Ming Zhang1, Zhengrui Xi1, Karen Misquitta1, Christine Sato1, Danielle Moreno1, Yan Liang1, Elizabeth Slow2, Ekaterina Rogaeva1,3, Maria Carmela Tartaglia1,3,4. 1. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada. 2. Krembil Neuroscience Center, Movement Disorder's Clinic, Toronto Western Hospital, Ontario, Canada. 3. Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada. 4. Krembil Neuroscience Center, University Health Network Memory Clinic, Toronto Western Hospital, Ontario, Canada.
Abstract
BACKGROUND: Intermediate interrupted ataxin 2 (ATXN2) alleles (27-33 CAG-repeats) increase the risk for amyotrophic lateral sclerosis and are reported as modifiers in chromosome 9 open reading frame 72 (C9orf72) carriers, rendering susceptibility to amyotrophic lateral sclerosis rather than frontotemporal lobar degeneration. The clinical presentation of C9orf72 patients with pathogenic ATXN2 alleles (≥35 CAG-repeats) is unknown. METHODS: Blood samples were collected from a family affected by ataxia, dementia, and parkinsonism, but not amyotrophic lateral sclerosis. Mutation analyses of the proband included C9orf72 and 14 ataxia genes, followed by segregation analyses in family members. RESULTS: Both affected siblings carry an uninterrupted 37-repeat expansion in ATXN2 and a methylated G4 C2 -repeat allele in C9orf72 that is typical of large pathogenic expansions. CONCLUSIONS: The CAG-expansion in ATXN2 likely caused the ataxia, whereas the dementia may be linked to both C9orf72 and ATXN2 repeat expansions. The pathological uninterrupted ATXN2 repeat may not have the same modifying effect as intermediate interrupted alleles.
BACKGROUND: Intermediate interrupted ataxin 2 (ATXN2) alleles (27-33 CAG-repeats) increase the risk for amyotrophic lateral sclerosis and are reported as modifiers in chromosome 9 open reading frame 72 (C9orf72) carriers, rendering susceptibility to amyotrophic lateral sclerosis rather than frontotemporal lobar degeneration. The clinical presentation of C9orf72patients with pathogenic ATXN2 alleles (≥35 CAG-repeats) is unknown. METHODS: Blood samples were collected from a family affected by ataxia, dementia, and parkinsonism, but not amyotrophic lateral sclerosis. Mutation analyses of the proband included C9orf72 and 14 ataxia genes, followed by segregation analyses in family members. RESULTS: Both affected siblings carry an uninterrupted 37-repeat expansion in ATXN2 and a methylated G4 C2 -repeat allele in C9orf72 that is typical of large pathogenic expansions. CONCLUSIONS: The CAG-expansion in ATXN2 likely caused the ataxia, whereas the dementia may be linked to both C9orf72 and ATXN2 repeat expansions. The pathological uninterrupted ATXN2 repeat may not have the same modifying effect as intermediate interrupted alleles.
Authors: Karla P Figueroa; Shi-Rui Gan; Susan Perlman; George Wilmot; Christopher M Gomez; Jeremy Schmahmann; Henry Paulson; Vikram G Shakkottai; Sarah H Ying; Theresa Zesiewicz; Khalaf Bushara; Michael Geschwind; Guangbin Xia; S H Subramony; Tetsuo Ashizawa; Stefan M Pulst; Sheng-Han Kuo Journal: Mov Disord Date: 2017-11-29 Impact factor: 10.338
Authors: Philip McGoldrick; Ming Zhang; Marka van Blitterswijk; Christine Sato; Danielle Moreno; Shangxi Xiao; Ashley B Zhang; Paul M McKeever; Anna Weichert; Raphael Schneider; Julia Keith; Leonard Petrucelli; Rosa Rademakers; Lorne Zinman; Janice Robertson; Ekaterina Rogaeva Journal: Neurology Date: 2017-12-27 Impact factor: 9.910