Defining neurodegeneration on Guam by targeted genomic sequencing

Ann Neurol. 2015 Mar;77(3):458-68. doi: 10.1002/ana.24346. Epub 2015 Feb 3.


Objective: Amyotrophic lateral sclerosis/parkinsonism-dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic.

Methods: In this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros.

Results: Genes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations.

Interpretation: The findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi-incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / epidemiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Dementia / epidemiology
  • Dementia / genetics*
  • Dynactin Complex
  • Guam / epidemiology
  • Humans
  • Huntingtin Protein
  • Male
  • Microtubule-Associated Proteins / genetics*
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Parkinson Disease / epidemiology
  • Parkinson Disease / genetics*
  • Pedigree
  • Protein Kinases / genetics*
  • RNA-Binding Protein FUS / genetics*
  • Syndrome


  • DCTN1 protein, human
  • Dynactin Complex
  • HTT protein, human
  • Huntingtin Protein
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • RNA-Binding Protein FUS
  • Protein Kinases
  • PTEN-induced putative kinase