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PubMed2003

Liver glycogenosis as early manifestation in type 1 diabetes mellitus.

Clinical symptoms and biochemical findings related to liver dysfunction are not generally reported among the presentation features of Type 1 diabetes mellitus (T1DM) in infancy and childhood. To our knowledge this is the first paper reporting two children with a clinical and biochemical picture of hepatic glycogenosis at the presentation of T1DM. In both cases at beginning of insulin therapy liver function and dimensions were absolutely normal, even though glycometabolic status had been severely altered for many days at T1DM onset. Both hepatomegaly and aminotransferase abnormalities were first found only some days after the institution of treatment with supraphysiological insulin doses. In both patients the improvement of glycometabolic control under insulin therapy was followed within some weeks by a complete physical and biochemical recovery, as typically reported in hepatic glycogenosis. These case reports demonstrate that hepatic glycogenosis can occur at any stage of T1DM and may even be one of its earliest manifestations, together with those classically reported at the onset of T1DM. Since long-standing hyperglycaemia and overinsulinisation are metabolic pre-requisites for hepatic glycogen storage, liver glycogenosis should be expected to be not uncommon during the first phases of T1DM, especially in the cases who are initially treated with supraphysiological insulin doses.

Adolescent↗
PubMed1995

[Type IA glycogenosis with acute pancreatitis].

Type IA glycogenosis, or von Gierke disease, is the most common among the glycogenoses with enlarged liver. Acute pancreatitis is a rare manifestation of type IA glycogenosis and has been attributed to elevated serum fat levels. We report a case of type IA glycogenosis with acute pancreatitis. The radiologists should be familiar with the computed tomography findings in this rare complications of type IA glycogenosis.

Acute Disease↗
PubMed1997

[Molecular pathology and gene diagnosis of muscle glycogenosis].

Three types of muscle glycogenosis are briefly reviewed for recent progress in molecular pathology and gene diagnosis, type II glycogenosis (Pompe disease), type V glycogenosis (McArdle disease) and type VII glycogenosis (Tarui disease). Various mutations of the gene responsible for each enzyme defect have been identified and used for diagnosis. Correlation between phenotype and genotype is not clearly understood in these disease, although some mutations are definitely correlated to specific clinical types.

Genes, Recessive↗
PubMedDate not supplied

[Corn starch in the treatment of patients with glycogenosis type I and III].

RATIONALE: Administering raw corn starch can maintain normoglycemia for long periods after being ingested, thus facilitating control in patients with type I and III glycogenosis. METHODS: The metabolic effects and the effects on the nutritional status of a treatment with fractionated administrations of raw starch are assessed in two patients with type I glycogenosis (ages 18 and 12 years) and one patient with type III glycogenosis (aged 13 years). In the first two cases the response was previously studied after administering a load of raw corn starch in a water suspension, in an amount similar to the estimated rate of endogenous glucose production during the fasting period (5 mg/kg/minute). RESULTS: The results of the overload of starch showed a normoglycemia and an absence of lactoacidosis between 4 and 6 hours after its ingestion. The three patients were given two doses of raw corn starch (2 g/kg/dose) at 1.00 and 5.00 hours during the night. After one year of treatment, all patients showed glycemia levels at 9.00 AM that were greater than 90 mg/dl and lactic acid levels that were lower than 2.4 mmol/l. Moreover, in two of the cases there was an increase in the growth rate. In all cases the amount of the hepatomegaly decreased as did the size of the hepatic adenomas that were present in two of the cases. CONCLUSIONS: In patients with type I and III glycogenosis, raw corn starch can balance the results of the nightly gastric glucose infusion, both with regard to the metabolic control and with regard to the growth.

Glycogen Storage Disease Type I↗
PubMed1990

Skin biopsy findings in glycogenosis III: clinical, biochemical, and electrophysiological correlations.

Electron microscopy of skin specimens was performed in 4 patients (age range, 7 months-40 years) with glycogenosis III and revealed consistent abnormalities. Massive glycogen storage was observed in epithelial secretory cells of eccrine sweat glands and, less markedly, in smooth muscle fibers from the erector pili. Other cells, including Schwann cells of myelinated and unmyelinated fibers, were not affected. The extent of glycogen storage was similar in all patients and unrelated to age or duration of disease. The extralysosomal nature and selectivity of glycogen deposits, sparing fibroblasts and other cells, differ clearly from the findings in skin from patients with glycogenosis II. The purpose of this study was to show that glycogen deposits in glycogenosis III are not restricted to skeletal muscle and liver, and to assess the usefulness of skin biopsy in this disorder.

