Chart of GBE1 mutations

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H. Orhan Akman, PhD; Or Kakhlon, PhD; Jorida Coku, MS; Lorenzo Peverelli, MD; Hanna Rosenmann, PhD; Lea Rozenstein-Tsalkovich, BSc; Julie Turnbull, PhD; Vardiella Meiner, MD; Liat Chama, BSc; Israela Lerer, PhD; Shoshi Shpitzen, MS; Eran Leitersdorf, MD; Carmen Paradas, MD; Mary Wallace, LD, CCRC; Raphael Schiffmann, MD; Salvatore DiMauro, MD; Alexander Lossos, MD; Berge A. Minassian, MD. “Deep Intronic GBE1 Mutation in Manifesting Heterozygous Patients With Adult Polyglucosan Body Disease.” JAMA Neurology, Vol 72, No. 4, April 2015.

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Busard HL, Gabreels-Festen AA, Renier WO et al. Adult polyglucosan body disease: the diagnostic value of axilla skin biopsy. Ann Neurol. 1991;29:448-451.

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Colombo I., Pagliarani S., Testolin S., Salsano E.,  Napoli L.M., Bordoni A., Salani S., D’Adda E., Morandi L., Farina L., Magri F., Riva M., Prelle A., Sciacco M.,  Comi G.P., Moggio M. Adult Polyglucosan Body Disease: Clinical and histological heterogeneity of a large Italian family. Neuromuscular Disorders 25 (2015) 423–428

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D. Sean Froese, Amit Michaeli, Thomas J. McCorvie, Tobias Krojer, Meitav Sasi, Esther Melaev, Amiram Goldblum, Maria Zatsepin, Alexander Lossos, Rafael Alvarez, Pablo V. Escriba, Berge A. Minassian, Frank von Delft, Or Kakhlon, and Wyatt W. Yue. “Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design.” Human Molecular Genetics, Vol. 24, Issue 20, pp 5667-5676
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Hellmann MA1, Kakhlon O, Landau EH, Sadeh M, Giladi N, Schlesinger I, Kidron D, Abramsky O, Reches A, Argov Z, Rabey JM, Chapman J, Rosenmann H, Gal A, Moshe Gomori J, Meiner V, Lossos A. “Frequent misdiagnosis of adult polyglucosan body disease.” J Neurology, 2015 Oct;262(10):2346-51. doi: 10.1007/s00415-015-7859-4. Epub 2015 Jul 21.

Kahlon, O, A Lossos, H Glickstein, N Feinstein, Y Liu, O Baba, T Terashima, HO Akman, and S DiMauro. “Polyglucosan neurotoxicity caused by glycogen branching enzyme deficiency can be reversed by inhibition of glycogen synthase.” Journal of Neurochemistry 10.1111 (2013): n. pag. Journal of Neurochemistry. Web. 9 May 2013.

Or Kakhlon, … , Wyatt W. Yue, H. Orhan Akman. Guaiacol as a drug candidate for treating adult polyglucosan body disease. JCI Insight. 2018;3(17):e99694. View Paper.
Appendix 1. Appendix 2 Appendix 3

Kakkis et al. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints. Orphanet Journal of Rare Diseases (2015) 10:16 DOI 10.1186/s13023-014-0195-4

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Klein CJ, Boes CJ, Chapin JE et al. Adult polyglucosan body disease: case description of an expanding genetic and clinical syndrome. Muscle Nerve. 2004;29:323-328.

Klein CJ. Adult polyglucosan body disease. GeneReviews. Seattle: University of Washington, 2009.

Kniffin, Cassandra L. Polyglucosan body disease, adult form.

Kollberg Gittan, Tulinius Már, Gilljam Thomas,Östman-Smith Ingegerd,Forsander Gun, Jotorp Peter, Oldfors Anders and Holme Elisabeth. Cardiomyopathy and Exercise Intolerance in Muscle Glycogen Storage Disease 0. The New England Journal of Medicine. 2007;357:1507-14.

