Unusual electrophysiological findings in a Chinese ALS 4 family with SETX-L389S mutation: a three-year follow-up

J Neurol. 2021 Mar;268(3):1050-1058. doi: 10.1007/s00415-020-10246-2. Epub 2020 Sep 30.


Amyotrophic lateral sclerosis type 4 (ALS4) is a familial form of ALS caused by mutations in the SETX gene. To date, there are seven unrelated ALS4 families with four missense mutations (L389S, T31I, R2136H, and M386T) in SETX. ALS4 is characterized by early onset, distal muscle weakness and atrophy, pyramidal signs, and the absence of sensory deficits. Motor conduction studies often present normality or reduced amplitudes of compound muscle action potential (CMAP). The conduction blocks (CBs) are rare and only observed in one male of an Italian ALS4 family. Our study showed that seven symptomatic patients presented the classical ALS4 phenotype with two asymptomatic females in a Chinese family spanning three generations. Sequencing analysis revealed a heterozygous c.1166T > C/p.L389S mutation in SETX that co-segregated with disease phenotype in the family. The same mutation has been identified previously in three ALS4 families from the United States and Italy, respectively. Specifically, three young males presented multiple CBs and abnormal temporal dispersions (TD) in the median, ulnar and tibial nerves over the three-year follow-up period. Moreover, for the first time, we found that senataxin was also expressed in the myelin sheath of peripheral nerves besides axons. The study indicates that CBs and abnormal TD are the characteristics in the ALS4 family, providing pivotal familial evidence of CBs and TD of motor nerves in ALS4. The unusual electrophysiological features may be associated with the expression of senataxin in peripheral nerves.

Keywords: Amyotrophic; Conduction block; Electrophysiology; Familial; Lateral sclerosis (ALS); SETX; Temporal dispersion.

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • China
  • DNA Helicases
  • Female
  • Follow-Up Studies
  • Humans
  • Italy
  • Male
  • Multifunctional Enzymes
  • Mutation
  • RNA Helicases


  • Multifunctional Enzymes
  • SETX protein, human
  • DNA Helicases
  • RNA Helicases

Supplementary concepts

  • Amyotrophic Lateral Sclerosis 2, Juvenile