Genetic reports abstractScreening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS
Introduction
Amyotrophic lateral sclerosis (ALS) is an adult-onset, devastating, and untreatable neurodegenerative disorder. ALS is characterized by wasting and weakness of limbs and bulbar and respiratory muscles due to degeneration of motor neurons in the spinal cord, brainstem, and motor cortex, over a time course of approximately 3–5 years from symptom onset. Although most cases of ALS are sporadic (sALS), approximately 5% of ALS patients are known to have familial forms (fALS), often with an autosomal dominant pattern of inheritance (Andersen, 2006, Chiò et al., 2008; Logroscino et al., 2010, Rowland and Shneider, 2001).
To date, a number of genetic loci and disease causing mutations in several genes have been reported to be associated with typical ALS or atypical motor neuron diseases, which are further classified from ALS1 to ALS12 (Ticozzi et al., 2011). Mutations in the Cu/Zn superoxide dismutase 1 gene (SOD1, MIM 147450) are the most common cause of ALS, accounting for about 20% of fALS and less than 1% of sALS cases (Chiò et al., 2008, Rosen et al., 1993). However, the prevalence of SOD1 mutations in both fALS and sALS cases varies because studies have typically been based on case series and specific ethnic groups (Chiò et al., 2008, van Es et al., 2010). Mutations in TARDBP, which encodes the transactive response DNA-binding protein 43 (TDP-43), are responsible for approximately 5% of ALS cases (Corrado et al., 2010, Kabashi et al., 2008, Van Deerlin et al., 2008). Recently, mutations in FUS, which also encodes the DNA/RNA binding protein, were found in approximately 5% of patients with ALS who tested negative for SOD1 and TARDBP mutations (Kwiatkowski et al., 2009, Vance et al., 2009). Pathogenic mutations in other genes have also been identified and account for < 5% of ALS cases (Greenway et al., 2006, Maruyama et al., 2010).
Although many studies have been performed to estimate the proportion of fALS and the frequency of mutations in fALS and sALS patients in various populations, there are currently no data in Korean patients with ALS. In the present study, we sought to estimate the proportion of fALS in a consecutive series of ALS patients and to investigate the mutational frequencies and spectrums of SOD1, TARDBP, FUS, ANG, and OPTN genes.
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Subjects
A consecutive series of ALS patients from the ALS Clinic in the Neurology Department at Hanyang University Hospital in Seoul, Korea were prospectively enrolled from October 2006 to November 2010. All patients were of Korean descent. All subjects were selected according to revised El Escorial criteria, fulfilling the criteria for probable or definite ALS (Brooks et al., 2000). ALS patients were classified as familial when they had at least 1 family member in the same pedigree that was reported
Clinical findings
A total of 258 consecutive ALS patients were included in this study. The clinical findings are summarized in Table 1. Of the 258 patients, 164 were male and 94 were female (male:female ratio of 1.7:1.0) and the mean age of onset was 53.4 ± 11.5 years (range, 25–81 years). There were 36 patients with ages of onset younger than 40 years. In male patients, the mean onset age was 52.9 years, similar to females (54.3 years; p = 0.358). Nine ALS patients (9/258; 3.5%) had family histories of ALS
Discussion
In this study, which included a detailed genetic analysis of the SOD1, FUS, TARDBP, OPTN, and ANG genes from 9 fALS index patients and 249 sALS patients, we identified fifteen mutations in 8 fALS and 7 sALS patients, including 9 SOD1 mutations in 10 patients and 5 FUS mutations in 5 patients. No mutations or novel variants in OPTN, TARDBP, and ANG were identified in this cohort, which is consistent with previous findings (Cronin et al., 2008, Guerreiro et al., 2008, Sugihara et al., 2011).
Disclosure statement
The authors disclose no conflicts of interest.
Acknowledgements
This study was supported by a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A101712), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2010-0004450) and a grant from IN-SUNG Foundation for Medical Research.
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Contributed equally to this work.