Labauge P. Magnetic resonance findings in leucodystrophies and MS. Int MS J. 2009;16:47-56.

Lossos A, Meiner Z, Barash V et al. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogenbranching enzyme gene. Ann Neurol. 1998;44:867-872.

Lossos A, Barash V, Soffer D et al. Hereditary branching enzyme dysfunction in adult polyglucosan body disease: a possible metabolic cause in two patients. Ann Neurol. 1991;30:655-662.

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Massa R, Bruno C, Martorana A et al. Adult polyglucosan body disease: proton magnetic resonance spectroscopy of the brain and novel mutation in the GBE1 gene. Muscle Nerve. 2008;37:530-536.

McConkie-Rosell A, Wilson C, Piccoli DA et al. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis. 1996;19:51-58.

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Mochel Fanny et al. Adult Polyglucosan Body Disease: Natural History and Key MRI Findings. Accepted Article, doi: 10.1002/ana.23598

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Rifai Z, Klitzke M, Tawil R et al. Dementia of adult polyglucosan body disease. Evidence of cortical and subcortical dysfunction. Arch Neurol. 1994;51:90-94.

Robitaille Y, Carpenter S, Karpati G, DiMauro SD. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing. Brain. 1980;103:315-336.

Scheper GC, van der Klok T, van Andel RJ et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet. 2007;39:534-539.

Schroder JM, May R, Shin YS et al. Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type IV glycogenosis). Acta Neuropathol. 1993;85:419-430.

Schuster J, Sundblom J, Thuresson AC et al. Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms. Neurogenetics. 2011;12:65-72.

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Sindern E, Ziemssen F, Ziemssen T et al. Adult polyglucosan body disease: a postmortem correlation study. Neurology. 2003;61:263-265.

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Tay SK, Akman HO, Chung WK et al. Fatal infantile neuromuscular presentation of glycogen storage disease type IV. Neuromuscul Disord. 2004;14:253-260.

Ubogu EE, Hong ST, Akman HO et al. Adult polyglucosan body disease: a case report of a manifesting heterozygote. Muscle Nerve. 2005;32:675-681.

Van der Knaap MS, Breiter SN, Naidu S et al. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology. 1999;213:121-133.

Vucic S, Pamphlett R, Wills EJ, Yiannikas C. Polyglucosan body disease myopathy: an unusual presentation. Muscle Nerve. 2007;35:536-539.

Yasuo Harigaya, MD, PhD, Takashi Matsukawa, MD, PhD, Yukio Fujita, MD, PhD, Kazuyuki Mizushima, MD, PhD, Hiroyuki Ishiura, MD, PhD, Jun Mitsui, MD, PhD, Shinichi Morishita, MD, PhD, Mikio Shoji, MD, PhD, Yoshio Ikeda, MD, PhD, and Shoji Tsuji, MD, PhD Novel GBE1 mutation in a Japanese family with adult polyglucosan body disease. Neurol Genet. 2017 Apr; 3(2): e138. Published online 2017 Feb 24. doi: 10.1212/NXG.0000000000000138

Ziemssen F, Sindern E, Schroder JM et al. Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease. Ann Neurol. 2000;47:536-540.



Manifesting Heterozygotes




  • Carmen Paradas, MD; Hasan O. Akman, PhD; Carolina Ionete, MD; Heather Lau, MD; Peter N. Riskind, MD, PhD; David E. Jones, MD; Thomas W. Smith, MD; Michio Hirano, MD; Salvatore DiMauro, MD
    Branching Enzyme Deficiency Expanding the Clinical Spectrum
    Keywords:  Adult Polyglucosan Body Disease (APBD); Glycogen Storage Disease Type IV; Leukodystrophy; Multiple Sclerosis, Relapsing-Remitting; Polyneuropathy

Intronic mutation