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Yuantsong Chen - One of the best experts on this subject based on the ideXlab platform.

  • Glycogen Branching Enzyme deficiency leads to abnormal cardiac development novel insights into Glycogen storage disease iv
    Human Molecular Genetics, 2011
    Co-Authors: Chia Jung Chang, Yuantsong Chen, Deeksha Bali
    Abstract:

    Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease caused by a deficiency in Glycogen-Branching Enzyme (GBE1) activity that results in the accumulation of amylopectin-like polysaccharide, which presumably leads to osmotic swelling and cell death. This disease is extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestation. The most severe fetal form presents as hydrops fetalis; however, its pathogenetic mechanisms are largely unknown. In this study, mice carrying a stop codon mutation (E609X) in the Gbe1 gene were generated using a gene-driven mutagenesis approach. Homozygous mutants (Gbe 2/2 mice) recapitulated the clinical features of hydrops fetalis and the embryonic lethality of the severe fetal form of GSD-IV. However, contrary to conventional expectations, little amylopectin accumulation and no cell degeneration were found in Gbe 2/2 embryonic tissues. Glycogen accumulation was reduced in developing hearts of Gbe 2/2 embryos, and abnormal cardiac development, including hypertrabeculation and noncompaction of the ventricular wall, was observed. Further, Gbe1 ablation led to poor ventricular function in late gestation and ultimately caused heart failure, fetal hydrops and embryonic lethality. We also found that the cell-cycle regulators cyclin D1 and c-Myc were highly expressed in cardiomyocytes and likely contributed to cardiomyocyte proliferation and trabeculation/compaction of the ventricular wall. Our results reveal that early molecular events associated with Gbe1 deficiency contribute to abnormal cardiac development and fetal hydrops in the fetal form of GSD-IV.

  • Glycogen storage disease type IV: novel mutations and molecular characterization of a heterogeneous disorder
    Journal of Inherited Metabolic Disease, 2010
    Co-Authors: Sing Chung Li, Yuantsong Chen, Jeryuarn Wu, Chiao-ming Chen, Jennifer L. Goldstein, Emmanuelle Lemyre, Thomas Andrew Burrow, Peter B. Kang, Deeksha S. Bali
    Abstract:

    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.

  • amylopectinosis disease isolated to the heart with normal Glycogen Branching Enzyme activity and gene sequence
    Pediatric Transplantation, 2005
    Co-Authors: Michael R Narkewicz, Ronald J Sokol, Yuantsong Chen, Deeksha Bali, Sing Chung Li, M R Matthews, Gary W Mierau
    Abstract:

    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 amylo- pectinosis 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 defici- ency (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.

  • hepatic and neuromuscular forms of Glycogen storage disease type iv caused by mutations in the same Glycogen Branching Enzyme gene
    Journal of Clinical Investigation, 1996
    Co-Authors: Priya S Kishnani, Jeryuarn Wu, Yuantsong Chen
    Abstract:

    Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient Glycogen-Branching Enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-IV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of GBE activity, whereas the Y329S resulted in loss of approximately 50% of GBE activity. The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation (ag to aa). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease. Further study of genotype/phenotype correlations may yield useful information in predicting the clinical outcomes.

Alexander Lossos - One of the best experts on this subject based on the ideXlab platform.

  • triacylglycerol mimetics regulate membrane interactions of Glycogen Branching Enzyme implications for therapy
    Journal of Lipid Research, 2017
    Co-Authors: Rafael Alvarez, Alexander Lossos, Jesus Casas, David J Lopez, Maitane Ibarguren, Ariadna Suaririvera, Silvia Teres, Francisca Guardiolaserrano, Xavier Busquets, Or Kakhlon
    Abstract:

    : Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant Glycogen Branching Enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble Glycogen, which tends to aggregate. We explore here whether, despite being a soluble Enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the Enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD.

  • structural basis of Glycogen Branching Enzyme deficiency and pharmacologic rescue by rational peptide design
    Human Molecular Genetics, 2015
    Co-Authors: Sean D Froese, Alexander Lossos, Amit Michaeli, Thomas J Mccorvie, T Krojer, Meitav Sasi, Esther Melaev, Amiram Goldblum, Maria Zatsepin, Rafael Alvarez
    Abstract:

