Multisystem proteinopathy (MSP) is a dominantly inherited,

pleiotropic Pleiotropy () is a condition in which a single gene or genetic variant influences multiple phenotypic traits. A gene that has such multiple effects is referred to as a ''pleiotropic gene''. Mutations in pleiotropic genes can impact several trait ...

, degenerative disorder of humans that can affect muscle, bone, and/or the central nervous system. MSP can manifest clinically as classical

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

(ALS),

frontotemporal dementia Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal lobe, frontal and tempor ...

(FTD), inclusion body myopathy (IBM),

Paget's disease of bone Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) is a condition involving Bone remodeling, cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone ...

(PDB), or as a combination of these disorders. Historically, several different names have been used to describe MSP, most commonly "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)." However, IBMPFD and IBMPFD/ALS are now considered outdated classifications and are more properly referred to as MSP, as the disease is clinically heterogeneous and its phenotypic spectrum extends beyond IBM, PDB, FTD, and ALS to include motor neuron disease, Parkinson's disease features, and

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

features. Although MSP is rare, growing interest in this syndrome derives from the molecular insights the condition provides into the etiological relationship between common age-related degenerative diseases of muscle, bone, and brain.

Signs and symptoms

A useful operational definition of MSP is dominantly inherited degeneration that includes neurological involvement (either motor neuron disease or dementia) in combination with either distal myopathy or Pagetic bone degeneration. Most MSP patients present with weakness, and of these, approximately 65% present with motor neuron involvement. Although rare, MSP can also include involvement of cardiac, hepatic, visual, auditory, sensory, and autonomic systems. The histopathology of tissues affected by MSP includes

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

-positive cytoplasmic inclusions of RNA-binding proteins, such as

TDP-43 Transactive response DNA binding protein 43 kDa (TAR DNA-binding protein 43 or TDP-43) is a protein that in humans is encoded by the ''TARDBP'' gene. Structure TDP-43 is 414 amino acid residues long. It consists of four domains: an N-ter ...

, HNRNPA1, HNRNPA2B1, and other components of RNA granules.

Genetics

MSP is a dominantly inherited and genetically heterogenous disease. The most common genetic cause of MSP is missense mutations affecting the

valosin-containing protein Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase (TER ATPase) also known as p97 in mammals and CDC48 in '' S. cerevisiae,'' is an enzyme that in humans is encoded by the ''VCP'' gene. The TER ATPase is an ATPase enz ...

(VCP) gene, which causes a subtype of MSP known as MSP1 (). Other pathogenic variants have been identified in HNRNPA2B1 and HNRNPA1, which cause MSP2 () and MSP3 () respectively. Additional genes linked to MSP include MATR3, OPTN, and p62/

SQSTM1 Sequestosome-1 is a protein that in humans is encoded by the ''SQSTM1'' gene. Also known as the ubiquitin-binding protein p62, it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interac ...

Diagnosis

References

External links

{{Medical resources , ICD10 = , ICD9 = , ICDO = , OMIM = , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = , GeneReviewsNBK = NBK1476 , GeneReviewsName = , Orphanet = 52430 Amyotrophic lateral sclerosis Rare diseases Genetic diseases and disorders