<h3>Objective:</h3> To define phenotypic and genotypic spectrum of multisystem proteinopathies (MSP) and MSP-like disorders. <h3>Background:</h3> 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). <h3>Design/Methods:</h3> 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. <h3>Results:</h3> Thirty-one individuals (11 female) from 27 unrelated families were identified. Pathogenic mutations were in: <i>VCP</i> (17 patients/14 families), <i>SQSTM1+TIA1</i> (5 patients/5 families), <i>TIA1</i> (5 patients/4 families), <i>MATR3, HNRNPA1</i>, <i>HSPB8</i>, and <i>TFG</i> (1 patient each). Myopathy occurred in all but 2 <i>VCP</i>-MSP patients and was the initial presentation at median age of 52. Patterns of weakness were limb-girdle in 12/15 <i>VCP</i>-MSP and distal-predominant in the remaining patients. Twenty/24 muscle biopsies showed myopathy with rimmed vacuoles. MND and FTD occurred in 5 (4 <i>VCP</i>, 1 <i>TFG</i>) and 4 (3 <i>VCP</i>, <i>1 SQSTM1+TIA1</i>) patients, respectively. PDB was present in 4 <i>VCP</i>-MSP. Twenty-one patients had last echocardiogram 8 years (median; range 3–22 years) after disease onset showing diastolic dysfunction in 2 <i>VCP</i>-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 <i>VCP</i>-MSP patients. <h3>Conclusions:</h3> Among MSP and MSP-related disorders, <i>VCP</i> was the most common causative gene, followed by <i>SQSTM1+TIA1</i> and <i>TIA1</i>; myopathy with rimmed vacuoles was the most frequent manifestation; distal-predominant weakness occurred frequently in non-<i>VCP</i>MSP; loss of ambulation was observed only in <i>VCP</i>-MSP at 11.5-year follow-up. <b>Disclosure:</b> Dr. Chompoopong has nothing to disclose. Dr. Oskarsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. The institution of Dr. Oskarsson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Oskarsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AnnJi. The institution of Dr. Oskarsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi. Dr. Oskarsson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Tsumura. The institution of Dr. Oskarsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MediciNova. The institution of Dr. Oskarsson has received research support from Biogen. The institution of Dr. Oskarsson has received research support from Medicinova. The institution of Dr. Oskarsson has received research support from Cytokinetics. The institution of Dr. Oskarsson has received research support from Calico. The institution of Dr. Oskarsson has received research support from Mitsubishi. The institution of Dr. Oskarsson has received research support from Tsumura. The institution of Dr. Oskarsson has received research support from Sanofi. The institution of Dr. Oskarsson has received research support from AZTherapeutics. The institution of Dr. Oskarsson has received research support from Orion. The institution of Dr. Oskarsson has received research support from Esaii. Dr. Madigan has nothing to disclose. Dr. Mirman has nothing to disclose. Dr. Martinez-Thompson has nothing to disclose. Dr. Liewluck has nothing to disclose. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.