    Glycogen Branching Enzyme 1 (GBE1) plays an essential role in Glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the Glycogen polymer. Mutations in the GBE1 gene lead to the heterogeneous early-onset Glycogen storage disorder type IV (GSDIV) or the late-onset adult polyglucosan body disease (APBD). To better understand this essential Enzyme, we crystallized human GBE1 in the apo form, and in complex with a tetra- or hepta-saccharide. The GBE1 structure reveals a conserved amylase core that houses the active centre for the Branching reaction and harbours almost all GSDIV and APBD mutations. A non-catalytic binding cleft, proximal to the site of the common APBD mutation p.Y329S, was found to bind the tetra- and hepta-saccharides and may represent a higher-affinity site employed to anchor the complex Glycogen substrate for the Branching reaction. Expression of recombinant GBE1-p.Y329S resulted in drastically reduced protein yield and solubility compared with wild type, suggesting this disease allele causes protein misfolding and may be amenable to small molecule stabilization. To explore this, we generated a structural model of GBE1-p.Y329S and designed peptides ab initio to stabilize the mutation. As proof-of-principle, we evaluated treatment of one tetra-peptide, Leu-Thr-Lys-Glu, in APBD patient cells. We demonstrate intracellular transport of this peptide, its binding and stabilization of GBE1-p.Y329S, and 2-fold increased mutant enzymatic activity compared with untreated patient cells. Together, our data provide the rationale and starting point for the screening of small molecule chaperones, which could become novel therapies for this disease.

  • polyglucosan neurotoxicity caused by Glycogen Branching Enzyme deficiency can be reversed by inhibition of Glycogen synthase
    Journal of Neurochemistry, 2013
    Co-Authors: Or Kakhlon, Hasan O. Akman, Hava Glickstein, Naomi Feinstein, Otto Baba, Tatsuo Terashima, Salvatore Dimauro, Alexander Lossos
    Abstract:

    Uncontrolled elongation of Glycogen chains, not adequately balanced by their Branching, leads to the formation of an insoluble, presumably neurotoxic, form of Glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological Glycogenoses, we have modeled the typical Glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing Glycogen Branching Enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of Glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its Glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that Glycogen Branching Enzyme repression in Glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. Knockdown of Glycogen Branching Enzyme in neurons led to accumulation of an insoluble form of Glycogen called polyglucosan, to apoptosis and to activation of Glycogen synthase. These effects were reversed by Glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of Glycogen synthase inhibition for treating Glycogen storage disorders.

  • adult polyglucosan body disease in ashkenazi jewish patients carrying the tyr329 ser mutation in the Glycogen Branching Enzyme gene
    Annals of Neurology, 1998
    Co-Authors: Alexander Lossos, Zeev Meiner, Varda Barash, Dov Soffer, Ilana Schlesinger, Oded Abramsky, Zohar Argov, Shoshi Shpitzen, Vardiella Meiner
    Abstract:

    : Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by Glycogen Branching Enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by Glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

  • Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329 Ser mutation in the Glycogen‐Branching Enzyme gene
    Annals of Neurology, 1998
    Co-Authors: Alexander Lossos, Zeev Meiner, Varda Barash, Dov Soffer, Ilana Schlesinger, Oded Abramsky, Zohar Argov, Shoshi Shpitzen, Vardiella Meiner
    Abstract:

    : Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by Glycogen Branching Enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by Glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

Andreas R Janecke - One of the best experts on this subject based on the ideXlab platform.

  • Congenital type IV Glycogenosis: the spectrum of pleomorphic polyglucosan bodies in muscle, nerve, and spinal cord with two novel mutations in the GBE1 gene
    Acta Neuropathologica, 2008
    Co-Authors: Kay W. Nolte, Matthias Vorgerd, Andreas R Janecke, Joachim Weis, J. Michael Schröder
    Abstract:

    A diagnosis of GSD-IV was established in three premature, floppy infants based on characteristic, however unusually pleomorphic polyglucosan bodies at the electron microscopic level, Glycogen Branching Enzyme deficiency in two cases, and the identification of GBE1 mutations in two cases. Pleomorphic polyglucosan bodies in muscle fibers and macrophages, and less severe in Schwann cells and microglial cells were noted. Most of the inclusions were granular and membrane-bound; others had an irregular contour, were more electron dense and were not membrane bound, or homogenous (‘hyaline’). A paracrystalline pattern of granules was repeatedly noted showing a periodicity of about 10 nm with an angle of about 60° or 120° at sites of changing linear orientation. Malteser crosses were noted under polarized light in the larger inclusions. Some inclusions were PAS positive and others were not. Severely atrophic muscle fibers without inclusions, but with depletion of myofibrils in the plane of section studied indicated the devastating myopathic nature of the disease. Schwann cells and peripheral axons were less severely affected as was the spinal cord. Two novel protein-truncating mutations (c.1077insT, p.V359fsX16; g.101517_127067del25550insCAGTACTAA, DelExon4-7) were identified in these families. The present findings extend previous studies indicating that truncating GBE1 mutations cause a spectrum of severe diseases ranging from generalized intrauterine hydrops to fatal perinatal hypotonia and fatal cardiomyopathy in the first months of life.

