Despite the genetic heterogeneity reported in familial ALS (FALS), Cu/Zn superoxide-dismutase (SOD1) gene mutations are the most frequent cause of FALS, accounting for around 20% of familial cases (ALS1) and isolated sporadic cases. Some mutations are associated with a long survival time, while others are linked to a very rapid progression. Clinical-genetic characterization of ALS1 families is therefore important as it can provide information on the phenotype associated with a given mutation, the distribution of SOD1 mutations in different ethnic groups, and can clarify the genotype-phenotype correlation in patients with SOD1 gene mutations.
To describe the phenotype linked to this previously reported SOD1 gene mutation, p.E22G (E21G in the old nomenclature), in a large ALS1 Spanish kindred. This mutation was previously reported in a Canadian family but no clinical information was available.
Clinical characterization including gender, age at onset, site of onset and survival time was available from 15 affected members belonging to a seven-generation pedigree. The possibility of gender predominance or anticipation was also analyzed. DNA samples were available from three of the living symptomatic members. Informed consent for blood samples was obtained. We used direct sequencing to screen for SOD1 gene mutations.
An A-to-G transition at nucleotide position 65 (c.65A>G) leading to a p.E22G sequence change at protein level was identified in the three affected ALS patients. The phenotype was similar in all affected members in our p.E22G family. Initial symptoms occurred in the distal limb muscles, predominantly in the legs, and there was a mean survival time of 13.2+/-8.6 years. The mean age at onset was 51.8+/-10.1. The prevalence in males and females was similar, with no difference in phenotype as regards gender. The age range for onset of symptoms was between 38 and 71 years of age, although 60% of the members presented symptoms before their fiftieth birthday. The information available for five affected parent/affected offspring pairs suggested no apparent anticipation.
p.E22G is the ninth SOD1 gene mutation reported in Spain, and the third of these to be associated with long survival (the other two being p.G38R--previously G37R, and p.D77V--previously D76V). Our results emphasize the importance of genetic and clinical characterization of ALS1 families around the world for understanding the genotype-phenotype relationships of each SOD1 gene mutant and their relative frequency in different ethnic groups worldwide.