multisystem proteinopathy

Multisystem proteinopathy (MSP) is a rare, dominantly inherited disorder that affects multiple systems in the body, including muscle, bone, and the central nervous system [1]. It is characterized by the accumulation of abnormal proteins in various tissues, leading to degeneration and dysfunction [2].

The clinical manifestations of MSP can vary widely among affected individuals, but common features include:

• Muscle weakness and atrophy (myopathy)
• Bone disease, such as Paget's disease of bone
• Neurodegeneration, including frontotemporal dementia and amyotrophic lateral sclerosis (ALS)

MSP is associated with mutations in several genes, including VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 [3]. These genetic alterations disrupt normal protein function and lead to the formation of abnormal protein aggregates, which are a hallmark of MSP.

The age of onset for MSP can vary, but it typically affects adults in their 50s or 60s. The disease progression is often slow, with symptoms worsening over time [4].

It's worth noting that MSP is a rare disorder, and its exact prevalence is unknown. However, research has identified several families with affected members, highlighting the importance of genetic counseling for individuals with a family history of the condition [5].

Multisystem proteinopathy (MSP) is a rare inherited disorder that can affect multiple systems in the body, including muscle, bone, and the nervous system. The signs and symptoms of MSP can vary from person to person, but they often include:

• Muscle weakness: Muscle weakness, particularly in the distal muscles (those farthest from the center of the body), is a common initial symptom of MSP. This can manifest as difficulty walking or performing daily activities.
• Limb weakness: Weakness in the limbs, particularly in the arms and legs, is another common symptom of MSP.
• Muscle wasting: As the disease progresses, muscle wasting can occur, leading to a decrease in muscle mass and strength.
• Bone disease: Paget's disease of bone (PDB) is often associated with MSP. This can lead to symptoms such as:
  • Bone pain
  • Deformity of the bones
  • Increased risk of fractures
• Neurological symptoms: The nervous system can also be affected, leading to symptoms such as:
  • Frontotemporal dementia (FTD): A progressive brain disorder that affects personality, behavior, and language.
  • Motor neuron disease: A group of diseases that affect the nerve cells responsible for controlling voluntary muscle movement.
• Parkinsonian symptoms: Some people with MSP may experience parkinsonian symptoms, such as slow movement, rigid muscles, and poor balance.

It's worth noting that the age of symptom onset can vary widely, ranging from 19 to 75 years old. The median age of symptom onset is around 51 years old [2]. Additionally, the first symptom of IBMPFD (a subtype of MSP) is often muscle weakness, which typically appears in mid-adulthood [6].

References:

[1] Context result 10 [2] Context result 2 [3] Context result 7 [4] Context result 15 [5] Context result 9 [6] Context result 11

Diagnostic Tests for Multisystem Proteinopathy (MSP)

Multisystem proteinopathy (MSP) is a rare genetic disorder characterized by the accumulation of abnormal proteins in various organs and tissues. Diagnosing MSP can be challenging, but several diagnostic tests are available to confirm the condition.

• Genetic Testing: Genetic testing is considered the most definitive way to diagnose MSP. It involves analyzing the VCP gene for mutations that cause the disease [1][2][6][9]. This test can identify pathogenic mutations in the VCP gene, confirming a diagnosis of MSP.
• Muscle Biopsy: A muscle biopsy may be performed to examine muscle tissue for signs of abnormal protein accumulation. However, this test is not as sensitive as genetic testing and should be used in conjunction with other diagnostic tests [2].
• Creatine Kinase (CK) Levels: Elevated CK levels can indicate muscle damage, which may be a sign of MSP. However, this test is not specific to MSP and can be elevated in other conditions as well.
• Radionuclide Bone Scan: A radionuclide bone scan can show intense tracer uptake in bones affected by MSP, making it a useful diagnostic tool [5].

Diagnostic Considerations

When diagnosing MSP, it's essential to consider the following:

• Family History: A family history of MSP or other protein-related disorders may indicate a genetic predisposition.
• Clinical Presentation: Patients with MSP often present with symptoms such as muscle weakness, wasting, and cognitive impairment [1].
• Imaging Studies: Imaging studies like MRI or CT scans can help identify affected organs and tissues.

References

[1] by P Chompoopong · 2023 · Cited by 12 — Cognitive impairment was determined by bedside cognitive evaluation (Kokmen mental status short test) and formal neuropsychological testing. The ...

[2] by G Pfeffer · 2022 · Cited by 42 — Our recommendation is to use genetic testing as the means to reach definitive diagnosis. Additional tests such as muscle biopsy, creatine ...

[5] by M Korb · 2022 · Cited by 27 — Diagnosis. When a patient exhibits signs of PDB, the most sensitive diagnostic test is a radionuclide bone scan, which shows intense tracer ...

[6] by B Roy · 2023 · Cited by 5 — Genetic testing is the only definitive way to diagnose VCP myopathy, and single-variant testing in the case of a known familial VCP variant, or ...

[9] by B Roy · 2023 · Cited by 5 — Genetic testing is the only definitive way to diagnose VCP myopathy, and single-variant testing in the case of a known familial VCP variant, or multi-gene panel ...

Multisystem proteinopathy (MSP) is a rare genetic disorder that affects multiple systems in the body, including muscles, nerves, and bones. When diagnosing MSP, it's essential to consider other conditions that may present with similar symptoms. Here are some differential diagnoses for MSP:

• Inclusion Body Myopathy (IBM): This is one of the primary manifestations of MSP, characterized by muscle weakness and wasting. However, IBM can also be caused by mutations in other genes, such as MATR3 [5].
• Amyotrophic Lateral Sclerosis (ALS): ALS is a progressive neurodegenerative disease that affects motor neurons. While ALS is often associated with VCP pathogenic variants, it's essential to consider other causes of ALS in the differential diagnosis [6].
• Parkinson's Disease: Some patients with MSP may exhibit features of Parkinson's disease, such as tremors and bradykinesia. However, these symptoms can also be caused by other conditions, such as mutations in the SNCA gene.
• Ataxia: Ataxia is a condition characterized by impaired coordination and balance. While ataxia can be a feature of MSP, it's essential to consider other causes of ataxia, such as mutations in the ATXN1 gene.
• Paget's Disease of Bone: This is a rare genetic disorder that affects bone metabolism. Some patients with MSP may exhibit features of Paget's disease, but these symptoms can also be caused by other conditions, such as mutations in the SQSTM1 gene [9].
• Frontotemporal Dementia (FTD): FTD is a group of neurodegenerative disorders that affect the frontotemporal regions of the brain. While some patients with MSP may exhibit features of FTD, it's essential to consider other causes of FTD, such as mutations in the GRN gene.

When considering the differential diagnosis for MSP, it's crucial to remember that each patient's presentation can be unique and influenced by various factors, including genetic background and environmental factors. A comprehensive evaluation by a multidisciplinary team of healthcare professionals is essential to accurately diagnose and manage MSP [8].

References:

[5] MATR3 encodes Matrin 3, which has been associated with phenotypes resembling MSP and should be considered in the differential diagnosis.

[6] Pathogenic variants in VCP cause multisystem proteinopathy (MSP) manifesting with inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS), ...

[8] We report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease mechanisms remain unclear.

[9] Multisystem proteinopathy 1, or inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia, is a rare autosomal dominant disorder that should be considered in the differential diagnosis for MSP.