Objective: This work sought to investigate the frequency and characteristics of movement disorders (MD) associated with repeat expansions or intermediate repeats in the C9orf72 gene.

Background: An hexanucleotide repeat expansion GGGGCC in the first intron of the C9orf72 gene is a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) [1]. Recent work has identified C9orf72 in Huntington’s disease phenocopies [2], and also to be associated with Parkinson’s disease [3] as well as with atypical parkinsonism [4]. Moreover, intermediate repeats have also been linked with increased susceptibility to neurodegenerative MD [5,6].
The exact phenomenology of MD in patients with C9orf72 expansions or intermediate repeats remain to be determined.

Method: We evaluated the clinical characteristics of patients with intermediate repeats (21-90) and expansions (>90) in the C9orf72 gene evaluated at our institution.

Results: 501 patients were tested for mutations in the C9orf72 gene. 446 had <20 repeats, 5 had intermediate number of repeats and 55 had the expanded allele.
There was sufficient clinical information about 39/55 patients with the expansion. 14/39 had associated MD. Among patients with MD, mean age at onset was 49 (range 8 to 69) and age at onset of MD was 52 years (19-72). Five were female. Five patients were already deceased with an average of seven years (1-12) between onset to death. 10/14 patients developed FTD and 4/14 ALS. 10/14 patients had more than one MD. Mild, symmetric parkinsonism was the most frequent MD being present in 9/14 patients. 8/14 patients had tremor, mainly postural, distal and affecting both arms. 6/14 patients had myoclonus which was also distal and affecting upper limbs. 5/14 patients had cervical dystonia, 2/14 had chorea and 3/14 patients had orolingual dyskinesias.

Among the five patients with intermediate repeats four had MD.  Of those two were female and age at onset was 56.5 years (25 to 67). One patient had early onset parkinsonism, one had generalized chorea, another one had progressive supranuclear palsy-corticobasal syndrome and there was also a patient with progressive dystonia and ataxia.

Conclusion: MD, especially in combination, are commonly present among patients with expansions in the C9orf72 gene. Global parkinsonism, cervical dystonia, as well as tremor or myoclonus affecting upper limbs distally are the most common MD.

References: [1] Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–68. [2] Hensman DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 2014;82:292–9. [3] Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 2013;136:385–91. [4] Schottlaender L V., Polke JM, Ling H, MacDoanld ND, Tucci A, Nanji T, et al. The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism. Neurobiol Aging 2015;36:1221.e1-1221.e6. [5] Nuytemans K, Bademci G, Kohli MM, Beecham GW, Wang L, Young JI, et al. C9orf72 intermediate repeat copies are a significant risk factor for parkinson disease. Ann Hum Genet 2013;77:351–63. [6] Cannas A, Solla P, Borghero G, Floris GL, Chio A, Mascia MM, et al. C9ORF72 intermediate repeat expansion in patients affected by atypical Parkinsonian syndromes or parkinson’s disease complicated by psychosis or dementia in a Sardinian population. J Neurol 2015;262:2498–503.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/movement-disorders-associated-with-expansions-and-intermediate-repeats-in-the-c9orf72-gene/