The purpose of our study was to elucidate the genetic epidemiology of diseases associated with the clinical picture of amyotrophic lateral sclerosis (ALS).

Recent studies have demonstrated that a certain number of sporadic patients harbored mutations in causative genes for ALS. In Western population C9ORF72 accounts for majority of these patients, whereas it is very rare in the Japanese population. Because diagnosing of ALS inflicts a great mental blow, very careful clinical judgment is needed. Typical ALS is not hard to diagnose, but when it comes to atypical forms, it can sometimes be difficult to diagnose.

Forty five subjects diagnosed as ALS according to El Escorial Airlie House revised criteria were enrolled in this study with informed consent. Whole exome sequencing analysis was conducted and nonsynonymous variants were filtered with the allele frequency <0.002. This study was approved by the Institutional Review Board of National Center of Neurology and Psychiatry.

Thirteen (29%) subjects harbored likely pathogenic mutations in nine genes including ANSXA11 (2 subjects), ERBB4, HNRNPA1, MFN2, MPZ, MORC2, SOD1 (4 subjects), UBQLN2, and VCP. Five in nine (56%) patients with family history and eight in 36 (22%) patients without family history had pathogenic mutations. Ten patients were accounted for by genes causative for ALS, whereas three were by genes causative for Charcot-Marie-Tooth disease (CMT) including MFN2, MPZ, MORC2. These three patients had upper motor neuron signs and their nerve conduction study showed normal findings.

We found a mutation leading to CMT that can also be associated with the clinical picture of ALS. Although ALS and CMT have a considerable overlap in these phenotypes, correct identification of these syndromes is important because their treatment and prognoses are definitely different. Molecular background of ALS is very diverse, warranting the application of WES to realize precision medicine for ALS.