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February 25, 2020; 94 (8) Article

Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation

A tale of the unexpected

Willem De Ridder, Abdelkrim Azmi, Christoph S. Clemen, Ludwig Eichinger, Andreas Hofmann, Rolf Schröder, Katherine Johnson, Ana Töpf, Volker Straub, Peter De Jonghe, Stuart Maudsley, Jan L. De Bleecker, Jonathan Baets
First published December 17, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008763
Willem De Ridder
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Abdelkrim Azmi
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Christoph S. Clemen
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Ludwig Eichinger
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Andreas Hofmann
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Rolf Schröder
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Katherine Johnson
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Ana Töpf
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Volker Straub
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Peter De Jonghe
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Stuart Maudsley
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Jan L. De Bleecker
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Jonathan Baets
From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.
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Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation
A tale of the unexpected
Willem De Ridder, Abdelkrim Azmi, Christoph S. Clemen, Ludwig Eichinger, Andreas Hofmann, Rolf Schröder, Katherine Johnson, Ana Töpf, Volker Straub, Peter De Jonghe, Stuart Maudsley, Jan L. De Bleecker, Jonathan Baets
Neurology Feb 2020, 94 (8) e785-e796; DOI: 10.1212/WNL.0000000000008763

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Abstract

Objective To assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.

Methods We studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.

Results The index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.

Conclusion We report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.

Glossary

CK=
creatine kinase;
DDR=
DNA damage response;
FDR=
false discovery rate;
FDT=
frontotemporal dementia;
IBM=
inclusion body myopathy;
MHC-I=
major histocompatibility complex I;
MS=
mass spectrometer;
MSP1=
multisystem proteinopathy 1;
PDB=
Paget disease of bone;
sIBM=
sporadic inclusion body myopathy;
VCP=
valosin-containing protein gene

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received June 3, 2019.
  • Accepted in final form August 28, 2019.
  • © 2019 American Academy of Neurology
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Neurology | Print ISSN:0028-3878
Online ISSN:1526-632X

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