A 69-year-old Belgian Caucasian man complained of cramps in the right calf and walking difficulties that had started 6 months previous but had progressed to the point of needing support from the banisters when walking up a staircase. He did not report sensory disturbances. His personal history included arterial hypertension, hypercholesterolemia, complete deafness of the right ear due to a mastoidectomy in early childhood, and completely asymptomatic PDB that had been diagnosed 7 years previously by elevated alkaline phosphatases in a routine blood check, and had been confirmed by bone diphosphonate technetium-99m scintigraphy. His sister had died of dementia at the age of 62 years, while his mother had died at 67 years suffering from dementia and walking difficulties. At the first neurological examination he had slight paresis of the dorsal extensors of the left foot, eft quadriceps, and right deltoid muscle, atrophy of the left thigh, and diffuse tendon hyperreflexia. Fasciculations were noted in the right deltoid muscle but not in the tongue, which was not atrophic. Cranial nerves and sensibility were intact and there was no Babinski sign. The first electromyography (EMG) investigation revealed a diffuse chronic neurogenic pattern in all tested muscles of the left leg and in the right deltoid muscle, without signs of subacute denervation such as fibrillations or positive sharp waves. There was a marked slowing of the motor nerve conduction of the right peroneal nerve, without conduction block. An extensive laboratory workup produced normal results except for slight elevations of alkaline phosphatase (115 mU/mL, normal range 30-90 mU/mL) and lactate dehydrogenase (308 mU/mL, normal range 140-280 mU/mL). Magnetic resonance imaging (MRI) of the lumbar spine and computed tomography scans of the cervical spine and pelvis did not reveal significant abnormalities. Walking for longer than 20 minutes had become difficult in the intervening 3 years since these initial investigations, with the patient reporting falls and intermittent paresthesias in the left big toe. The patient presented with a right Babinski sign and absent ankle reflexes. Further electrophysiological studies () revealed diffuse sensorimotor neuropathy with a chronic neurogenic denervation pattern in the bilateral tibialis anterior and rectus femoris muscles, the right vastus lateralis, and soleus. There were signs of subacute denervation (fibrillations and/or fasciculations) in the right tibialis anterior muscle, the left vastus lateralis, and the biceps of the right arm. The desirability of performing muscle and nerve biopsies was discussed with the patient, but they were refused. Somatosensory evoked potentials (SEP) suggested subcortical, supramedullary slowing of central somatosensory pathways, while motor evoked potentials (MEP) induced by transcranial magnetic stimulation (TMS) of the central motor pathways revealed elevated stimulus thresholds and slightly delayed central conduction, which were restricted to the lower limbs. A lumbar puncture showed normal protein, glucose, cytology, and IgG index, and identical oligoclonal bands in the serum and cerebrospinal fluid. Syphilis and borrelia serology was negative. The levels of serum human T-lymphotropic virus 1 antibodies, serum arylsulphatase-A, and urinary catecholamines were normal. A further workup for polyneuropathy (including vitamin B status, diabetes screening, thyroid function, protein electrophoresis, and tumor markers) did not reveal any metabolic, inflammatory, paraneoplastic, or toxic cause of polyneuropathy. MRI of the brain showed bilateral frontotemporal atrophy (). MRI of the dorsal spine showed focal atrophy spanning about 5 cm of the spinal cord at the D4 level, with secondary centromedullary dilatation (unfortunately these images could not be retrieved). The patient rapidly developed frontal lobe symptoms 8 years later. He stayed fully oriented but became apathetic, dysphoric, and verbally aggressive. He showed perseverations and paraphasias in conversation and had become deaf in his left ear. He had no hallucinations, frontal release signs, or sphincter problems, and normal oculomotricity. He had paraparesis that especially affected the psoas muscles, hamstrings, and dorsiflexors of the feet, with relative sparing of flexor muscles. There was slight muscle atrophy, which, like the paraparesis, was more pronounced in the left quadriceps (). However, the upper limbs could exert normal forces. The Babinski sign had disappeared but there was a bilateral Hoffmann-Trömner sign and generalized hyperreflexia, except for the ankle reflexes, which were absent. The patient refused formal neuropsychological testing. The presence of personal and familial histories of dementia and progressive gait disturbance and the history of (albeit asymptomatic) PDB led to a putative diagnosis of IBMPFD. A sequence analysis of the 17 coding exons of the VCP gene (Born-Bünge Institute, University of Antwerp) confirmed the existence of a simple base mutation in codon 159 (Arg>His), which was confirmed in a second independent analysis. The patient died 1 year later due to a respiratory infection. An autopsy was not performed.