1. Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome
- Author
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Satoko Miyatake, Kunihiro Yoshida, Eriko Koshimizu, Hiroshi Doi, Mitsunori Yamada, Yosuke Miyaji, Naohisa Ueda, Jun Tsuyuzaki, Minori Kodaira, Hiroyuki Onoue, Masataka Taguri, Shintaro Imamura, Hiromi Fukuda, Kohei Hamanaka, Atsushi Fujita, Mai Satoh, Takabumi Miyama, Nobuko Watanabe, Yusuke Kurita, Masaki Okubo, Kenichi Tanaka, Hitaru Kishida, Shigeru Koyano, Tatsuya Takahashi, Yoya Ono, Kazuhiro Higashida, Nobuaki Yoshikura, Katsuhisa Ogata, Rumiko Kato, Naomi Tsuchida, Yuri Uchiyama, Noriko Miyake, Takayoshi Shimohata, Fumiaki Tanaka, Takeshi Mizuguchi, and Naomichi Matsumoto
- Subjects
Adult ,Cerebellar Ataxia ,Reflex, Abnormal ,Vestibular Diseases ,Bilateral Vestibulopathy ,Humans ,Peripheral Nervous System Diseases ,Ataxia ,Syndrome ,Neurology (clinical) ,Replication Protein C ,Vestibular Neuronitis - Abstract
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.
- Published
- 2022