Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: A tale of the unexpected
De Ridder W, Azmi A, Clemen CS, Eichinger L, Hofmann A, Schröder R, Johnson K, Töpf A, Straub V, De Jonghe P, Maudsley S, De Bleecker JL, Baets J (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 94
Pages Range: e785-e796
Journal Issue: 8
DOI: 10.1212/WNL.0000000000008763
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.
Additional Organisation(s)
Involved external institutions
Belgium (BE)How to cite
APA:
De Ridder, W., Azmi, A., Clemen, C.S., Eichinger, L., Hofmann, A., Schröder, R.,... Baets, J. (2020). Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: A tale of the unexpected. Neurology, 94(8), e785-e796. https://dx.doi.org/10.1212/WNL.0000000000008763
MLA:
De Ridder, Willem, et al. "Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: A tale of the unexpected." Neurology 94.8 (2020): e785-e796.
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