De Ridder, Willem, Azmi, Abdelkrim, Clemen, Christoph S., Eichinger, Ludwig, Hofmann, Andreas, Schroeder, Rolf, Johnson, Katherine ORCID: 0000-0002-3593-7966, Topf, Ana, Straub, Volker ORCID: 0000-0001-9046-3540, De Jonghe, Peter, Maudsley, Stuart, De Bleecker, Jan L. and Baets, Jonathan (2020). Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: A tale of the unexpected. Neurology, 94 (8). S. E785 - 12. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1526-632X

Full text not available from this repository.

Abstract

ObjectiveTo 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.MethodsWe 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.ResultsThe 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.ConclusionWe 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
De Ridder, WillemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azmi, AbdelkrimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichinger, LudwigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, KatherineUNSPECIFIEDorcid.org/0000-0002-3593-7966UNSPECIFIED
Topf, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Straub, VolkerUNSPECIFIEDorcid.org/0000-0001-9046-3540UNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maudsley, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Bleecker, Jan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baets, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-344001
DOI: 10.1212/WNL.0000000000008763
Journal or Publication Title: Neurology
Volume: 94
Number: 8
Page Range: S. E785 - 12
Date: 2020
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1526-632X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INCLUSION-BODY MYOPATHY; GENOTYPE-PHENOTYPE; PAGET-DISEASE; VALOSIN; SPECTRUM; VCP/P97Multiple languages
Clinical NeurologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34400

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item