Multisystem proteinopathy

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Multisystem proteinopathy
Specialty Neurology

Multisystem proteinopathy (MSP) is a rare, inherited degenerative disease characterized by progressive dysfunction across multiple organ systems, primarily affecting muscle, bone, and the nervous system. Individuals with this condition typically do not develop symptoms until mid-adulthood and these symptoms vary from person to person, even among family members. [1] An individual with MSP typically develops one or more of these more common diseases: amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB) [2] 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 However, IBMPFD and IBMPFD/ALS are now considered outdated classifications and are more properly referred to as MSP, [2] [3] as the disease is clinically heterogeneous and its phenotypic spectrum extends beyond IBM,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 features. [4] [5] 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.

Contents

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. [5] Although rare, MSP can also include involvement of cardiac, hepatic, visual, auditory, sensory, and autonomic systems. [5] The histopathology of tissues affected by MSP includes ubiquitin-positive cytoplasmic inclusions of RNA-binding proteins, such as TDP-43, HNRNPA1, HNRNPA2B1, and other components of RNA granules. [4]

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 (VCP) gene, which causes a subtype of MSP known as MSP1 (OMIM: 167320). Other pathogenic variants have been identified in HNRNPA2B1 and HNRNPA1, which cause MSP2 (OMIM: 615422) and MSP3 (OMIM: 615424) respectively. Additional genes linked to MSP include MATR3, OPTN, and p62/SQSTM1. [6]

Diagnosis

References

  1. ↑ Korb, Manisha; Peck, Allison; Alfano, Lindsay N.; Berger, Kenneth I.; James, Meredith K.; Ghoshal, Nupur; Healzer, Elise; Henchcliffe, Claire; Khan, Shaida; Mammen, Pradeep P. A.; Patel, Sujata; Pfeffer, Gerald; Ralston, Stuart H.; Roy, Bhaskar; Seeley, William W. (2022-01-29). "Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy". Orphanet Journal of Rare Diseases. 17 (1): 23. doi: 10.1186/s13023-022-02172-5 . ISSN   1750-1172. PMC   8800193 . PMID   35093159.
  2. 1 2 Harrison AF, Shorter J (April 2017). "RNA-binding proteins with prion-like domains in health and disease". Biochem. J. 474 (8): 1417–1438. doi:10.1042/BCJ20160499. PMC   5639257 . PMID   28389532.
  3. ↑ Milone M, Liewluck T (March 2019). "The unfolding spectrum of inherited distal myopathies". Muscle Nerve. 59 (3): 283–294. doi:10.1002/mus.26332. PMID   30171629. S2CID   52140733.
  4. 1 2 Ramaswami M, Taylor JP, Parker R (August 2013). "Altered ribostasis: RNA-protein granules in degenerative disorders". Cell. 154 (4): 727–36. doi:10.1016/j.cell.2013.07.038. PMC   3811119 . PMID   23953108.
  5. 1 2 3 Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A, Kimonis V (1993). "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia". PMID   20301649.{{cite journal}}: Cite journal requires |journal= (help)
  6. ↑ Ralston SH, Taylor JP (May 2019). "Rare Inherited forms of Paget's Disease and Related Syndromes". Calcif. Tissue Int. 104 (5): 501–516. doi:10.1007/s00223-019-00520-5. PMC   6779132 . PMID   30756140.
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