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Congenital type IV glycogenosis: the spectrum of pleomorphic polyglucosan bodies in muscle, nerve, and spinal cord with two novel mutations in the GBE1 gene

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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.

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Acknowledgments

Clinical data and specimens from cases 1 and 2 were submitted for diagnostic purposes by Chefarzt Dr. med. H. Rickers, Marienhospital Osnabrück, Germany; those of case 3 by Prof. Dr. med. Florian Heinen, Klinikum Duisburg, Wedau Kliniken, Germany. Autopsy data and specimens were kindly provided by Privatdozent Dr. med. R. Krech, Head of the Department of Pathology of the City Hospital of Osnabrück, Germany. Glycogen branching enzyme assays were performed by Prof. Dr. Shin, Universitätskinderklinik München, Germany. Alpha-1,4-glucosidase (acid maltase) and N-acetyl-glucosaminidase activity assays were performed by Prof. Dr. Gerbitz, München, Germany. The technical help of Verena Wild, Hannelore Mader, Hannelore Wiederholt, and Astrid Knischewski, and the secretarial help of Doris Dahmen are gratefully acknowledged. This study was supported in part by grants of the BMBF (MD-Net) to M.V. and J. W. and by the START and IZKF programs of the RWTH to J. W.

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  1. Department of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany

    Kay W. Nolte, Joachim Weis & J. Michael Schröder

  2. Division of Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria

    Andreas R. Janecke

  3. Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany

    Matthias Vorgerd

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  1. Kay W. Nolte
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  2. Andreas R. Janecke
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  5. J. Michael Schröder
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Correspondence to J. Michael Schröder.

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Kay W. Nolte and Andreas R. Janecke contributed equally to this study.

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Nolte, K.W., Janecke, A.R., Vorgerd, M. et al. 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 Neuropathol 116, 491–506 (2008). https://doi.org/10.1007/s00401-008-0417-8

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