A cross-sectional analysis of clinical evaluation in 35 individuals with mutations of the valosin-containing protein gene

Abstract

Inclusion body myopathy (IBM) associated with Paget disease of the bone and frontotemporal dementia or IBMPFD is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 35 (28 affected individuals, 7 presymptomatic gene carriers) individuals versus 14 unaffected first-degree relatives in 14 families to establish useful biomarkers for IBMPFD and identify the most meaningful tests for monitoring disease progression in future clinical trials. Comprehensive studies included the Inclusion Body Myositis Functional Rating Scale (IBMFRS) and fatigue severity scale questionairres, strength measurements using the Manual Muscle Test with Medical Research Council (MRC) scales, hand-held dynamometry using the microFET and Biodex dynamometers, 6 minute walk test (6MWT), and pulmonary function studies. Strong correlation was observed between the IBMFRS and measurements of muscle strength with dynamometry and the other functional tests, indicating that it may be utilized in long-term follow-up assessments due to its relative simplicity. This cross-section study represents the most comprehensive evaluation of individuals with VCP disease to date and provides a useful guide for evaluating and possible monitoring of muscle weakness and pulmonary function progression in this unique cohort of individuals.

Keywords: Dynamometry; IBMFRS; IBMPFD; Inclusion Body Myopathy; Paget disease; VCP.

Copyright © 2018. Published by Elsevier B.V.

Figures

Fig. 1. Comparison of affected individuals with various disease durations.

There is a declining trend in affected individuals with increased disease duration compared to more recently symptomatic individuals. However, the relationships are not strong. (a) IBMFRS score vs. Disease Duration (y = −0.4017x + 31.735, r 2 = 0.09) (b) 6MWT distance vs. Disease Duration (y = −9.7058x + 481.33, r 2 = 0.10) (c) MRC Total vs. Disease Duration (y = −1.5003x + 122.25, r 2 = 0.24).

Fig. 2. Comparison of patients of varying ages.

Affected are represented as diamonds, carriers as squares, and unaffected as triangles. (a) IBMFRS Score v. Age. IBMFRS declines in affected individuals with older individuals in this cohort, while unaffected stays constant. The trendline for unaffected individuals is solid (y = 0.0009x + 39.838, p-value = 0.92). The trendline for carriers is dotted (y = −0.1735x + 45.264, p-value = 0.31). The trendline for affected individuals is dashed (y = −0.5363x + 55.096, p-value = 0.01). (b) 6MWT v. Age. Decline in all groups at older age, regardless of condition. The trendline for unaffected individuals is solid (y = −4.0252x + 744.03, p-value = 0.02). The trendline for carriers is dotted (y = −7.828x + 796.11, p-value = 0.12). The trendline for affected individuals is dashed (y = −7.4643x + 758.23, p-value = 0.08). (c) Manual Muscle Test Total MRC Score v. Age. MRC score declines for older affected individuals, while unaffected stays constant. The trendline for unaffected individuals is solid (y = −0.0591x + 282.6, p-value = 0.40). The trendline for carriers is dotted (y = 0.0155x + 266.35, p-value = 0.99). The trendline for affected individuals is dashed (y = −3.4974x + 385.03, p-value = 0.01).

Fig. 3. Hand-held dynamometry in affected individuals and presymptomatic carriers.

Strength in nine muscle groups expressed as percentage of normal muscle strength in unaffected individuals (top), presymptomatic carriers (bottom). ∗ denotes p-value differences ≤0.05.