To define phenotypic and genotypic spectrum of multisystem proteinopathies (MSP) and MSP-like disorders.

MSPs are genetically heterogenous disorders featured by neurodegeneration including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), inclusion body myopathy (IBM), and Paget disease of bone (PDB), sharing similar pathological findings of protein aggregation. Additional genes encoding RNA-binding proteins or proteins involved in quality-control pathways also lead to myopathy or neurodegeneration, although not necessarily within the same family, causing similar pathological abnormalities (MSP-like disorders).

We searched Mayo Clinic database (1/1/2010-6/30/2022) to identify patients with mutations in genes causative of MSP and MSP-like disorders. Clinical and laboratory data were reviewed.

Thirty-one individuals (11 female) from 27 unrelated families were identified. Pathogenic mutations were in: VCP (17 patients/14 families), SQSTM1+TIA1 (5 patients/5 families), TIA1 (5 patients/4 families), MATR3, HNRNPA1, HSPB8, and TFG (1 patient each). Myopathy occurred in all but 2 VCP-MSP patients and was the initial presentation at median age of 52. Patterns of weakness were limb-girdle in 12/15 VCP-MSP and distal-predominant in the remaining patients. Twenty/24 muscle biopsies showed myopathy with rimmed vacuoles. MND and FTD occurred in 5 (4 VCP, 1 TFG) and 4 (3 VCP, 1 SQSTM1+TIA1) patients, respectively. PDB was present in 4 VCP-MSP.  Twenty-one patients had last echocardiogram 8 years (median; range 3-22 years) after disease onset showing diastolic dysfunction in 2 VCP-MSP patients. Six patients demonstrated restrictive ventilatory impairment 15 years after disease-onset. At median follow-up of 11.5 years, 15 patients were ambulating without gait-aids; loss of ambulation (n=5) and death (n=3) were recorded only in VCP-MSP patients.