Marked intrafamilial phenotypic variation in a family with SOD1 C111Y mutation

Abstract

Objectives: To identify the disease-causing mutation in and report on the clinical features of a Japanese family that had coexisting phenotypes of amyotrophic lateral sclerosis and spinal muscular atrophy. Methods: The family comprised 9 patients (6 men and 3 women). We reviewed their clinical records and performed mutation analysis of the copper/zinc superoxide dismutase (SOD1) gene in some of these patients. Results:The patients either had a rapid (n = 7) or an extremely long (n = 2) clinical course. The mean age at onset was 39.0 ± 13.7 years (range: 20-68 years). The initial symptoms were bulbar palsy (n = 2), upper (n = 4) or lower (n = 2) limb muscle weakness, or leg cramps (n = 1). The total disease duration varied widely, ranging from 1 year to >69 years. We identified a SOD1 C111Y mutation in the patients of this family. Conclusion: The family showed a marked intrafamilial phenotypic variation associated with the SOD1 C111Y mutation. Elucidating the biological basis of disease expression in patients with SOD1 C111Y mutation may provide us with useful information to develop therapeutic approaches and to prevent disease progression.

Familial amyotrophic lateral sclerosis with an I104F mutation in the SOD1 gene: Multisystem degeneration with neurofilamentous aggregates and SOD1 inclusions

“…Of interest was that one of the present five family members, i.e., patient III‐2 (the proband) developed respiratory failure 6 years after disease onset, whereas none of the patients in the family studied by Ikeda et al ., including those with a disease duration of more than 10 years, developed respiratory failure . Similar intra‐familial variability in disease progression has been described for FALS with C111Y, I113T, E141X, and C146R mutations in the SOD1 gene. On the other hand, it has been reported that the rate of disease progression was uniformly faster in patients with SOD1 A4V and L106 V mutations, and uniformly slower in patients with the SOD1 H46R mutation …”

Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis

“…Two cases (III-5 and IV-6 reported in [26]; Additional file 1: Table S1) examined here had the disease duration of 1.2 and 4.0 years, respectively. It has been reported that SOD1-positive inclusions are observed at the cytoplasm and neurites of spinal motor neurons in those SOD1 -ALS cases with C111Y mutation [27].…”

“…To test the immunoreactivity of our anti-SOD1 int antibody in human cases, the double immunofluorescence staining with anti-SOD1 int and anti-SOD1 antibodies was performed on the ventral horn of the lumbar spinal cord section of the SOD1 -ALS patients with C111Y mutation (the case IV-6 in [26]; Additional file 1: Table S1). As shown in Fig.…”

“…7b), furthermore, the abnormally accumulated SOD1 in cytoplasm and neurites of a Betz cell were also immunostained by anti-SOD1 int antibody. In another SOD1 -ALS case with C111Y mutation (the case III-4 in [26]; Additional file 1: Table S1), the disease duration was exceptionally long (69 years), but the motor neurons in the ventral horn of the lumbar spinal cord exhibited immunoreactivity to anti-SOD1 int antibody (Fig. 7c).…”

Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis

“…All ALS cases except ALS10 were sporadic, among which no mutation in exons of SOD1 gene was further confirmed in ALS1, 2, 3, 4, 6, 7, 8, and 9 (Table 2). ALS10 was a familial ALS case with the C111Y mutation in the SOD1 gene [40].…”