Multisystem proteinopathy

Multisystem proteinopathy (MSP) is an inherited pleiotropic degenerative disorder that can affect muscle, bone, and the nervous system and was first reported as familial motor neuron disease in association with Paget disease of bone (PDB).1 The MSP phenotype also involves inclusion body myopathy (IBM) or frontotemporal dementia (FTD).2 The acronym “IBMPFD” describes some families with this syndrome, but it has outlived its usefulness since other phenotypic features sometimes dominate the clinical picture: parkinsonism3,4 and peripheral neuropathy5,6 occur, and motor neuron dysfunction is frequent (11 of 17 consecutive MSP cases in one series).7 An operational definition of MSP is a combination of 2 or more of IBM, PDB, and amyotrophic lateral sclerosis (ALS)/FTD (where ALS and FTD are considered as one spectrum). Histopathologically, MSP-affected tissues have ubiquitin-positive inclusions that contain RNA-binding proteins, such as TDP-43, hnRNPA1, and hnRNPA2B1, but may also include positive staining for proteins that mediate ubiquitin-dependent autophagy, including p62/SQSTM1, VCP, optineurin, and ubiquilin-2.8–10