Glycogen Storage Disorder due to Glycogen Branching Enzyme (GBE) Deficiency: A Diagnostic Dilemma.

Glycogen branching enzyme deficiency/Andersen disease can manifest with a spectrum of clinical phenotypes, making the diagnosis difficult. An 11-year-old Pakistani boy presented with a history of progressive weakness and delayed milestones. Echocardiography showed features of dilated cardiomyopathy. He was suspected to have congenital myopathy and was evaluated further. Muscle biopsy showed subsarcolemmal accumulation of basophilic material, which stained positively with Periodic acid-Schiff reagent (diastase-resistant). Ultrastructural examination revealed accumulation of structurally abnormal forms of filamentous glycogen, confirming the diagnosis as Andersen disease. As histopathological and immunohistochemical evaluation of muscle biopsies is not always diagnostic, ultrastructural examination may serve as a valuable adjunct in difficult cases.

Adult polyglucosan body disease: a rare presentation with chronic liver disease and ground-glass hepatocellular inclusions.

Liver involvement in genetic and metabolic disorders may result in intrahepatic accumulation of specific precursors or byproducts, which have distinctive features on light microscopy. The "polyglucosan disorders" are diseases in which polyglucosan (abnormal glycogen with decreased branching) is formed and deposited in various tissues because of decreased or absent glycogen branching enzyme activity. These disorders include Lafora disease (myoclonus epilepsy) and type IV glycogen storage disease. Polyglucosan deposits in both conditions result in ground-glass hepatocellular inclusions resembling those seen in chronic hepatitis B virus infection. In the present report, we describe a case of the rare, adulthood form of glycogen branching enzyme deficiency, adult polyglucosan body disease (APBD), in which abnormal serum liver tests prompted a liver biopsy. The pathologic findings of periportal ground-glass hepatocellular inclusions, mild chronic portal inflammation, and periportal fibrosis are not well described in APBD, but resemble the chronic changes that have been reported in Lafora disease. The differential diagnosis of ground-glass hepatocytes and the genetic basis of APBD are discussed.

Glycogen storage disease type IV: novel mutations and molecular characterization of a heterogeneous disorder.

Glycogen storage disease type IV (GSD IV; Andersen disease) is caused by a deficiency of glycogen branching enzyme (GBE), leading to excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues. The accumulated glycogen lacks multiple branch points and thus has longer outer branches and poor solubility, causing irreversible tissue and organ damage. Although classic GSD IV presents with early onset of hepatosplenomegaly with progressive liver cirrhosis, GSD IV exhibits extensive clinical heterogeneity with respect to age at onset and variability in pattern and extent of organ and tissue involvement. With the advent of cloning and determination of the genomic structure of the human GBE gene (GBE1), molecular analysis and characterization of underlying disease-causing mutations is now possible. A variety of disease-causing mutations have been identified in the GBE1 gene in GSD IV patients, many of whom presented with diverse clinical phenotypes. Detailed biochemical and genetic analyses of three unrelated patients suspected to have GSD IV are presented here. Two novel missense mutations (p.Met495Thr and p.Pro552Leu) and a novel 1-bp deletion mutation (c.1999delA) were identified. A variety of mutations in GBE1 have been previously reported, including missense and nonsense mutations, nucleotide deletions and insertions, and donor and acceptor splice-site mutations. Mutation analysis is useful in confirming the diagnosis of GSD IV--especially when higher residual GBE enzyme activity levels are seen and enzyme analysis is not definitive--and allows for further determination of potential genotype/phenotype correlations in this disease.

Glycogen storage disease type IV: dilated cardiomyopathy as the isolated initial presentation in an adult patient.

Glycogen storage disease type IV (GSD IV, Andersen disease) is a rare autosomal recessive condition. The childhood neuromuscular subtype of GSD IV is characterised by a progressive skeletal myopathy with cardiomyopathy also reported in some individuals. We report a case of a 19-year-old man who presented with severe non-ischaemic dilated cardiomyopathy (NIDCM) necessitating heart transplantation, with biopsy showing aggregations of polyglucosan bodies in cardiac myocytes. He had no signs or symptoms of muscle weakness, liver dysfunction or neurologic involvement. A homozygous GBE1 c.607C>A (p.His203Asn) variant was identified. Our case is unusual in that our patient presented with an isolated NIDCM in the absence of other clinical manifestations of GSD IV. This case highlights the importance of considering storage disorders in young adults presenting with isolated NIDCM of unknown aetiology. It also emphasises the potential synergy between histopathological evaluation and genomic testing in enhancing diagnostic certainty.

Multisystem involvement in a patient due to accumulation of amylopectin-like material with diminished branching enzyme activity.

