Genetic reports abstractBrief communicationIdentification of C9orf72 repeat expansions in patients with amyotrophic lateral sclerosis and frontotemporal dementia in mainland China
Introduction
Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset disorder that affects upper and lower motor neurons and leads to progressive muscular weakness and atrophy, with eventual death within 3–5 years after the onset primarily as a result of respiratory failure (Koppers et al., 2012). Frontotemporal dementia (FTD) is the second most common cause of young-onset dementia, which primarily affects individuals younger than 65 years old. FTD involves a range of progressive cognitive impairment syndromes associated with frontal and temporal lobe atrophy, characterized by behavioral changes, executive dysfunction, and language difficulties (Cerami et al., 2012). Recent compelling evidence has suggested that these 2 neurodegenerative disorders are associated through overlapping clinical features and pathologic spectrums. Approximately 10% of patients with FTD presented clinical and pathologic evidence of ALS. Similarly, 5%–15% of patients with ALS show severe behavioral changes and/or language dysfunctions that meet the diagnosis of FTD (Lillo et al., 2011, Piguet et al., 2011, Trojsi et al., 2012).
ALS and FTD have a strong genetic basis, with familial forms occurring in approximately 10% of ALS patients and 30%–50% of FTD patients, with an autosomal dominant pattern of inheritance (Borroni et al., 2013, Hardiman et al., 2011). The causative genes have been identified in patients with ALS or FTD and, among them, MAPT and GRN account for a significant number of patients with familial FTD (Pickering-Brown et al., 2008). SOD1, TARDBP, and FUS mutations are more common in patients with familial ALS (Andersen and Al-Chalabi, 2011). A recent breakthrough finding revealed GGGGCC repeat expansions in the noncoding region of C9orf72 in patients with familial or sporadic ALS and FTD in white populations. The distribution of GGGGCC repeats in healthy individuals commonly ranges from 2–23 repeats; the expansion sequence contains up to 500–1600 repeats in patients with ALS and FTD. The prevalence of expanded repeats was reported to be as high as 23.5%–47% for familial ALS or FTD and 4.1%–21.0% for sporadic ALS in Italy, Germany, Belgium, the United Kingdom, and the United States (DeJesus-Hernandez et al., 2011, Gijselinck et al., 2012, Renton et al., 2011). However, studies in East Asian suggest that the prevalence of pathogenic repeats was comparatively lower than that in Europe. Across these studies, the C9orf72 mutation accounted only for 18% of familial ALS and 2% of sporadic ALS in Taiwan (Tsai et al., 2012), and an even lower prevalence was observed in a cohort of patients with sporadic ALS in Japan (Ogaki et al., 2012), whereas no pathogenic mutation was observed in patients with ALS in mainland China and Korea (Jang et al., 2013, Zou et al., 2013), indicating that the expanded repeat sequences in the C9orf72 gene probably vary according to geographic region.
In addition, Mok et al. (2012) demonstrated that most of the patients with ALS and FTD carrying C9orf72 expanded repeats shared the same 20-single nucleotide polymorphism (SNP) risk haplotype associated with the C9orf72 gene in populations from Finland, Ireland, Italy, the United Kingdom, and the United States, suggesting that ALS/FTD associated with the C9orf72 mutation is probably derived from a single founder. However, it remains unclear whether patients with ALS/FTD in mainland China carry the same risk haplotype identified in white populations. To resolve this issue, in the current study, we examined the repeat expansions and risk haplotype of C9orf72 in patients with ALS/FTD from mainland China.
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Study participants
We recruited 128 patients with ALS and/or FTD (60.9% men; mean age at onset, 41.1 ± 11.5 years) and 150 healthy control subjects from mainland China for this study. All patients, including 110 with ALS (10 familial ALS) and 18 with FTD (5 familial FTD), were recruited consecutively from the outpatient neurology clinic of Xiangya Hospital, and standard clinical neurologic examinations were performed on each patient. All patients met the El Escorial criteria for ALS and the Lund-Manchester
Detection of expanded repeats in the C9orf72 gene
The C9orf72 expanded repeats were observed in the proband and the 2 asymptomatic siblings from an family with ALS-FTD and a patient with sporadic FTD (Fig. 1A and Fig. E1); no abnormal repeat expansion was identified in other patients and control individuals. A wide range of 2–20 repeats was observed in these patients, except for the 2 mutation carriers, and the frequency of repeats was 2 U (30.5%), followed by 7 U (29.7%) and 6 U (13.3%), with an average repeat number of 6.2 ± 4.8. A wide
Discussion
A hexanucleotide repeat expansion in the first intron of the C9orf72 gene was recently identified as a major cause of the chromosome 9p21-associated diseases ALS and FTD. Although the detailed pathologic mechanism is unknown, the general causes include primarily an inhibition of normal expression of the encoded protein or the loss of protein function through the generation of abnormal, toxic RNA foci that disrupt normal cellular pathways (Renton et al., 2011). A recent pathologic study has
Disclosure statement
The authors have no actual or potential conflicts of interest. The study was approved by the expert committee (equivalent to an institutional review board) of Xiangya Hospital, Central South University, China, and written informed consent was obtained from all patients or their guardians.
Acknowledgements
We are grateful to all subjects for participation in our study. This study was supported by the National Basic Research Program (973 Program; no. 2011CB510000 to Dr Shen) and the National Natural Science Foundation of China (no. 81171068 to Dr Shen).
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