Adolescent↗
PubMed1994

Localization of a new type of X-linked liver glycogenosis to the chromosomal region Xp22 containing the liver alpha-subunit of phosphorylase kinase (PHKA2).

We describe here a new type of X-linked liver glycogen storage disease. The main symptoms include liver enlargement and growth retardation. The clinical and biochemical abnormalities of this glycogenosis are similar to those of classical X-linked liver glycogenosis due to phosphorylase kinase deficiency (XLG). However, in contrast to patients with XLG, the patients described here have no reduced phosphorylase kinase activity in erythrocytes and leukocytes, and no enzyme deficiency could be found. Linkage analysis of four families with this X-linked type of liver glycogenosis assigned the disease gene to Xp22. Lod scores obtained with the markers DXS987, DXS207, and DXS999 were 3.97, 2.71, and 2.40, respectively, all at 0% recombination. Multipoint linkage analysis localized the disease gene between DXS143 and DXS989 with a maximum lod score of 4.70 at theta = 0, relative to DXS987. As both the classical XLG gene and the liver alpha-subunit of PHK (PHKA2) are also located in Xp22, this variant type of XLG may be allelic to classical XLG, and both diseases may be caused by mutations in PHKA2. Therefore, we propose to classify XLG as XLG type I (the classical type of XLG) and XLG type II (the variant type of XLG).

Adolescent↗
PubMed1976

[Pseudodystrophic muscle glycogenosis in adults. (Acid maltase deficiency syndrome) (author's transl)].

A 40-year-old man suffered for 5 years from a progressive proximal myopathy mimicking an atypical limb-girdle dystrophy. A "myopathic" pattern with myotonic and pseudomyotonic discharges was determined by electromyography. Enzyme histochemical and ultrastructural investigations of muscle and liver biopsies pointed to a glycogenosis. Biochemical investigations of muscle and liver samples confirmed this diagnosis, disclosing an acid maltase deficiency. Glycogen filled lysosomes were also revealed electron optically in skin fibroblasts but not in white blood cells. The literature concerning the late onset forms of acid maltase deficiency (type II glycogenosis) has been reviewed, and the clinical course has been compared with that of the infantile form (Pompe's disease). In early infancy the disease has a short and fatal course, with involvement of many organs. primarily skeletal muscules, liver and heart. In the late infantile and juvenile forms the course of the disease is slower, the organ involvement beeing not as severe; muscular symptoms begin to prevail. In adults, type II glycogenosis mimics muscular dystrophy with its prolonged course and the almost exclusive clinical involvement of proximal muscles. Biochemical and ultrastructural investigations have nevertheless demonstrated that other organs and tissues are also involved. The reasons for the variability of organ involvements in different ages are as yet unknown.

Adolescent↗
PubMed1984

Neutropenia and impaired neutrophil function in glycogenosis type Ib.

The impairment of different neutrophil functions has recently been reported in some patients with glycogenosis Ib and neutropenia. However, no satisfactory explanation for these findings has so far been supplied. In order to investigate this problem, we have studied neutrophil functions (random locomotion and chemotaxis, O-2 release, [1-14C]glucose oxidation and cellular cytotoxicity) in two further patients with glycogenosis Ib and neutropenia. The results show that neutrophil dysfunctions related to the involvement of both hexose monophosphate shunt and anaerobic glycolysis were variable. The heterogeneity of neutrophil functional impairment in glycogenosis Ib and their possible relationship with the basic metabolic defect of the disease are discussed.

Agranulocytosis↗
PubMed1997

Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical phenotype in blood cells associated with a missense mutation in the beta subunit gene (PHKB).

We have identified mutations in the phosphorylase kinase (Phk) beta subunit gene in a male patient with liver glycogenosis caused by Phk deficiency. The patient's DNA has been analyzed for mutations in the genes encoding the alpha L, beta, and gamma TL subunits of Phk, all of which can be responsible for liver glycogenosis, by a strategy primarily based on reverse transcription/polymerase chain reaction of blood RNA and complemented by analysis of genomic DNA. His alpha L and gamma TL coding sequences are normal, whereas he is compound-heterozygous for two mutations in the beta subunit gene, PHKB. The first is a splice-site mutation (IVS4 [-2A-->G]) causing the reading-frame-disrupting deletion of exon 5 in the mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon 5. This is the first missense mutation identified in PHKB, as opposed to nine translation-terminating mutations described to date. It offers an explanation for the unique biochemical phenotype of this patient. In his leukocytes, low Phk activity is measured when tested with the endogenous liver isoform of phosphorylase as the protein substrate, but normal activity is observed when tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his erythrocytes is low with both substrates. The missense mutation may selectively impair the interaction of Phk with one isoform of its substrate protein and may destabilize the enzyme in a cell-type-specific way. This phenotype shares some aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising from missense mutations in the alpha L subunit gene (PHKA2), but differs from XLG2 in other respects. The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types. Moreover, it emphasizes that missense mutations in Phk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.

