Axonal hyperpolarization in inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD).

INTRODUCTION

Inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) gene. Patients with this disorder may have neuropathic or myopathic features.

METHODS

Peripheral nerve function and axonal excitability were studied in three members from two families with VCP mutations (p.Arg155Leu and p.Leu198Trp).

RESULTS

Patients from the first family had neurogenic patterns on needle electromyography (EMG), whereas those in the second family had myopathic EMG changes. In threshold electrotonus for motor axons, the changes to depolarizing and hyperpolarizing conditioning currents were at or outside control limits in all three patients. Superexcitability was increased, and the relative refractory period was reduced. The strength-duration time constant was normal. In sensory axons of all three patients, there were similar changes in threshold electrotonus, but not in superexcitability.

DISCUSSION

These features are best explained by axonal hyperpolarization. The findings provide insight into the pathophysiological mechanisms in these genotypes and, possibly, into all patients with IBMPFD.