Novel valosin-containing protein mutations associated with multisystem proteinopathy

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Rheumatology

Background:

• Valosin-containing protein (VCP) gene mutations are linked to a rare autosomal dominant adult-onset progressive disorder.
• This disorder presents with a variable combination of inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS).

Observation:

• This study reports on four new patients/families with novel VCP mutations.
• Clinical manifestations included myopathy, PDB, ALS, and Parkinson's disease.
• Frontotemporal dementia was notably absent in these families, and one patient exhibited severe PDB, mimicking neoplasia.

Findings:

• Four novel missense mutations in the VCP gene were identified: c.474 G>A (p.M158I), c.478 G>C (p.A160P), c.383G>C (p.G128A), and c.382G>T (p.G128C).
• Observed clinical features encompassed myopathy, PDB, ALS, and Parkinson's disease.
• Significant inter- and intra-familial variability in disease presentation and onset complicates genotype-phenotype correlations.

Implications:

• Recognizing the broad spectrum of VCP-related disease manifestations is crucial for accurate diagnosis.
• Early diagnosis can facilitate proactive management and prevention of associated clinical features, particularly PDB.
• Further research is needed to fully elucidate genotype-phenotype correlations in VCP-associated disorders.