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Multisystem Proteinopathy (MSP)

What is Multisystem Proteinopathy (MSP)?

Multisystem proteinopathy (MSP) is an inherited degenerative disorder that affects multiple organ systems including the muscle, bone and the nervous system. The phenotypes of MSP encompass inclusion body myopathy (IBM) characterized by progressive muscle weakness, Paget’s disease of bone (PDB) that disrupts the replacement of old bone tissue with new bone tissue, and the frontotemporal dementia (FTD) characterized by deterioration in behavior, personality and/or difficulty with producing or comprehending language. Parkinson Disease and motor neuron dysfunction can also occur as additional clinical features. A combination of two or more phenotypes of IBM, PDB and FTD can be defined as MSP. A hallmark of the disease is the formation of cellular protein aggregates called inclusion bodies that disrupts normal cell functions. 
 

 

Multisystem proteinopathy (MSP) is an inherited degenerative disorder that affects multiple organ systems including the muscle, bone and the nervous system. The phenotypes of MSP encompass inclusion body myopathy (IBM) characterized by progressive muscle weakness, Paget’s disease of bone (PDB) that disrupts the replacement of old bone tissue with new bone tissue, and the frontotemporal dementia (FTD) characterized by deterioration in behavior, personality and/or difficulty with producing or comprehending language. Parkinson Disease and motor neuron dysfunction can also occur as additional clinical features. A combination of two or more phenotypes of IBM, PDB and FTD can be defined as MSP. A hallmark of the disease is the formation of cellular protein aggregates called inclusion bodies that disrupts normal cell functions. 
 

Acknowledgement of Multisystem Proteinopathy (MSP) has not been added yet.

MSP is a rare disease. It has been diagnosed in several hundreds of people worldwide

Synonyms for Multisystem Proteinopathy (MSP) has not been added yet.

MSP is inherited in an autosomal dominant manner. There are two copies of each gene in our cells. One copy is inherited from the mother and another copy from the father. For an autosomal dominant inheritance pattern, the affected individuals have one copy of the altered gene and one copy of the normal gene to manifest the disease. 

Mutations in three genes-VCP, HnRNPA2B1 and HnRNPA1- are causative for MSP. Other genes involved in cellular protein degradation pathways have also been associated with MSP. 

VCP
Mutations in VCP are the most commonly found genetic mutations that cause MSP. The VCP gene provides instructions for making a catalytic protein named valosin-containing protein (VCP). VCP protein has a wide range of functions in the cell. One of the most important functions is to help degrade useless, abnormal proteins and cellular trash. 

Mutations in the VCP gene can disrupt the VCP enzyme activity or interfere its interaction with other proteins that are important to break down cellular trash. As a result, excess and abnormal proteins are built up (forming inclusion bodies) inside of the cells of muscle, bone and the nervous tissue. These excess protein aggregates accumulate and disrupt normal cellular functions. 


HNRNPA2B1 and HNRNPA1 
Mutations in HnRNPA2B1 and HnRNPA1 account for a very small number of MSP. The HnRNPA2B1 gene and the HnRNPA1 gene provide instructions for making proteins that bind to RNA in the cells. The functions of HnRNPA2B1 and HnRNPA1 remain largely unknown. Studies have suggested that HnRNPA2B1 and HnRNPA1 proteins by themselves have a tendency to form small fibers that are difficult to break down in the cells. When mutated, the formation of undegradable fibers is increased which could lead to accumulation disrupting normal cellular functions.

The first symptom of MSP is often muscle weakness (also known myopathy), which appears in patients in the late 30s. The muscle weakness first occurs in shoulder and hip muscles. Affected individuals often find it difficult to climb stairs or raise the arms above their shoulders. The weakness later can develop to affect arms and legs. Heart muscle can also be affected, and eventually may lead to cardiac failure. 

~50% of the affected individuals also develop Paget disease of bone, which often occurs in bones of the hip, spine, skull, and the long bones of the arms and legs. Paget disease of bone is characterized by the hyperactivation of bone eating cells called osteoclasts, causing bones to become fragile and misshapen. Patients may experience pain in the hip and spine bones. 

~30% of the affected individuals can develop dysfunctioning in the nervous system, one of which is frontotemporal dementia (FTD). People with FTD may initially have trouble speaking and remembering words. The condition can be worsened over time, and patients can have personality changes, loss of judgement and inappropriate social behaviors.
 

Diagnosis of MSP typically begins with the observation of the associated clinical symptoms and is confirmed via genetic testing.

MSP is diagnosed with genetic testing. The diagnosis can be established when one copy of pathogenic mutations in HNRNPA1, HNRNPA2B1, or VCP is identified in combination with typical clinical symptoms.

There is currently no cure for the disease. Treatment is offered based on disease manifestation. For example, Paget disease of bones can be treated with Nitrogen-containing bisphosphonates 
That reduces osteoclast-mediated bone absorption. Physical therapy can be helpful for patients experiencing muscle weakness to promote mobility. Physical activity, weight management and emotional support are important for patients to stay positive and maintain social involvement.

According to limited studies, people with MSPs start showing muscle weakness in their 30s, and develop FTD later in life. The affected individuals usually live into their fifties or sixties, with cardiac and respiratory failure as the main cause of demise.

Tips or Suggestions of Multisystem Proteinopathy (MSP) has not been added yet.

Kimonis V. Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia. 2007 May 25 [Updated 2019 Sep 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1476/

Kim, H., Kim, N., Wang, Y. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013). https://doi.org/10.1038/nature11922

Multisystem proteinopathy: Intersecting genetics in muscle, bone, and brain degeneration
J. Paul Taylor, Neurology Aug 2015, 85 (8) 658-660; DOI: 10.1212/WNL.0000000000001862

Kimonis VE, Mehta SG, Fulchiero EC, Thomasova D, Pasquali M, Boycott K, Neilan EG, Kartashov A, Forman MS, Tucker S, Kimonis K, Mumm S, Whyte MP, Smith CD, Watts GD. Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. Am J Med Genet. 2008;146A:745–57.
 

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