Multisystem proteinopathy

Multisystem proteinopathy (MSP) is a rare, inherited disorder that causes progressive damage to several organ systems at once, most often the muscles, bones, and nervous system. It appears in adulthood and can vary widely in its genetic origins. People with MSP typically develop one or more of these conditions: amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), or Paget's disease of bone (PDB). The condition is most frequently triggered by a missense mutation in the VCP gene, though at least four other genes are also known to cause it.

Historically, MSP went by names such as "inclusion body myopathy with early-onset Paget disease and frontotemporal dementia" (IBMPFD) or "inclusion body myopathy with frontotemporal dementia, Paget's disease of bone, and amyotrophic lateral sclerosis" (IBMPFD/ALS). These older labels are now considered outdated because MSP’s clinical picture is broader than just IBM, PDB, FTD, and ALS; it can also include motor neuron disease, features of Parkinson’s disease, and ataxia. Although rare, MSP has drawn growing scientific interest because it offers molecular clues to how common age-related degenerative diseases of muscle, bone, and brain are connected.

Signs and symptoms

Signs and symptoms vary by organ system. In muscle, inclusion body myopathy is often the first sign, leading to progressive weakness that makes climbing stairs, walking, lifting arms, and using hands difficult. Patients may also experience muscle pain, cramps, and spasms. In the skeleton, about half of MSP patients develop Paget’s disease of bone, which results from excessive bone turnover and can cause pain, fractures, hearing loss, and deformities.

Cognitively, roughly one-third of patients develop frontotemporal dementia, marked by behavioral changes, disinhibition, apathy, emotional dysregulation, and language problems. Alzheimer’s disease and mixed cognitive impairment have been reported in isolated cases. Respiratory issues are common and include shortness of breath, weak cough, aspiration, sleep-disordered breathing, infections, and respiratory failure. Motor neuron disease or ALS can also occur, with symptoms such as progressive weakness, tremors, fasciculations, swallowing difficulties, weight loss, and speech problems—many of which overlap with other MSP features.