We report a 13-year-old boy with multisystem involvement secondary to accumulation of amylopectin-like material. He was born to consanguineous parents at full term without any complications and his maternal perinatal history was uneventful. His parents were cousins. He had normal growth and development except for his weight. His sister died from an unexplained cardiomyopathy at the age of 8 years. Our patient's initial symptom was severe heart failure. Since he also had a complaint of muscle weakness, electromyography was performed which showed muscle involvement. The diagnosis was suggested by tissue biopsy of skeletal muscle showing intracellular, basophilic, diastase-resistant, periodic acid-Schiff-positive inclusion bodies and was confirmed by the presence of a completed branching enzyme deficiency. Similar intracytoplasmic inclusion-like bodies were also found in liver biopsy, but very few in number compared with the skeletal muscle. The patient died from an intercurrent infection. Postmortem endomyocardial biopsy revealed the same intracytoplasmic inclusions as described above affecting almost all myocardial cells. Ultrastructural examination of liver biopsy was nondiagnostic; however, myocardium showed prominent, large, intracytoplasmic deposits. Glycogen branching enzyme gene sequence was normal, and thus classical branching enzyme deficiency was excluded. Our patient represents the first molecular study performed on a patient in whom there was multiple system involvement secondary to accumulation of amylopectin-like material. We suggest that this is an as yet undefined and different phenotype of glycogen storage disease associated with multisystemic involvement.

Glycogen Storage Disease Type IV and Early Implantation Defect: Early Trophoblastic Involvement Associated with a New GBE1 Mutation.

A 29-year-old primigravida presented with a spontaneous miscarriage at 8 weeks of gestation. There was no consanguinity in the family. Aspiration was performed. Pathological examination showed immature villi with numerous slightly yellow intracytoplasmic inclusions within the early implantation stage cytotrophoblastic cells. Inclusions were periodic acid-Schiff and Alcian blue positive and partially positive with periodic acid-Schiff with amylase. Diagnosis of Glycogen storage disease type IV (GSD IV) was made. Genetic analysis of glycogen branching enzyme 1 gene (GBE1) was performed in parents and showed a novel deletion of 1 nucleotide, c.1937delT, affecting the mother and a mutation affecting a consensus splice site, c.691+2T>C, in the father. At time of subsequent pregnancy, genetic counseling with GBE1 gene analysis was performed on throphoblastic biopsy and showed a mutated allele, c.1937delT, inherited from the mother. The mother gave birth to a healthy, unaffected female newborn. Our findings demonstrate that GSD IV may affect early pregnancies, leading to trophoblastic damage and early fetal loss. Diagnosis can accurately be made on pathological examination and should be further documented by genetic analysis.

A novel neuromuscular form of glycogen storage disease type IV with arthrogryposis, spinal stiffness and rare polyglucosan bodies in muscle.

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder causing polyglucosan storage in various tissues. Neuromuscular forms present with fetal akinesia deformation sequence, lethal myopathy, or mild hypotonia and weakness. A 3-year-old boy presented with arthrogryposis, motor developmental delay, weakness, and rigid spine. Whole body MRI revealed fibroadipose muscle replacement but sparing of the sartorius, gracilis, adductor longus and vastus intermedialis muscles. Polyglucosan bodies were identified in muscle, and GBE1 gene analysis revealed two pathogenic variants. We describe a novel neuromuscular GSD IV phenotype and confirm the importance of muscle morphological studies in early onset neuromuscular disorders.

[Surgical treatment for the patient with atrial septal defect and Andersen syndrome].

An 18-year-old girl with atrial septal defect and Andersen syndrome is reported. Andersen syndrome was described as a hereditary disease characterized by periodic paralysis, prolongation of the QT interval with ventricular arrhythmia and characteristic physical features including low set ear and micrognathia. We successfully performed cardiac operation for this rare associated malformation.

Fatal infantile neuromuscular presentation of glycogen storage disease type IV.

Glycogen storage disease type IV or Andersen disease is an autosomal recessive disorder due to deficiency of glycogen branching enzyme. Typically, glycogen storage disease type IV presents with rapidly progressive liver cirrhosis and death in childhood. Variants include a cardiopathic form of childhood, a relatively benign myopathic form of young adults, and a late-onset neurodegenerative disorder (adult polyglucosan body disease). A severe neuromuscular variant resembling Werdnig-Hoffmann disease has also been described in two patients. The objective was to describe two additional infants with the neuromuscular variant and novel mutations in the GBE1 gene. Branching enzyme assay, Western blot, RT-PCR and sequencing were performed in muscle biopsies from both patients. The cDNA of patient 1 was subcloned and sequenced to define the mutations. Muscle biopsies showed accumulation of periodic acid Schiff-positive, diastase-resistant storage material in both patients and increased lysosomal enzyme activity in patient 1. Branching enzyme activity in muscle was negligible in both patients, and Western blot showed decreased branching enzyme protein. Patient 1 had two single base pair deletions, one in exon 10 (1238delT) and the other in exon 12 (1467delC), and each parent was heterozygous for one of the deletions. Patient 2 had a large homozygous deletion that spanned 627 bp and included exons 8-12. Patient 1, who died at 41 days, had neurophysiological and neuropathological features of Spinal Muscular Atrophy. Patient 2, who died at 5(1/2) weeks, had a predominantly myopathic process. The infantile neuromuscular form of glycogen storage disease type IV is considered extremely rare, but our encountering two patients in close succession suggests that the disease may be underdiagnosed.