Blood Cells↗
PubMed1998

Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene.

X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk alpha subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.

Amino Acid Sequence↗
PubMed1999

A mutation in GLUT2, not in phosphorylase kinase subunits, in hepato-renal glycogenosis with Fanconi syndrome and low phosphorylase kinase activity.

Fanconi-Bickel syndrome is characterized by hepato-renal glycogenosis with severe renal tubular dysfunction and rickets. It has recently been found to be associated with GLUT2 mutations in three families. In another family, low activities of liver phosphorylase kinase (Phk) have been observed, suggesting that Fanconi-Bickel syndrome might be genetically heterogeneous. We have analyzed this family for mutations in the GLUT2 gene and in the three Phk subunit genes that can cause liver glycogenosis (PHKA2, PHKB, and PHKG2). The coding sequences of all three Phk genes are normal but we have identified a homozygous missense mutation (Pro417Leu) in GLUT2. The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and is believed to be critical for the passage of glucose through the permease. Seven affected individuals from different branches of the same large consanguineous sibship all are homozygous for this mutation. These findings indicate that there is no specific subtype of genetic Phk deficiency giving rise to hepato-renal glycogenosis. Rather, they provide further evidence that Fanconi-Bickel syndrome is caused by GLUT2 mutations. The low Phk activity is probably a secondary phenomenon that contributes to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency.

Amino Acid Sequence↗
PubMed1985

Debranching enzyme in fibroblasts, amniotic fluid cells and chorionic villi: pre- and postnatal diagnosis of glycogenosis type III.

Glycogenosis type III is characterized by a deficiency of debranching enzyme in most tissues, and it can be detected by the inability to liberate glucose from limit dextrin. However, using this assay, the deficiency is not expressed in cultured fibroblasts from patients with glycogenosis type III. We have demonstrated that the failure to detect debranching enzyme deficiency in fibroblasts is entirely due to interference of acid alpha-glucosidase, which can also hydrolyse limit dextrin. A method is described to remove specifically acid alpha-glucosidase allowing clear discrimination between fibroblasts from patients and controls, whereas heterozygotes showed intermediate values. The results with amniotic fluid cells and chorionic villi suggest the feasibility of first- and second-trimester prenatal diagnosis of glycogenosis III.

Amniotic Fluid↗
PubMed1987

A simple differential immunoprecipitation assay of urinary acid and neutral alpha-glucosidases for glycogenosis II.

A specific assay for acid alpha-glucosidase in urine was developed to facilitate the diagnosis of glycogenosis II. This enzyme activity was calculated as a difference between the alpha-glucosidase activities before and after immunoprecipitation with antiserum to acid alpha-glucosidase. Acid alpha-glucosidase accounted for 86% of the total activity in control urine. All the cases of various clinical types of glycogenosis II showed either a marked decrease or a complete deficiency of this enzyme activity. A marked decrease of acid alpha-glucosidase was demonstrated by immunoblotting of the urine from patients with late-onset forms of this disease. These results indicate that assays of urinary acid alpha-glucosidase by this immunological method are useful for detection of the various types of glycogenosis II.

Adult↗
PubMed1986

Hepatic and renal tubular cell nuclear glycogenosis in goats.

Nuclear glycogenosis has not been reported in goats. This paper describes five cases of hepatocellular and/or renal tubular cell nuclear glycogenosis in goats in which the histological and ultrastructural details were studied. Our findings support the concept that nuclear glycogenosis reflects a compensatory adaptation by the cells rather than a degenerative process even though the initiating stimulus and pathogenesis are not known.

Animals↗
PubMed1991

Mapping of the gene for X-linked liver glycogenosis due to phosphorylase kinase deficiency to human chromosome region Xp22.

X-linked liver glycogenosis (XLG) is a glycogenosis due to deficient activity of phosphorylase kinase (PHK) in liver. PHK consists of four different subunits, alpha, beta, gamma, and delta. Although it is unknown whether liver and muscle PHK subunits are encoded by the same genes, the muscle alpha subunit (PHKA) gene was a likely candidate gene for the mutation responsible for this X-linked liver glycogenosis as it was assigned to the X chromosome at q12-q13. Linkage analysis with X-chromosomal polymorphic DNA markers was performed in two families segregating XLG. First, multipoint linkage analysis excluded the muscle PHKA region as the site of the XLG mutation. Second, evidence was obtained for linkage between the XLG locus and DXS197, DXS43, DXS16, and DXS9 with two-point peak lod scores Zmax = 6.64, 3.75, 1.30, and 0.88, all at theta max = 0.00, respectively. Multipoint linkage results and analysis of recombinational events indicated that the mutation responsible for XLG is located in Xp22 between DXS143 and DXS41.

