A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset and incomplete penetrance in China.
More than 100 mutations in the Cu/Zn superoxide dismutase (SOD) gene have been found, accounting for about 20% of familial ALS (FALS). However, few have been identified in Chinese patients with FALS. We present a five-generation Chinese family with FALS with a rare mutation in exon 4 of the Cu/Zn SOD gene codon position 105, converting serine to leucine. Forty-seven family members including the proband were examined clinically; two affected persons had EMG and nerve conduction studies. Genomic DNA was extracted from peripheral blood leukocytes of the family members after informed consent. All five exons of the Cu/Zn SOD gene were amplified by polymerase chain reaction (PCR) and DNA sequencing was performed on purified products. Exon 4 of the Cu/Zn SOD gene was amplified from genomic DNA isolated from not only the family members but also from 50 unrelated healthy Chinese control subjects. A rare S105L mutation, which is heterozygous with C by T at position 1,125 of the coding sequence in exon 4 of the Cu/Zn SOD gene, was found in the proband and her affected elder brother. The clinical phenotype within the FALS patients in this family is relatively variable. The age at onset ranged from 32 to 65 years, with initial symptoms in either the upper or lower extremities in different family members. Two subjects aged 72 and 60 years remained asymptomatic until their death from other causes, although their offspring carrying the same mutation have already developed clinical evidence of the disease. The S105L mutation was identified in another seven asymptomatic family members, aged 7 to 59 years. It is concluded that the S105L mutation in exon 4 of the Cu/Zn SOD gene is pathogenic. The phenotype is characterized by relatively variable clinical symptoms, with incomplete penetrance.