Motor neuron involvement in multisystem proteinopathy

Abstract

Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND).Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families.Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion:Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD. Neurology Inclusion body myopathy (IBM) with Paget disease and frontotemporal dementia (IBMPFD) is a rare multisystem degenerative disorder named after the organ systems originally recognized to be affected-muscle, bone, and brain. Mutations in the valosin-containing protein (VCP) gene were the first identified cause of IBMPFD, 1,2 but reports of families without linkage to chromosome 9 established the genetic heterogeneity of the disorder.3,4 It has recently emerged that mutations in the HNRNPA2B1 (chromosome 7) and HNRNPA1 (chromosome 12) genes account for some families with IBMPFD. 5 We first raised the possibility of a connection between IBMPFD and amyotrophic lateral sclerosis (ALS) after mutations in the VCP gene were identified in patients with familial ALS.6 Interestingly, the original report of IBMPFD 7 almost 30 years ago described it as a "familial disorder of combined lower motor neuron degeneration and skeletal disorganization"; the presence of fasciculations, EMG evidence of chronic reinnervation, and muscle biopsy showing grouped atrophy all pointing toward a primarily neurogenic process. This family was subsequently found to have an R155Q mutation in the VCP gene. 8 Since the original description, var...

Clinical and Electrophysiological Findings in Hereditary Inclusion Body Myopathy Compared With Sporadic Inclusion Body Myositis

“…Indeed, VCP mutations can manifest also with isolated motor neuron disease or peripheral neuropathy. 24,[37][38][39] The VCP-hIBM patient's neurogenic EMG changes had a myopathological correlate, as suggested by the histochemical signs of denervation (atrophic fibers of either histochemical type overreactive for nonspecific esterase) and reinnervation (grouping of muscle fibers of the same histochemical type) observed in their muscle biopsies.…”

“…13 Reported description of the electromyographic (EMG) findings in genetically proven hIBM patients show some resemblance to those encountered in sIBM with essentially mixed myopathic and neurogenic features. 9,[13][14][15][16][17][18][19][20][21][22][23][24][25][26] In this study, we describe the clinical and electrophysiological features of hIBM subjects in comparison with their sIBM counterparts to identify differences that might help the clinical differential diagnosis.…”

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis

“…Some carriers of VCP mutation also manifest additional symptoms, including Parkinsonism (Majounie et al, 2012), ataxia (Shi et al, 2012) (Djamshidian et al, 2009). The term 'multisystem proteinopathy' has been proposed as the nomenclature for an emerging family of genetic disorders that are unified by this characteristic variation in the penetrance of muscle, bone and CNS degenerative phenotypes along with the accumulation of ubiquitin and TDP-43-positive inclusions (Benatar et al, 2013;Kim et al, 2013a).…”

VCP mutations are not a major cause of familial amyotrophic lateral sclerosis in the UK

“…In general, most mutation carriers are positive for a family [28] was not included in this Table as frequency data was not available but is included in Table S3. history of multiple symptoms (Table S4). Amongst the previously reported families with at least one confirmed case of ALS, dementia was present in seven families, myopathy in five families and PDB in seven families (Table S4).…”