Genetic reports abstractNegative resultsAnalysis of the C9orf72 hexanucleotide repeat expansion in Korean patients with familial and sporadic amyotrophic lateral sclerosis
Introduction
Amyotrophic lateral sclerosis (ALS) is an adult-onset, devastating, and untreatable neurodegenerative disorder that is characterized by rapidly progressive wasting and weakness of the limb, bulbar, and respiratory muscles because of degeneration of motor neurons in the spinal cord, brainstem, and motor cortex. Though 5%–10% of ALS cases are familial (fALS), most patients present with sporadic ALS (sALS). To date, a number of genetic loci and disease-causing genes have been reported to be associated with typical ALS or atypical motor neuron diseases (Ticozzi et al., 2011).
Recently, the expansion of a noncoding hexanucleotide repeat (GGGGCC) in the chromosome 9 open reading frame 72 (C9orf72) gene was identified as the causative mutation in familial and sporadic forms of ALS (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The C9orf72 repeat expansion was present in 46.4% of fALS and 21.1% of sALS cases in Finnish patients with ALS but additional analysis to investigate the incidence of the expanded repeat suggested that it varied according to geographic region (Majounie et al., 2012; Renton et al., 2011). However, there are no data available on the frequency and distribution of the C9orf72 repeat expansion in the Korean population. Therefore, we attempted to determine the incidence and spectrum of the C9orf72 repeat expansion in 254 Korean patients with ALS who had previously been screened for mutations in 5 major genes including SOD1, TARDBP, FUS, ANG, and OPTN (Kwon et al., 2012).
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Methods
A consecutive series of ALS patients from the ALS Clinic of the Neurology Department at Hanyang University Hospital in Seoul, Korea were prospectively enrolled in our study from October 2006 to November 2010. All subjects were of Korean descent and were selected according to the revised El Escorial criteria, fulfilling the criteria for probable or definite ALS. The study was approved by the Institutional Review Board of Hanyang University Hospital. Eight (3.1%) of the index patients had at
Results
As demonstrated in Table 1, none of the patients had the C9orf72 repeat expansion, whereas the expected sawtooth pattern with a 6-base pair periodicity was observed in the 2 samples from the NINDS repository (data not shown). Using the genotyping primers, a homozygous pattern was observed in 130 patients (51.2%) and the expected homozygosity based on the frequencies of each allele was exactly the same (51.2%). The most common allele was 2 hexanucleotide repeats (353/508; 69.5%) followed by 6
Discussion
Although the pathogenic mechanism is largely unknown, the identification of the C9orf72 repeat expansion is a major advancement in the genetic study of ALS (Renton et al., 2011). A large study involving ALS cohorts from European, American, and nonwhite populations around the world found that the frequency of the C9orf72 repeat expansion differed according to geographic region (Majounie et al., 2012). High frequencies of repeat expansion ranging from 25% to 50% for fALS and 4% to 7% for sALS
Disclosure statement
The authors declare no conflicts of interest.
The study was approved by the Institutional Review Board of Hanyang University Hospital.
Acknowledgements
This study was supported by a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A101712), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0005340).
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These authors contributed equally to this work.