Cortical function in asymptomatic carriers and patients with C9Orf72 amyotrophic lateral sclerosis

Nimeshan Geevasinga, Parvathi Menon, Garth A. Nicholson, Karl Ng, James Howells, Jillian J. Kril, Con Yiannikas, Matthew C. Kiernan, Steve Vucic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)


IMPORTANCE: The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). OBJECTIVE: To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. DESIGN, SETTING, AND PARTICIPANTS: Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants. MAIN OUTCOMES AND MEASURES: Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants. RESULTS: Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2%[1.8%]) and sporadic ALS (1.6%[1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2%[1.8%]; F = 16.1; P <.001) and healthy control participants (11.8%[1.0%]; F = 16.1; P <.001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P <.01) and motor-evoked potential amplitude (P <.05) as well as a reduction in the resting motor threshold (P <.05) and cortical silent period duration (P <.001). CONCLUSIONS AND RELEVANCE: This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.

Original languageEnglish
Pages (from-to)1268-1274
Number of pages7
JournalJAMA Neurology
Issue number11
Publication statusPublished - 1 Nov 2015
Externally publishedYes


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