Chromosome Mapping↗
PubMed2004

Severe neonatal onset of glycogenosis type IV: clinical and laboratory findings leading to diagnosis in two siblings.

Glycogenosis type IV is an autosomal recessive disease, exceptionally diagnosed at birth: only very few reports of the fatal perinatal neuromuscular form have been described. We report on two sibling male newborns who died at 10 and 4 weeks of age with clinical signs of a systemic storage disease. Prenatal history included polyhydramnios, reduced fetal movements and fetal hydrops, and Caesarean section was performed at 36 weeks of gestational age because of fetal distress. At birth, both babies showed severe hypotonia, hyporeflexia and no spontaneous breathing activity. They never showed active movements, sucking and swallowing and were respirator-dependent until death. A muscle biopsy revealed, in both patients, the presence of PAS-positive and partially diastase-resistant cytoplasmic inclusions containing granular and filamentous amylopectin-like material. This suggested that the stored material consisted of abnormal glycogen. At autopsy, ultrastructural examination of cardiac and skeletal muscle, liver, kidney and brain showed PAS-positive diastase-resistant eosinophilic cytoplasmic inclusions. Determination of branching enzyme activity, in cultured fibroblasts from the second patient, showed markedly reduced enzyme activity, confirming diagnosis of glycogenosis type IV. Our patients showed the full spectrum of both prenatal signs (hydrops, polyhydramnios) and postnatal signs (hypotonia, hyporeflexia, absence of active movements, cardiomegaly), which have been reported previously. They suffered from a very severe form of glycogenosis type IV with clinical and histological involvement of many tissues and organs. Diagnosis was accomplished on the second baby and required several biochemical and histological studies, in order to rule out both neuromuscular disorders and the most common storage diseases with neonatal onset. In our experience, the correct interpretation of the histological findings was essential in the search for the diagnosis.

Age of Onset↗
PubMed2000

Hepatic glycogenosis: reversible hepatomegaly in type 1 diabetes.

OBJECTIVE: To describe the aetiology, clinical features and appropriate treatment for hepatic glycogenosis in poorly controlled type 1 diabetes. METHODS: A review of three adolescents with poor diabetes control, hepatomegaly and elevated serum liver transaminase concentrations. RESULTS: Symptoms included abdominal pain, anorexia, nausea and vomiting. All had tender hepatomegaly; two had splenomegaly. Liver biopsy was performed on two patients. Histology revealed hepatic glycogenosis in both; one also demonstrated macrovesicular steatosis. With improved glycaemic control, all three showed resolution of their symptoms, organomegaly and elevated serum liver transaminase concentrations. CONCLUSIONS: Insulin-reversible hepatic glycogenosis is the most common cause of hepatomegaly and raised serum liver transaminase concentrations in children and adolescents with type 1 diabetes. Having excluded other causes of hepatic dysfunction, a 4 week therapeutic trial of improved glycaemic control is recommended prior to more invasive investigations.

Adolescent↗
PubMed1990

[Myopathy in the adult form of glycogenosis II. Two case reports and review of the literature].

Clinical, neurophysiological, morphological and biochemical investigations were performed in 2 patients with the adult form of glycogenosis II and related to the findings of 58 well-documented cases published in the literature. According to these findings three types can be distinguished from each other. The first one is characterized by an involvement of the limb-girdle muscles only. The second type shows the same pattern with additional progressive insufficiency of the respiratory muscles. The third type presents with weakness of the respiratory muscles without any other severe muscle involvement. Our case 1 can be related to the first, our case 2 to the second type. EMG-studies in case 1 showed myopathic changes and myotonic discharges without clinical signs of myotonia. A myotonic pattern was described in one third of the published cases. In case 2 neurogenic changes as well as in 4 cases in the literature were found. The muscle biopsy is the diagnostic clue in the differential diagnosis of progressive myopathy in the adult. Patients with glycogenosis II show glycogen storage specially in type I-fibres. The enzyme defect can be confirmed biochemically in muscle tissue or cultured fibroblasts. Various therapeutic concepts have been tried in patients with glycogenosis II but most of them remain disappointing. A diet with a low carbohydrate and a high protein proportion was observed to be of some benefit. In patients with respiratory muscle involvement artificial ventilation support showed a positive effect on the general condition for some time.

Adult↗