Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation

Abstract

Introduction. The valosin-containing protein (VCP) regulates several distinct cellular processes. Consistent with this, VCP mutations manifest variable clinical phenotypes among and within families and are a diagnostic challenge. Methods. A 60-year-old man who played ice hockey into his 50's was evaluated by electrodiagnostics, muscle biopsy, and molecular genetics. Results. With long-standing pes cavus and toe walking, our patient developed progressive weakness, cramps, memory loss, and paresthesias at age 52. An axonal sensorimotor neuropathy was found upon repeated testing at age 58. Neuropathic histopathology was present in the quadriceps, and exome sequencing revealed the VCP mutation c.290 C>T, p.Gly97Glu. Conclusions. Our patient reflects the clinical heterogeneity of VCP mutations, as his neurological localization is a spectrum between a lower motor neuron disorder and a hereditary axonal peripheral neuropathy such as CMT2. Our case demonstrates a rare manifestation of the c.290 C>T, pGly97Glu VCP mutation.

Figure 1

Evidence of pes cavus and hammer toes in our patient.

Figure 2

Muscle biopsy of the quadriceps revealed chronic active neurogenic atrophy ((a), H&E). Fiber type grouping is seen in immunoperoxidase staining for both slow myosin (b) and fast myosin (c). Some muscle fascicles are much more severely affected and show features of end stage muscle (d). Scale bar = 100 μm in panels (a) and (d); 150 μm in panels (b) and (c).

Figure 3

(a) Family Pedigree. Squares indicate men; circles, women; diagonal lines, deceased; black, VCP mutation. An arrow indicates the proband. (b) ATPase activity data that shows that the G97E (Gly97Glu mutation) has increased ATPase activity similar to other mutants. The detailed method was described previously [6]. Purified human p97 proteins (25 nM monomer final concentration) were used in Assay Buffer (50 mM Tris pH 7.4, 20 mM MgCl₂, 1 mM EDTA, and 0.5 mM TCEP) containing 0.01% Triton X-100 and 200 μM ATP. ATPase activity was determined by addition of Biomol Green Reagent (Enzo Life Sciences). Absorbance at 635 nm was measured after 4 min on the Synergy Neo Microplate Reader (BioTek).

Figure 4

Spectrum of phenotypic manifestations seen in our patient with a VCP mutation.