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

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, variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for -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 -linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes.

RESULTS

A total of 26 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.Asn132Argfs3 [N131Rfs3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with -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 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.