Article ; Online: Multisystem proteinopathies (MSPs) and MSP-like disorders: Clinical-pathological-molecular spectrum.
Annals of clinical and translational neurology
2023 Volume 10, Issue 4, Page(s) 632–643
Abstract: Objectives: Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1, encoding RNA-binding proteins or proteins in quality-control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical ... ...
| Abstract | Objectives: Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1, encoding RNA-binding proteins or proteins in quality-control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical combinations of inclusion body myopathy (IBM), neurodegeneration [motor neuron disorder (MND)/frontotemporal dementia (FTD)], and Paget disease of bone (PDB). Subsequently, additional genes were linked to similar but not full clinical-pathological spectrum (MSP-like disorders). We aimed to define the phenotypic-genotypic spectrum of MSP and MSP-like disorders at our institution, including long-term follow-up features. Methods: We searched the Mayo Clinic database (January 2010-June 2022) to identify patients with mutations in MSP and MSP-like disorders causative genes. Medical records were reviewed. Results: Thirty-one individuals (27 families) had pathogenic mutations in: VCP (n = 17), SQSTM1 + TIA1 (n = 5), TIA1 (n = 5), MATR3, HNRNPA1, HSPB8, and TFG (n = 1, each). Myopathy occurred in all but 2 VCP-MSP patients with disease onset at age 52 (median). Weakness pattern was limb-girdle in 12/15 VCP-MSP and HSPB8 patient, and distal-predominant in other MSP and MSP-like disorders. Twenty/24 muscle biopsies showed rimmed vacuolar myopathy. MND and FTD occurred in 5 (4 VCP, 1 TFG) and 4 (3 VCP, 1 SQSTM1 + TIA1) patients, respectively. PDB manifested in 4 VCP-MSP. Diastolic dysfunction occurred in 2 VCP-MSP. After 11.5 years (median) from symptom onset, 15 patients ambulated without gait-aids; loss of ambulation (n = 5) and death (n = 3) were recorded only in VCP-MSP. Interpretation: VCP-MSP was the most common disorder; rimmed vacuolar myopathy was the most frequent manifestation; distal-predominant weakness occurred frequently in non-VCP-MSP; and cardiac involvement was observed only in VCP-MSP. |
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| MeSH term(s) | Humans ; Middle Aged ; Frontotemporal Dementia/genetics ; Valosin Containing Protein/genetics ; Sequestosome-1 Protein/genetics ; Muscular Diseases/genetics ; RNA-Binding Proteins ; Nuclear Matrix-Associated Proteins |
| Chemical Substances | Valosin Containing Protein (EC 3.6.4.6) ; Sequestosome-1 Protein ; MATR3 protein, human ; RNA-Binding Proteins ; Nuclear Matrix-Associated Proteins |
| Language | English |
| Publishing date | 2023-03-01 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2740696-9 |
| ISSN | 2328-9503 ; 2328-9503 |
| ISSN (online) | 2328-9503 |
| ISSN | 2328-9503 |
| DOI | 10.1002/acn3.51751 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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