ALS-Plus syndrome: non-pyramidal features in a large ALS cohort

J Neurol Sci. 2014 Oct 15;345(1-2):118-24. doi: 10.1016/j.jns.2014.07.022. Epub 2014 Jul 18.

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.

Keywords: Amyotrophic lateral sclerosis; Cognitive; Genetics; Non-neuromuscular; Survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases
  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / complications*
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics
  • C9orf72 Protein
  • Cell Cycle Proteins
  • Cognition Disorders / etiology*
  • Cognition Disorders / genetics
  • Cohort Studies
  • DNA-Binding Proteins
  • Female
  • Genetic Testing
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation / genetics
  • Proteins / genetics
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Syndrome
  • Valosin Containing Protein

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proteins
  • SOD1 protein, human
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein