Molecular analysis in the Amyotrophic Lateral Sclerosis

• Main Authors: Ying-Ju Chen, 陳盈如
• Other Authors: Min-Jen Lee
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/53453883305620068458

碩士 === 臺灣大學 === 分子醫學研究所 === 98 === 　Amyotrophic lateral sclerosis (ALS), characterizing by progressive upper and lower motor neuron degeneration, is one of the most common forms of motor neuron disease. Clinically, it progressed rapidly and patients usually developed respiratory failure 2 to 5 years post the onset. Familial ALS is only 10% of ALS and it usually occurs at young age (<55 years old). The responsible genes and its associated mutation frequency are as follows, SOD1 (20%), TARDBP (2~5%), FUS (4%) and rare in ANG. In this study, we would screen the mutation frequency in a Taiwanese cohort with ALS (both young-onset and familial ALS). In total, we recruited 46 patients; 4 patients have a positive family history and the average age of onset for these patients are between 43 and 48 years old. 　The four responsible genes were selected for mutation detection. To identify a heteroduplex, the high resolution melting curve (HRM) analysis has been employed. A sequence variant resulting in a heteroduplex on the HRM, were subjected to sequencing. Because of the small size of transcript, direct sequencing has been used to identify the mutations in SOD1 and ANG genes. The result reveals 2 SOD1 (p.G85R and p.T136R), one TARDBP (p.M337V) missense mutations, one TARDBP 5’UTR -61 C>G mutations, and two FUS (p.G49G and p.T97T) silence mutations. No mutation was observed in ANG genes. Patients with a mutation develop the symptoms at 35 and 43 years of age. The symptoms progressed rapidly with early respiratory failure. The mutation frequency in the Taiwanese cohort is 25% for the SOD1 in familial ALS, 3% for the SOD1 in sporadic ALS. The data is similar to that found in Caucasian people in previous references. The mutation frequency of TARDBP in familial ALS (25%) is similar to previous references at Taiwan. 　In conclusion, the mutation rate in the sporadic ALS is not high and the SOD1 mutation remains the most common cause for familial ALS. Mutations in the newly identified responsible genes such as TARDBP, FUS and ANG are not common. Patients with a genetic defect developed a young-onset, rapid progressive motor neuron degeneration and a poor outcome. Further investigation is needed to clarify the pathogenic mechanism for this devastating disease.