title: Motor neuron involvement in multisystem proteinopathy: implications for ALS.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurology, University of Miami, Miami, FL, USA. mbenatar@miami.edu
authors: Michael
authors: M
authors: Benatar
authors: Joanne
authors: J
authors: Wuu
authors: Catalina
authors: C
authors: Fernandez
authors: Conrad C
authors: CC
authors: Weihl
authors: Heather
authors: H
authors: Katzen
authors: Julie
authors: J
authors: Steele
authors: Bjorn
authors: B
authors: Oskarsson
authors: J Paul
authors: JP
authors: Taylor
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000473:pathology*; D010001:Osteitis Deformans / Q000235:genetics* / Q000473:pathology*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C439768:hnRNP A2; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
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