Heterogeneous Movement Disorders in Patients With C9orf72 Hexanucleotide Expansions

Hands shaking parkinson’s disease
In this retrospective review, study researchers sought to assess the presentation of movement disorders in carriers of C9orf72 hexanucleotide repeat expansions.

Hexanucleotide repeat expansions (HREs) of C9orf72 were associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), tremors, Parkinsonism, and myoclonus according to results of a retrospective study published in Neurology Genetics.

Study researchers reviewed clinical records of patients (N=501) with HREs of C9orf72 for clinical characteristics. Included patients were tested at the National Hospital for Neurology and Neurosurgery in the United Kingdom between 2012 and 2019.

A total of 53 patients had greater than 30 repeats in C9orf72. Among the 40 patients with HRE who had available clinical data, 17 (women, 7) had a movement disorder (MD).  The median age of patients with MD was 58 (range, 8-70) years at onset. 64.7% had a first-degree relative with ALS or dementia, and all but 2 had large C9orf72 expansions.

Most patients (n=13) exhibited more than1 MD including tremor (n=11), Parkinsonism (n=11), myoclonus (n=7), dystonia (n=7), chorea (n=5; orofacial dyskinesias in 4 patients). Seizures occurred in 4 patients. At follow-up, 10 had developed FTD, 2 ALS, and 3 FTD/ALS overlap.

Among the patients with MD, 14 underwent a neuropsychological assessment. Executive dysfunction and/or memory impairment was observed among most (n=10), half (n=7) of patients exhibited slow processing speed, and 2 had visuospatial dysfunction, impaired calculation, or attention deficits. Additionally, 4 of the patients exhibited decreased verbal fluency.

15 of the patients with MD underwent a magnetic resonance imaging (MRI) scan which identified generalized atrophy (n=7), frontal atrophy (n=2), midbrain atrophy (n=1), and small vessel disease (n=2).

Patients with and without MD differed significantly for rates of seizures (23.5% vs 0%; P =.008) and ALS (29.4% vs 73.9%; P =.010). However, these differences were no longer significant after correcting for multiple comparisons.

This study was limited by its retrospective design and the lack of any neurophysiologic studies for included patients.

. Based on these findings, study researchers concluded that “MD are frequent in C9orf72” and “may precede signs of ALS or FTD, or even be present in isolation. Parkinsonism, tremor, and myoclonus are most commonly observed.”


Estevez-Fraga C, Magrinelli F, Moss DH, et al. Expanding the Spectrum of Movement Disorders Associated With C9orf72 Hexanucleotide Expansions. Neurol Genet. 2021;7(2):e575. doi:10.1212/NXG.0000000000000575