LAUSR

The valosin-containing protein (VCP) gene has been identified as being responsible for hereditary inclusion body myopathy (IBM) with Paget’s disease of the bones and frontotemporal dementia (IBMPFD) [1] as well as familial amyotrophic lateral sclerosis [2]. Pathologically, phosphorylated TDP-43 accumulates in various tissues, such as motor neurons in the anterior horn, cerebral cortex, bone, muscle, and substantia nigra [2–4]. Recently, a family with a VCP mutation showed diverse clinical manifestations, including parkinsonism; thus, the concept of multisystem proteinopathy was proposed [3]. Here we report a case of a patient with a VCP mutation who presented with limb-girdle muscle weakness/atrophy and Ldopa-unresponsive parkinsonism related to a progressive supranuclear palsy (PSP)-like symptoms. A 51-year-old woman visited our hospital because of postural abnormality and gait instability that had developed 7 years previously and had progressed gradually. Neurological examination revealed proximal weakness in her upper limbs, as indicated by aMedical ResearchCouncil scale grade of 4/5 for the deltoid and biceps brachii muscles, and in her trunk, as evidenced by a waddling gait. She had muscle atrophy of the upper-limb girdle, bilateral scapular winging (Fig. 1a), and lumbar hyperlordosis. However, facial, distal upper-limb, and lower-limb weakness were not observed. In addition, mild but significant parkinsonism (e.g., slight limitation of vertical eye movement compensated by doll’s eye phenomenon, loss of postural reflexes, cervical dystonic features, difficulty rising from a chair, mild bilateral rigidity, limited facial expression, and mild bradykinesia; Suppl Video) was observed. Generalized hyperreflexia without sensory loss, ataxia, and autonomic disturbances was not observed. No obvious dementia was noted, and her MiniMental State Examination scores were 29/30. A detailed past history suggested that she had gradually developed emotional blunting and showed a decline in personal grooming. She had a family history of muscle and neurological diseases: her father and uncle had similar symptoms of waddling gait and muscle weakness, and her uncle’s muscle biopsy revealed rimmed vacuolarmyopathy. In addition, her grandmother had been diagnosed with Parkinson’s disease. Brain magnetic resonance (MR) imaging revealed frontoparietal cortical atrophy (Fig. 2a), but the midbrain/ pons ratio (M/P ratio) [5] and MR parkinsonism index (MRPI) [6] were 0.257 and 10.55, respectively; this indicated that significant atrophies of the midbrain, pons, and superior/middle cerebellar peduncle were absent (Fig. 2b– d). Brain single-photon emission computed tomography (SPECT) showed significantly decreased blood flow in the frontotemporal cortex (Fig. 2e). Biopsy of the right biceps brachii muscle revealed IBM with rimmed vacuoles (Fig. 1b), and nuclear and cytoplasmic aggregates showed abnormal phosphorylated TDP-43 staining (data not shown). Genetic analysis revealed a p.R191Q mutation (c.572G[A) in VCP (Fig. 1c); thus, IBMPFD was diagnosed. She was started on levodopa/carbidopa therapy (300 mg/day), but her parkinsonism did not improve. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8467-2) contains supplementary material, which is available to authorized users.