Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation
A tale of the unexpected
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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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