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Expanding the Spectrum of Movement Disorders Associated With C9orf72 Hexanucleotide Expansions
Carlos Estevez-Fraga1, Francesca Magrinelli1, Davina Hensman Moss1
1Department of Neurodegenerative Diseases (C.E.-F., D.H.M., S.J.T.), Department of Clinical and Movement Neurosciences (A.L, F.M., E.M., G.D.L., M.M., K.P.B.), and Department of Neuromuscular Disorders (H.H.), UCL Queen Square Institute of Neurology, United Kingdom; Department of Neurosciences, Biomedicine and Movement Sciences (F.M.), University of Verona, Italy; St George's University of London (D.H.M.), United Kingdom; Department of Systems Medicine (G.D.L.), University of Rome Tor Vergata, Italy; and Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health (M.M.), University of British Columbia, Vancouver, Canada.
Insights
Movement disorders are common in C9orf72 gene carriers and can appear before frontotemporal dementia or ALS symptoms, or even alone. Parkinsonism, tremor, and myoclonus are the most frequent movement disorders observed.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Hexanucleotide repeat expansions (HREs) in the C9orf72 gene are a leading genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
- Understanding the full spectrum of clinical manifestations in C9orf72 carriers is crucial for diagnosis and management.
Purpose of the Study:
- To investigate the frequency and clinical characteristics of movement disorders (MD) in individuals with C9orf72 HREs.
- To analyze the relationship between MD and other C9orf72-associated neurodegenerative diseases like FTD and ALS.
Main Methods:
- Retrospective review of clinical records of patients diagnosed with pathogenic range C9orf72 HREs.
- Comparison of clinical features between C9orf72 carriers with and without documented movement disorders.
Main Results:
- Movement disorders were identified in 17 out of 40 (42.5%) C9orf72 HRE carriers.
- In a significant subset, MD presented as the initial or sole symptom (6/17 and 2/17, respectively).
- Parkinsonism and tremor were the most prevalent MD (11/17 each), often co-occurring with myoclonus (5/17).
Conclusions:
- Movement disorders are a frequent and significant clinical feature in C9orf72 HRE carriers.
- MD can manifest early in the disease course, preceding or even occurring in isolation from FTD or ALS.
- Parkinsonism, tremor, and myoclonus are key movement disorder phenotypes associated with C9orf72 mutations.
Objective:
Hexanucleotide repeat expansions (HREs) in C9orf72 are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in C9orf72 through a retrospective review of patients' medical records.
Methods:
We retrospectively reviewed the clinical records of patients carrying a C9orf72 HRE in the pathogenic range and compared the characteristics of patients with and without MD.
Results:
Seventeen of 40 patients with a C9orf72 HRE had a documented MD. In 6 of 17, MD were the presenting symptom, and in 2 of 17, MD were the sole manifestation of the disease. FTD was present in 13 of 17 patients, ALS in 5 of 17 patients, and 2 of 17 patients did not develop FTD or ALS. Thirteen of 17 patients had more than one MD. The most common MD were parkinsonism and tremor (resembling essential tremor syndrome), each one present in 11 of 17 patients. Distal, stimulus-sensitive upper limbs myoclonus was present in 6 of 17 patients and cervical dystonia in 5 of 17 patients. Chorea was present in 5 of 17 patients, 4 of whom showed marked orofacial dyskinesias. The most frequent MD combination was tremor and parkinsonism, observed in 8 of 17 patients, 5 of whom also had myoclonus. C9orf72 patients without MD had shorter follow-up times and higher proportion of ALS, although these results did not survive the correction for multiple comparisons.
Conclusions:
MD are frequent in C9orf72. They may precede signs of ALS or FTD, or even be present in isolation. Parkinsonism, tremor, and myoclonus are most commonly observed.