  • neonatal type iv Glycogen storage disease associated with null mutations in Glycogen Branching Enzyme 1
    The Journal of Pediatrics, 2004
    Co-Authors: Andreas R Janecke, Susanne Dertinger, Uwepeter Ketelsen, Lothar Bereuter, Burkhard Simma, Thomas Muller, Wolfgang Vogel, Felix Offner
    Abstract:

    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.

Salvatore Dimauro - One of the best experts on this subject based on the ideXlab platform.

  • Compound heterozygosis of a splice site and the common Ashkenazi Jewish mutation in GBE1 causes adult onset polyglucosan body disease. (P2.026)
    Neurology, 2015
    Co-Authors: Orhan H Akman, Yasemin Gulcan Kurt, Raphael Schiffmann, Mary Wallace, Salvatore Dimauro
    Abstract:

    OBJECTIVE: To determine the genetic cause of Glycogen Branching Enzyme (GBE) deficiency leading to late onset Glycogenosis type IV BACKGROUND: Adult polyglucosan body disease (APBD) is a rare autosomal recessive disorder, caused by pathogenic mutations in Glycogen Branching Enzyme gene (GBE1). Disease is characterized by urinary dysfunction, spastic paraplegia with vibration sense loss, peripheral neuropathy, and cognitive impairment. Because of the similarities, APBD is misdiagnosed with multiple sclerosis, benign prostatic hyperplasia, and rarely with ALS and dementia. Symptoms start at 4th or 5th decade of life, the most common mutation causing APBD is c.A986C found in Ashkenazi Jewish population substituting tyrosine with serine in 329th codon (p.Y329S). Deficiency of GBE causes poorly branched Glycogen similar to starch found in plants. This alteration in structure makes polyglucosan precipitate in the cell adversely affecting the cell function. DESIGN/METHODS: Patient we report here is a 60 year old man. He has mainly neurogenic bladder and minor difficulty in executive function. His gait is virtually normal with minor balance deficit. We measured biochemical activity of GBE in white blood cells and sequence the GBE1 gene and cDNA to present the aberrant splicing of mRNA. RESULTS: We have determined that patient has 8[percnt] of normal GBE activity due to two pathogenic heterozygous mutations c.A986C and c.691+2T>C, one substituting tyrosine with serine and the second affecting the proper splicing of mRNA. CONCLUSIONS: APBD is an underdiagnosed disease, here we report the first time the occurrence of c.691+2T>C, mutation in an adult patient. This information is important for genetic diagnosis and management of the disease. Disclosure: Dr. Akman has nothing to disclose. Dr. Kurt has nothing to disclose. Dr. Wallace has nothing to disclose. Dr. Schiffmann has received personal compensation for activities with Amicus Therapeutics and Shire Human Genetic Therapies as a speaker. Dr. DiMauro has received personal compensation in an editorial capacity for MedLink Neurology.

  • Branching Enzyme Deficiency: Expanding the Clinical Spectrum
    JAMA Neurology, 2014
    Co-Authors: Carmen Paradas, Hasan O. Akman, Carolina Ionete, Peter Riskind, David E. Jones, Thomas W. Smith, Michio Hirano, Salvatore Dimauro
    Abstract:

