Heterogeneous movement disorders in patients with C9orf72 hexanucleotide expansions

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

The study researchers reviewed the clinical records of patients (N = 501) with HREs from C9orf72 for clinical features. The enrolled patients were tested between 2012 and 2019 at the National Hospital for Neurology and Neurosurgery in the UK.

A total of 53 patients had more than 30 repetitions in C9orf72. Of the 40 patients with HRE for whom clinical data were available, 17 (women, 7) had a movement disorder (MD). The mean age of patients with MD initially was 58 (range, 8-70) years. 64.7% had a first degree relative with ALS or dementia, and all but 2 had major C9orf72 expansions.

Most patients (n = 13) had more than 1 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.

Of the patients with MD, 14 underwent a neuropsychological evaluation. Executive dysfunction and / or memory impairment was observed in most (n = 10), half (n = 7) of slow-processing patients, and 2 had visual dysfunction, impaired computation, or attention deficit. In addition, 4 of the patients showed reduced verbal language skills.

Fifteen of the patients with MD underwent magnetic resonance imaging (MRI) that revealed generalized atrophy (n = 7), frontal atrophy (n = 2), midbrain atrophy (n = 1), and small vascular disease ( n = 2) were found. .

Patients with and without MD differed significantly in terms of seizure rates (23.5% versus 0%; P = 0.008) and ALS (29.4% versus 73.9%; P = 0.010). However, after correcting several comparisons, these differences were no longer significant.

This study was limited to enrolled patients because of its retrospective design and the lack of neurophysiological studies.

. Based on these results, the researchers concluded that “MD is common in C9orf72” and “signs of ALS or FTD may precede or even exist in isolation. Parkinsonism, tremors, and myoclonus are most commonly seen. “


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

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