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Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

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), neurodegen...

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Autores principales: Chompoopong, Pitcha, Oskarsson, Björn, Madigan, Nicolas N., Mirman, Igal, Martinez‐Thompson, Jennifer M., Liewluck, Teerin, Milone, Margherita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10109322/
https://www.ncbi.nlm.nih.gov/pubmed/36861178
http://dx.doi.org/10.1002/acn3.51751
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author Chompoopong, Pitcha
Oskarsson, Björn
Madigan, Nicolas N.
Mirman, Igal
Martinez‐Thompson, Jennifer M.
Liewluck, Teerin
Milone, Margherita
author_facet Chompoopong, Pitcha
Oskarsson, Björn
Madigan, Nicolas N.
Mirman, Igal
Martinez‐Thompson, Jennifer M.
Liewluck, Teerin
Milone, Margherita
author_sort Chompoopong, Pitcha
collection PubMed
description 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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spelling pubmed-101093222023-04-18 Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum Chompoopong, Pitcha Oskarsson, Björn Madigan, Nicolas N. Mirman, Igal Martinez‐Thompson, Jennifer M. Liewluck, Teerin Milone, Margherita Ann Clin Transl Neurol Research Articles 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. John Wiley and Sons Inc. 2023-03-01 /pmc/articles/PMC10109322/ /pubmed/36861178 http://dx.doi.org/10.1002/acn3.51751 Text en © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Chompoopong, Pitcha
Oskarsson, Björn
Madigan, Nicolas N.
Mirman, Igal
Martinez‐Thompson, Jennifer M.
Liewluck, Teerin
Milone, Margherita
Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum
title Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum
title_full Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum
title_fullStr Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum
title_full_unstemmed Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum
title_short Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum
title_sort multisystem proteinopathies (msps) and msp‐like disorders: clinical‐pathological‐molecular spectrum
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10109322/
https://www.ncbi.nlm.nih.gov/pubmed/36861178
http://dx.doi.org/10.1002/acn3.51751
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