    Importance The neuromuscular presentation of Glycogen Branching Enzyme deficiency includes a severe infantile form and a late-onset variant known as adult polyglucosan body disease. Herein, we describe 2 patients with adult acute onset of fluctuating neurological signs and brain magnetic resonance imaging lesions simulating multiple sclerosis. A better definition of this new clinical entity is needed to facilitate diagnosis. Objectives To describe the clinical presentation and progression of a new intermediate variant of Glycogen Branching Enzyme deficiency and to discuss genotype-phenotype correlations. Design, Setting, and Participants Clinical, biochemical, morphological, and molecular study of 2 patients followed up for 6 years and 8 years at academic medical centers. The participants were 2 patients of non-Ashkenazi descent with adult acute onset of neurological signs initially diagnosed as multiple sclerosis. Main Outcomes and Measures Clinical course, muscle and nerve morphology, longitudinal study of brain magnetic resonance imaging, and Glycogen Branching Enzyme activity and GBE1 molecular analysis. Results Molecular analysis showed that one patient was homozygous (c.1544G>A) and the other patient was compound heterozygous (c.1544G>A and c.1961-1962delCA) for GBE1 mutations. Residual Glycogen Branching Enzyme activity was 16% and 30% of normal in leukocytes. Both patients manifested acute episodes of transient neurological symptoms, and neurological impairment was mild at age 45 years and 53 years. Brain magnetic resonance imaging revealed nonprogressive white matter lesions and spinocerebellar atrophy similar to typical adult polyglucosan body disease. Conclusions and Relevance GBE1 mutations can cause an early adult–onset relapsing-remitting form of polyglucosan body disease distinct from adult polyglucosan body disease in several ways, including younger age at onset, history of infantile liver involvement, and subacute and remitting course simulating multiple sclerosis. This should orient neurologists toward the correct diagnosis.

  • polyglucosan neurotoxicity caused by Glycogen Branching Enzyme deficiency can be reversed by inhibition of Glycogen synthase
    Journal of Neurochemistry, 2013
    Co-Authors: Or Kakhlon, Hasan O. Akman, Hava Glickstein, Naomi Feinstein, Otto Baba, Tatsuo Terashima, Salvatore Dimauro, Alexander Lossos
    Abstract:

    Uncontrolled elongation of Glycogen chains, not adequately balanced by their Branching, leads to the formation of an insoluble, presumably neurotoxic, form of Glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological Glycogenoses, we have modeled the typical Glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing Glycogen Branching Enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of Glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its Glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that Glycogen Branching Enzyme repression in Glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. Knockdown of Glycogen Branching Enzyme in neurons led to accumulation of an insoluble form of Glycogen called polyglucosan, to apoptosis and to activation of Glycogen synthase. These effects were reversed by Glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of Glycogen synthase inhibition for treating Glycogen storage disorders.

  • Branching Enzyme deficiency/Glycogenosis storage disease type IV presenting as a severe congenital hypotonia: muscle biopsy and autopsy findings, biochemical and molecular genetic studies.
    Neuromuscular Disorders, 2010
    Co-Authors: Ana Lia Taratuto, Hasan O. Akman, M. Saccoliti, Miguel A. Riudavets, Naomi Arakaki, L. Mesa, Gustavo Sevlever, Hans-hilmar Goebel, Salvatore Dimauro
    Abstract:

    The fatal infantile neuromuscular presentation of Branching Enzyme deficiency (Glycogen storage disease type IV) due to mutations in the gene encoding the Glycogen Branching Enzyme, is a rare but probably underdiagnosed cause of congenital hypotonia. We report an infant girl with severe generalized hypotonia, born at 33 weeks gestation who required ventilatory assistance since birth. She had bilateral ptosis, mild knee and foot contractures and echocardiographic evidence of cardiomyopathy. A muscle biopsy at 1 month of age showed typical polyglucosan storage. The autopsy at 3.5 months of age showed frontal cortex polymicrogyria and polyglucosan bodies in neurons of basal ganglia, thalamus, substantia innominata, brain stem, and myenteric plexus, as well as liver involvement. Glycogen Branching Enzyme activity in muscle was virtually undetectable. Sequencing of the GBE1 gene revealed a homozygous 28 base pair deletion and a single base insertion at the same site in exon 5. This case confirms previous observations that GBE deficiency ought to be included in the differential diagnosis of congenital hypotonia and that the phenotype correlates with the ‘molecular severity’ of the mutation.

  • Placental Involvement in Glycogen Storage Disease Type IV
    Placenta, 2008
    Co-Authors: Anastasia E. Konstantinidou, Susanne Dertinger, Hector Anninos, A. Nonni, Michael B. Petersen, C. Karadimas, Sophia Havaki, Evangelos Marinos, H.o. Akman, Salvatore Dimauro
    Abstract:

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by Glycogen Branching Enzyme (GBE) deficiency and resulting in the storage of abnormal Glycogen (polyglucosan). Prenatal diagnosis is based on biochemical assay of GBE activity or on mutation analysis, but polyglucosan can also be identified histologically in fetal tissues. We document placental involvement at 25 and 35 weeks of gestation in two cases with genetically confirmed GSD IV. Intracellular inclusions were seen mainly in the extravillous trophoblast. Our findings suggest the possibility of prenatal diagnosis by histological evaluation of placental biopsies.

J F Cannon - One of the best experts on this subject based on the ideXlab platform.