Hereditary Inclusion Body Myopathy: A Decade of Progress

Office of the Clinical Director, National Human Genome Research Institute, National institutes of Health, Bethesda, MD 20892, USA
Biochimica et Biophysica Acta (Impact Factor: 4.66). 09/2009; 1792(9):881-887. DOI: 10.1016/j.bbadis.2009.07.001


Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, quadriceps sparing type commonly referred to as HIBM but also termed h-IBM or Inclusion Body Myopathy 2 (IBM2). The clinical manifestations begin with muscle weakness progressing over the next 10–20 years uniquely sparing the quadriceps until the most advanced stage of the disease. Histopathology of an HIBM muscle biopsy shows rimmed vacuoles on Gomori's trichrome stain, small fibers in groups and tubulofilaments without evidence of inflammation. In affected individuals distinct mutations have been identified in the GNE gene, which encodes the bifunctional enzyme uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetyl-mannosamine (ManNAc) kinase (GNE/MNK). GNE/MNK catalyzes the first two committed steps in the biosynthesis of acetylneuraminic acid (Neu5Ac), an abundant and functionally important sugar. The generation of HIBM animal models has led to novel insights into both the disease and the role of GNE/MNK in pathophysiology. Recent advances in therapeutic approaches for HIBM, including administration of N-acetyl-mannosamine (ManNAc), a precursor of Neu5Ac will be discussed.

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    • "Sialic acids can mediate or modulate a wide variety of physiological and pathological processes, and sialic acids have roles in both health and multiple disease areas, including immunology, cardiology, hematology, oncology, and others [2]. GNE myopathy is an autosomal recessive muscular disorder characterized by progressive muscle weakness and atrophy with onset in early adulthood [4] [5]. GNE myopathy is caused by biallelic mutations in the GNE gene, which encodes the bifunctional enzyme uridine diphospho-N-acetylglucosamine 2- 1570-0232/© 2015 Elsevier B.V. All rights reserved. "
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    ABSTRACT: N-acetylneuraminic acid (Neu5Ac or NANA) is the most predominant sialic acid in mammals. As a terminal component in many glycoproteins and glycolipids, sialic acid is believed to be an important biomarker related to various diseases. Its precursor, N-acetylmannosamine (ManNAc), is being investigated as a potential treatment for GNE myopathy. In this work, we developed two highly sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for the quantitation of ManNAc and free Neu5Ac in human plasma. A fit-for-purpose approach was adopted during method validation and sample analysis. To measure the endogenous compounds and overcome the interference from plasma samples, a surrogate matrix that contained 5% bovine serum albumin (BSA) was used for the preparation of calibration standards and certain levels of quality control (QC) samples. QC samples at higher concentrations were prepared in the authentic matrix (human plasma) to best mimic incurred samples. For both methods, an Ostro 96-well phospholipid removal plate was used for sample extraction, which efficiently removed the phospholipids from the plasma samples prior to LC injection, eliminated matrix effect, and improved sensitivity. Chromatographic separation was achieved using hydrophilic interaction chromatography (HILIC) and gradient elution in order to retain the two polar compounds. The lower limit of quantitation (LLOQ) for ManNAc and Neu5Ac was 10.0 and 25.0ng/mL, respectively. The overall accuracy of the two assays was within 100%±8.3% based on three levels of QC samples. Inter- and intra-run precision (coefficient of variation (%CV)) across three analytical runs was less than 6.7% for ManNAc and less than 10.8% for Neu5Ac. These methods have been validated to support clinical studies. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jul 2015 · Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
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    • "In this case, the diagnosis of DMRV is confirmed by a molecular genetics study for mutations in the GNE gene. Our patient harbors compound heterozygous GNE mutations of the epimerase domain at c.1057A>G (p.K353E) on exon 6 and of the kinase domain at c.2086G>A (p.V696M) on exon 12. Interestingly, although c.2086G>A (p.V696M) is a common mutation which is present in all Thai DMRV patients [6, 7], it is also present in Indian, Algerian, and Chinese patients [8, 9]. To our knowledge, the c.1057A>G (p.K353E) mutation has not been reported elsewhere. "
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    ABSTRACT: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive or sporadic early adult-onset myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase (GNE) gene. Characteristic pathologic features of DMRV are rimmed vacuoles on muscle biopsy and tubulofilamentous inclusion in ultrastructural study. Presence of inflammation in DMRV is unusual. We report a sporadic case of DMRV in a 40-year-old Thai man who presented with slowly progressive distal muscle weakness. Gene analysis revealed a compound heterozygous mutation of the GNE gene including a novel mutation c.1057A>G (p.K353E) and a known mutation c.2086G>A (p.V696M). The latter is the most common mutation in Thai DMRV patients. The muscle pathology was compatible with DMRV except for focal inflammation.
    Full-text · Article · Mar 2014 · Case Reports in Neurology
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    • "This enzyme is the key factor in the biosynthesis of sialic acid, known to be involved in diverse biological pathways, linked to cell–cell interactions, and in particular has a special role in brain development (Keppler et al. 1999; Varki 1997). To date, over 60 mutations in GNE have been reported to cause the disease worldwide (Huizing and Krasnewich 2009), but a single homozygous missense "
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    ABSTRACT: GNE myopathy is a rare neuromuscular autosomal recessive disease, resulting from mutations in the gene UDP N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). The most frequent mutation is the single homozygous missense mutation, M712T-the Middle Eastern mutation-located ten amino acids before the end of the protein. We have used an adeno-associated virus (AAV)-based trans-splicing (TS) vector as a gene therapy tool to overcome this mutation by replacing the mutated last exon of GNE by the wild-type exon while preserving the natural endogenous regulatory machinery. We have designed relevant plasmids directed either to mouse or to human GNE. Following transfection of C2C12 murine muscle cells with the mouse TS vectors, we have been able to detect by nested RT-PCR trans-spliced molecules carrying the wild-type exon 12 of GNE. Similarly, transfection of HEK293 human cells with the human-directed TS vectors resulted in the generation of trans-spliced human GNE RNA molecules. Furthermore, infection of primary muscle cells from a GNE myopathy patient carrying the homozygous M712T mutation, with an AAV8-based viral vector carrying a human-directed TS construct, resulted in the generation of wild-type GNE transcripts in addition to the mutated ones. These studies provide a proof of concept that the TS approach could be used to partially correct the Middle Eastern mutation in GNE myopathy patients. These results provide the basis for in vivo research in animal models using the AAV platform with TS plasmids as a potential genetic therapy for GNE myopathy.
    Full-text · Article · Nov 2013 · Neuromolecular medicine
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