Multisystem proteinopathy (MSP) is a dominantly inherited,

pleiotropic Pleiotropy (from Greek , 'more', and , 'way') occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic ge ...

, 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 Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(ALS),

frontotemporal dementia Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...

(FTD),

inclusion body myopathy Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body m ...

(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 cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the ...

(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 However, IBMPFD and IBMPFD/ALS are now considered outdated classifications and are more properly referred to as MSP, as the disease is clinically heterogeneous and its phenotypic spectrum extends beyond IBM, PDB, FTD,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 is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

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

TDP-43 TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene. Structure TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...

, HNRNPA1,

HNRNPA2B1 Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the ''HNRNPA2B1'' gene. Structure ''HNRNPA2B1'' gene contains 12 exons, including a B1 protein specific 36-nucleotide mini-exon. The entire length of intron/ ...

, 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 enzyme ...

(VCP) gene, which causes a subtype of MSP known as MSP1 (). Other pathogenic variants have been identified in

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 interacti ...

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