Premium
Defining neurodegeneration on G uam by targeted genomic sequencing
Author(s) -
Steele John C.,
Guella Ilaria,
SzuTu Chelsea,
Lin Michelle K.,
Thompson Christina,
Evans Daniel M.,
Sherman Holly E.,
VilariñoGüell Carles,
Gwinn Katrina,
Morris Huw,
Dickson Dennis W.,
Farrer Matthew J.
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24346
Subject(s) - amyotrophic lateral sclerosis , neurodegeneration , parkinsonism , pathogenesis , dementia , genetics , biology , optineurin , disease , medicine , pathology
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. Ann Neurol 2015;77:458–468