title: ALS-Plus syndrome: non-pyramidal features in a large ALS cohort.
abstract: OBJECTIVE
  Autopsy studies show widespread pathology in amyotrophic lateral sclerosis (ALS), but clinical surveys of multisystem disease in ALS are rare. We investigated ALS-Plus syndrome, an understudied group of patients with clinical features extending beyond pyramidal and neuromuscular systems with or without cognitive/behavioral deficits.
  
  
  METHODS
  In a large, consecutively-ascertained cohort of 550 patients with ALS, we documented atypical clinical manifestations. Genetic screening for C9orf72 hexanucleotide expansions was performed in 343 patients, and SOD1, TARDBP, and VCP were tested in the subgroup of patients with a family history of ALS. Gray matter and white matter imaging was available in a subgroup of 30 patients.
  
  
  RESULTS
  Seventy-five (13.6%) patients were identified with ALS-Plus syndrome. We found disorders of ocular motility, cerebellar, extrapyramidal and autonomic functioning. Relative to those without ALS-Plus, cognitive impairment (8.0% vs 2.9%, p=0.029), bulbar-onset (49.3% vs 23.2%, p<0.001), and pathogenic mutations (20.0% vs 8.4%, p=0.015) were more than twice as common in ALS-Plus. Survival was significantly shorter in ALS-Plus (29.66 months vs 42.50 months, p=0.02), regardless of bulbar-onset or mutation status. Imaging revealed significantly greater cerebellar and cerebral disease in ALS-Plus compared to those without ALS-Plus.
  
  
  CONCLUSIONS
  ALS-Plus syndrome is not uncommon, and the presence of these atypical features is consistent with neuropathological observations that ALS is a multisystem disorder. ALS-Plus syndrome is associated with increased risk for poor survival and the presence of a pathogenic mutation.
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: Shannon
authors.initials: S
authors.lastname: Vandriel
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, United States.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: Ashley
authors.initials: A
authors.lastname: Boller
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, United States.
authors.forename: Elisabeth McCarty
authors.initials: EM
authors.lastname: Wood
authors.affiliation: Department of Radiology, University of Pennsylvania, United States.
authors.forename: John
authors.initials: J
authors.lastname: Woo
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.affiliation: Department of Neurology, University of Pennsylvania, United States.
authors.forename: Katya
authors.initials: K
authors.lastname: Rascovsky
authors.affiliation: Department of Neurology, University of Pennsylvania, United States. Electronic address: mgrossma@upenn.edu.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
mesh_terms: D000251:Adenosine Triphosphatases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D000073885:C9orf72 Protein; D018797:Cell Cycle Proteins; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013577:Syndrome; D000074405:Valosin Containing Protein
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Amyotrophic lateral sclerosis; Cognitive; Genetics; Non-neuromuscular; Survival
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