidentified genes.

Adult↗

PubMed2000

Hepatocellular carcinoma and focal hepatic glycogenosis after prolonged azathioprine therapy.

A 22-year-old woman without predisposing liver disease developed focal hepatic glycogenosis and hepatocellular carcinoma after 6 years of azathioprine therapy for Crohn's disease. Hepatocellular carcinoma without cirrhosis has previously been described during immunosuppression, but this is the first report of disseminated focal hepatic glycogenosis after long-term azathioprine therapy.

Adult↗

PubMed1992

cDNA cloning of a liver isoform of the phosphorylase kinase alpha subunit and mapping of the gene to Xp22.2-p22.1, the region of human X-linked liver glycogenosis.

We have cloned cDNA molecules encoding another isoform of the alpha subunit of phosphorylase kinase (ATP:phosphorylase-b phosphotransferase, EC 2.7.1.38). Sequence comparison with the previously characterized muscle isoform reveals a pattern of highly conserved and variable domains and demonstrates that the isoforms are the products of distinct genes. In contrast to the muscle isoform gene, PHKA1, the gene of this additional isoform, PHKA2, is predominantly expressed in liver and other nonmuscle tissues. It was mapped to the distal short arm of the human X chromosome (Xp22.2-p22.1), the same region to which human X-linked liver glycogenosis due to phosphorylase kinase deficiency has been mapped. Thus, X-linked liver glycogenosis is probably caused by mutations affecting PHKA2.

Amino Acid Sequence↗

PubMed1983

Cardiomyopathy in generalised glycogenosis type II in cattle.

The clinical, electrocardiographic and postmortem findings in five cattle affected by generalised glycogenosis type II are described. Three of the affected animals showed generalised muscle weakness for some months before being killed at 11, 15 and 16 months of age. Of the remaining two, one developed severe respiratory distress when 3 months old and died within 6 h of first being noticed to be ill. The other animal showed respiratory distress on exertion at 5 months of age, became recumbent and died when 7 months old. The sum of the QRS complex amplitudes in ECG leads I, II, a VR, aVL and aVF of the affected animals was significantly increased from the control or carrier animals, but only the two affected animals which showed clinical and pathological signs of congestive heart failure had increased heart weight to body weight, left and right ventricular weight to body weight ratios. In view of the lack of correlation between the increased QRS amplitudes and the presence of cardiac enlargement, it is suggested that the increased QRS amplitudes are a reflection of a conduction disorder. It is further suggested that QRS complex abnormalities in generalised glycogenosis in man, particularly in the late onset form may be due to a similar phenomenon.

Animals↗

PubMed1995

A new variant of type IV glycogenosis with primary cardiac manifestation and complete branching enzyme deficiency. In vivo detection by heart muscle biopsy.

Type IV glycogenosis (polyglucosan body disease) is a rare congenital autosomal recessive inherited disorder, caused by lack of the branching enzyme (amylo-1,4-1,6 transglucosidase). This deficiency leads to storage of abnormal glycogen (polyglucosan bodies) in the liver and other tissues. The clinical onset of the disease is insidious with non-specific gastrointestinal symptoms followed by progressive hepatic failure. Usually patients die due to hepatic cirrhosis within 4 years. Sometimes myopathy of the heart and skeletal muscle is also present. In these cases, the clinical onset is often later than in typical cases. We report on two brothers with primarily cardiac manifestation and late onset of the disease. The older one started to suffer from progressive dilated cardiomyopathy at the age of 18 years, presenting with severe heart failure, hepatosplenomegaly, ascites and peripheral oedema. He also demonstrated myopathy and muscular atrophy especially of the shoulder and lower limbs. Initially he improved on medical therapy, but one year later severe heart failure recurred followed shortly afterwards by sudden cardiac death. Right heart and skeletal muscle biopsies were performed while he was alive. These, as well as the autopsy, revealed massive accumulation of polyglucosan bodies. In both heart and skeletal muscle, complete branching enzyme deficiency could be proven. His 14-year-old brother showed similar clinical findings of mild dilated cardiomyopathy. His muscle biopsy also revealed polyglucosan body myopathy. Thus, in young patients presenting with congestive cardiomyopathy, type IV glycogenosis has to be considered in the differential diagnosis.

1,4-alpha-Glucan Branching Enzyme↗