Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Abstract

Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.

Keywords: ALS; IBMPFD; MSP1; VCP; multisystem proteinopathy-1; valosin-containing protein.

Figure 1

Pedigree of proband 1. Proband (III:3) is indicated by the arrow.

Figure 2

Clinical signs, biopsy, and MRI findings from proband 1 (III:3): (A) bilateral scapular winging prominent on the right, with humeral muscle atrophy and bilateral thigh muscle atrophy; (B) thigh biopsy stained with modified Gomori Trichrome on a cryosection, where variability in the muscle fiber size with areas of fiber size variation and vacuoles can be seen; (C) MRI of bilateral thighs demonstrating prominent atrophy and fatty replacement in both the anterior and posterior compartments.

Figure 3

Pedigree of family 2. The proband (IV:12) is indicated by the arrow.

Figure 4

Pedigree of family 3. The proband (III:3) is indicated by the arrow.

Figure 5

Biopsy findings for proband 3 (III:3). (A) Representative low-power magnification of an H&E-stained cryosection of skeletal muscle demonstrating fascicular architecture with mild myofiber size variation without definite endomysial fibrosis, fatty replacement, perimysial pathology, vasculitis, inflammatory or necrotizing myopathy, or perifascicular atrophy/necrosis. Rare areas with marked myofiber atrophy and very rare degenerating myofibers were also noted (not shown). (B) High power magnification of the same H&E-stained section as seen in (A) showing an atrophic fiber with mildly basophilic sarcoplasm with subsarcolemmal rimmed clefts/defects with granular eosinophilic material (rimmed vacuoles) (black arrowhead). (C) High-power magnification of a TDP43 immunohistochemical (IHC) stain performed on a cryosection demonstrating subsarcolemmal aggregates (black arrowhead). (D) Phospho-TDP43 (Ser409/Ser410) (1D3) IHC stain on formalin-fixed paraffin embedded (FFPE) tissue showing staining compatible with sarcoplasmic aggregates and rimmed vacuoles (black arrowheads).