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11/42. A mild juvenile variant of type IV glycogenosis.

    The mild juvenile form of type IV glycogenosis, confirmed by a profound deficiency of the brancher enzyme in tissue specimens is reported from three Turkish male siblings who, foremost, suffered from chronic progressive myopathy. Muscle fibers contained polyglucosan inclusions of typical fine structure i.e. a mixture of granular and filamentous glycogen. They reacted strongly for myophosphorylase, but were resistant to diastase. These inclusions were ubiquitinated and reacted with antibody KM-279 which previously has been shown to bind to Lafora bodies, corpora amylacea and polyglucosan material in hepatic and cardiac cells of type IV glycogenosis as well as polyglucosan body myopathy without brancher enzyme deficiency. Our findings confirm that although rate, a mild form of type IV glycogenosis is marked by polyglucosan inclusion not only in myofibers, but also in smooth muscle and sweat gland epithelial cells. This further implies that when polyglucosan inclusions are observed within myofibers it is mandatory to examine the muscle tissue for brancher enzyme activity since the brancher enzyme activities in circulating erythrocytes and leucocytes were normal in all three affected siblings and their parents. Therefore, it can be concluded that the patients reported on here represent a variant form of type IV glycogenosis, in which the defect is limited to muscle tissue. This further indicates that there are several different types of type IV glycogenosis with variable clinical manifestations. ( info)

12/42. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV).

    BACKGROUND: glycogen storage disease type iv (GSD-IV) is a clinically heterogeneous autosomal recessive disorder due to glycogen branching enzyme (GBE) deficiency and resulting in the accumulation of an amylopectin-like polysaccharide. The typical presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular form of GSD-IV varies in onset (perinatal, congenital, juvenile, or adult) and severity. OBJECTIVE: To identify the molecular bases of different neuromuscular forms of GSD-IV and to establish possible genotype/phenotype correlations. methods: Eight patients with GBE deficiency had different neuromuscular presentations: three had fetal akinesia deformation sequence (FADS), three had congenital myopathy, one had juvenile myopathy, and one had combined myopathic and hepatic features. In all patients, the promoter and the entire coding region of the GBE gene at the rna and genomic level were sequenced. RESULTS: Nine novel mutations were identified, including nonsense, missense, deletion, insertion, and splice-junction mutations. The three cases with FADS were homozygous, whereas all other cases were compound heterozygotes. CONCLUSIONS: This study expands the spectrum of mutations in the GBE gene and confirms that the neuromuscular presentation of GSD-IV is clinically and genetically heterogeneous. ( info)

13/42. Neonatal type IV glycogen storage disease associated with "null" mutations in glycogen branching enzyme 1.

    The fatal neonatal form of type IV glycogen storage disease (GSD IV) was diagnosed on light and electron microscopy and by analysis of GBE1 , the gene encoding glycogen branching enzyme. We report two novel truncating mutations, as well as the first genomic mutational analysis of GBE1 using denaturing high performance liquid chromatography. ( info)

14/42. 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. ( info)

15/42. Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence.

    We report a 17-month-old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin-like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex-transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart. ( info)

16/42. adult polyglucosan body disease: a case report of a manifesting heterozygote.

    A 62-year-old man developed progressive gait instability, bladder dysfunction, proximal weakness, distal sensory loss, and mild cognitive impairment over 6 years. neurologic examination revealed upper and lower motor neuron dysfunction in the lower extremities, with distal sensory loss. Electrodiagnostic studies, magnetic resonance imaging of the brain, and sural nerve biopsy were consistent with adult polyglucosan body disease. Biochemical and genetic analyses demonstrated reduced glycogen brancher enzyme levels associated with a heterozygous point mutation (Tyr329Ser or Y329S) in the glycogen brancher enzyme gene on chromosome 3. Mutational heterozygosity in the glycogen brancher enzyme gene has not been previously reported as a cause for this rare disease. A review of the clinical presentation, pathogenesis, etiology, and diagnosis of this disease is presented. ( info)

17/42. Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis.

    Orthotopic liver transplantation (OLT) has been proposed to treat patients with type IV glycogenosis because of early progressive cirrhosis. Reports have shown absence of disease progression in other organs after OLT and even regression of cardiac amylopectin infiltration in one case. We describe a 15-month-old child in whom a liver transplant was performed for type IV glycogenosis. There were no clinical signs of extrahepatic disease before OLT. Nine months later, the patient developed progressive cardiac insufficiency and died from cardiac failure. Because of massive amylopectin deposits, decreased myofibrils in cardiac cells, and exclusion of other causes of cardiac failure, death was attributed to amylopectionosis. Our observation contrasts with the Pittsburgh experience and suggests that cardiac amylopectionosis may progress after OLT. ( info)

18/42. Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family.

    We report on a family of three consecutive fetuses affected by type IV glycogen storage disease (GSD IV). In all cases, cervical cystic hygroma was observed on the 12-week-ultrasound examination. During the second trimester, fetal hydrops developed in the first pregnancy whereas fetal akinesia appeared in the second pregnancy. The diagnosis was suggested by microscopic examination of fetal tissues showing characteristic inclusions exclusively in striated fibers, then confirmed by enzymatic studies on frozen muscle. Antenatal diagnosis was performed on the third and fourth pregnancies: cervical cystic hygroma and low glycogen branching enzyme (GBE) activity on chorionic villi sample (CVS) were detected in the third pregnancy whereas ultrasound findings were normal and GBE activity within normal range on CVS in the fourth pregnancy. Molecular analysis showed that the mother was heterozygous for a c.1471G > C mutation in exon 12, leading to the replacement of an alanine by a tyrosine at codon 491 (p.A491T); the father was heterozygous for a c.895G > T mutation in exon 7, leading to the creation of a stop codon at position 299 (p.G299X). GSD IV has to be considered in a context of cervical cystic hygroma with normal karyotype, particularly when second trimester hydrops or akinesia develop. Enzymatic analysis of GBE must be performed on CVS or amniotic cells to confirm the diagnosis. Characteristic intracellular inclusions are specific to the disease and should be recognized, even in macerated tissues after fetal death. Genetic analysis of the GBE gene may help to shed some light on the puzzling diversity of GSD IV phenotypes. ( info)

19/42. Hereditary branching enzyme dysfunction in adult polyglucosan body disease: a possible metabolic cause in two patients.

    We describe 2 unrelated patients with adult polyglucosan body disease (APBD) diagnosed by sural nerve biopsy. Both patients were offspring of consanguineous marriages. They presented clinically with late onset pyramidal tetraparesis, micturition difficulties, peripheral neuropathy, and mild cognitive impairment. magnetic resonance imaging of the brain revealed extensive white matter abnormalities in both. In search of a possible metabolic defect, we evaluated glycogen metabolism in these patients and their clinically unaffected children. Branching enzyme activity in the patients' polymorphonuclear leukocytes was about 15% of control values, whereas their children displayed values of 50 to 60%, suggesting a possible autosomal recessive mode of transmission. This is the first report of an inherited metabolic defect in patients with adult polyglucosan body disease. We suggest that branching enzyme dysfunction may be implicated in the pathogenesis of some patients with adult polyglucosan body disease. ( info)

20/42. Type IV glycogen storage disease: first reported case in thailand.

    glycogen storage disease type iv is rare. The disease is characterized by widespread storage of a polysaccharide similar to amylopectin. An autopsy case of a 6-year-old Thai boy with cirrhosis and deposits in the liver, heart, muscle and central nervous system was described along with histochemical and electron microscopic findings. ( info)
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