Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants

Abstract

Background and objectives: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated.

Methods: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes.

Results: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 ± 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression.

Discussion: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.

Figure 1. The Variants in SOD1 for ALS

The predicted amino acid sequence of SOD1 (NP_000445.1) is shown. There are 211 variants and 6 intronic variants (c.72+19G>A, c.239+62T>C, c.358-304C>G, c.358-11A>G, c.358-10T>G, c.357+43_357+46delTACA) with DM of the variant class for ALS, MNDs, or SMA in HGMD 2022.3. Except for synonymous substitutions, data for SOD1-related variants in the ALSoD were collated and included if applicable to DM. SOD1 (NM_000454.5) variants colored red were identified in our cohort. We identified 2 novel variants†. Variants with an underline have been identified in Japan (the red line shows variants identified in Japanese patients). ALS = amyotrophic lateral sclerosis; ALSoD = Amyotrophic Lateral Sclerosis online Database; DM = disease-causing mutation; HGMD = Human Gene Mutation Database; MNDs = motor neuron diseases; SMA = spinal muscular atrophy.

Figure 2. Mean Age at Onset and Disease Duration of Patients With SOD1-Linked ALS

(A) Mean age at onset of patients with SOD1-linked ALS. The average age at onset varied among various variants, with the youngest carrying p.Ile36Phe (I35F) and the oldest carrying p.Ala5Asp (A4D). Error bars represent SD for multiple samples. (B) The mean disease duration was collected for patients with SOD1-linked ALS. Disease duration varied among variant types, ranging from rapid progression in p.Cys7Gly (C6G) (3 months) to more than 200 months.