Multisystem proteinopathies (MSPs) and MSP-like disorders: Clinical-pathological-molecular spectrum
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Published on: October 30, 2016
Pitcha Chompoopong1, Björn Oskarsson2, Nicolas N Madigan1
1Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
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.
Insights
Multisystem proteinopathies (MSP) and MSP-like disorders result from mutations in genes like VCP, leading to protein aggregation. This study defines the spectrum of these disorders, highlighting VCP-MSP as most common with distinct clinical features.
Area of Science:
- Genetics
- Neurology
- Pathology
Background:
- Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 cause multisystem proteinopathies (MSP), characterized by protein aggregation and a combination of inclusion body myopathy (IBM), neurodegeneration (motor neuron disorder/frontotemporal dementia), and Paget disease of bone (PDB).
- Additional genes have been identified that link to similar but not full clinical-pathological spectrum disorders, termed MSP-like disorders.
Purpose of the Study:
- To define the phenotypic-genotypic spectrum of multisystem proteinopathies (MSP) and MSP-like disorders.
- To include long-term follow-up features of these rare genetic disorders.
Main Methods:
- A retrospective review of patients with mutations in causative genes for MSP and MSP-like disorders was conducted.
- The study analyzed data from the Mayo Clinic database between January 2010 and June 2022.
Main Results:
- Thirty-one individuals (27 families) with pathogenic mutations in VCP, SQSTM1+TIA1, TIA1, MATR3, HNRNPA1, HSPB8, and TFG were identified.
- VCP-MSP was the most common, presenting with myopathy in most cases. Rimmed vacuolar myopathy was frequent. Neurodegenerative features (MND/FTD), PDB, and cardiac dysfunction were observed, primarily in VCP-MSP.
- Long-term follow-up showed that while many patients maintained ambulation, loss of ambulation and death occurred exclusively in VCP-MSP patients.
Conclusions:
- VCP-MSP is the most prevalent disorder within this group, characterized by specific clinical manifestations including rimmed vacuolar myopathy and cardiac involvement.
- Distal-predominant weakness is a frequent feature in non-VCP-MSP disorders.
- Understanding the broad phenotypic-genotypic spectrum and long-term outcomes is crucial for managing these complex genetic disorders.
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