Hepatocellular adenoma in glycogen storage disease type IV.

The development of hepatocellular adenoma has been recognized in association with glycogen storage disease type I and, less often, with glycogen storage disease type III, but, to our knowledge, it has not been reported in glycogen storage disease type IV. We had the opportunity to study an 11-month-old male infant who underwent orthotopic liver transplantation for cirrhosis that developed in the setting of glycogen storage disease type IV. A clinically unsuspected hepatocellular adenoma was present in the explanted liver. Glycogen storage disease type IV should be considered as a potential precursor to the development of hepatocellular adenoma. Recognition of this association is important, both in terms of the differential diagnosis of tumors that occur in this setting and also to anticipate potential complications of this benign neoplasm.

Nervous system involvement in type IV glycogenosis.

A 30-month-old girl exhibited the 19th known case of type IV glycogenosis. Extensive involvement of the nervous system was found at autopsy. This represents only the second patient in whom the fine structure of the CNS and skeletal muscle has been described. We have also identified the abnormal polysaccharide in peripheral nerve, a finding that, to our knowledge, has not been reported previously. Our review of the literature indicates that approximately 50% of these patients exhibit signs or symptoms referable to the neuromuscular system. Most clinical and pathologic studies have focused on the severe liver involvement; insufficient attention has been directed toward the nervous system. This emphasizes the need for more detailed neurologic and neuropathologic examinations of children with type IV glycogenosis.

Laboratory diagnosis of the neuromuscular glycogen storage diseases.

Of the 12 known genetic disorders of glycogen metabolism, five consistently involve the neuromuscular system. Pompe's disease is a generalized, fatal, lysosomal storage disease caused by absence of acid maltase. Structurally abnormal glycogen accumulates in Forbes-Cori and Andersen's diseases, resulting from deficient debranching and branching enzymes, respectively. Exercise intolerance, muscle cramps, and myoglobinuria characterize McArdle's syndrome or myophosphorylase deficiency. In Tauri's disease, absence of phosphofructokinase leads to glycogen accumulation indirectly owing to a metabolic block in glycolysis. Diagnosis of the symptomatic patient, antenatal diagnosis, and detection of heterozygous genetic carriers are accomplished using a variety of laboratory methods. Tissue enzyme assays, chemical analysis of glycogen, and studies of carbohydrate metabolism are available. Recent advances in biophysics, such as nuclear magnetic resonance, have opened up a new approach for the study of metabolic diseases.

[Severe cardiomyopathy revealing amylopectinosis. Two cases in adolescents from the same family]. / Cardiomyopathie sévère révélant une amylopectinose. Deux observations chez des adolescents d'une même fratrie.

Type IV glycogen storage disease, also termed Andersen's disease or amylopectinosis, is a rare autosomic recessive hereditary disease usually caused by a deficit in glycogen branching enzyme. We report our observation of two siblings with type IV glycogen storage disease who had normal branching enzyme activity. The initial symptom was severe heart failure. A 14-year-old boy, born to consanguinous parents, was seen for severe global heart failure. Growth retardation had been diagnosed since the age of 6 and abnormal fatigability since the age of 12. Muscle and endomyocardium biopsies revealed abnormal glycogen storage with normal branching enzyme activity. The patient's condition improved after symptomatic treatment, but death occurred due to infectious complications after orthoptic heart transplantation. One year later, the proband's 12-year-old sister, with an uneventful personal medical history, was hospitalized for severe left ventricular failure. Muscle and liver biopsies demonstrated the same anomalies, again without branching enzyme deficiency in the liver. Heart failure was controlled with symptomatic care and the patient's current condition remains satisfactory. This observation demonstrates the clinical expression of familial type IV glycogen storage disease in patients with normal branching enzyme activity. Age at onset is quite variable, reported from 5 to 70 years, as is the clinical course before diagnosis.

Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports.

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism due to intracellular enzyme deficiency resulting in abnormal storage of glycogen in tissues. GSD represents an indication for liver transplantation (OLT) when medical treatment fails to control the metabolic dysfunction and/or there is an high risk of malignant transformation of hepatocellular adenomas (HCA). Herein we have reported two cases of GSD, type Ia and type VI, which were both associated with rapidly growing HCA, and underwent OLT because of suspect changes in their radiological features. Final histological findings in the explanted liver showed the presence of hepatocellular carcinoma (HCC) in both cases. In GSD type Ia and VI, OLT is considered to be the treatment of choice when a liver neoplasm is suspected. While the association of HCC with GSD type Ia is well known, this is the first case of HCC in GSD type VI so far reported to the best of our knowledge.

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.