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Reply: Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations.

Brain. 2019 Oct 15. pii: awz306. doi: 10.1093/brain/awz306. [Epub ahead of print]

Authors/Editors: Brenner D, Rosenbohm A, Yilmaz R, Müller K, Grehl T, Petri S, Meyer T, Grosskreutz J, Weydt P, Ruf W, Neuwirth C, Weber M, Pinto S, Claeys KG, Schrank B, Jordan B, Knehr A, Günther K Hübers A, Zeller D, Kubisch C, Jablonka S, Sendtner M, Klopstock T, de Carvalho M, Sperfeld A, Borck G, Volk AE, Dorst J, Weis J, Otto M, Schuster J, Del Tredici K, Braak H, Danzer KM, Freischmidt A, Meitinger T, Ludolph AC, Andersen PM, Weishaupt JH; German ALS network MND-NET.
Publication Date: 2019


In 2018, we provided evidence that splice site mutations in the C-terminal cargo binding domain of KIF5A are a cause of familial amyotrophic lateral sclerosis (FALS) (Brenner et al., 2018). Shortly thereafter, a genome-wide significant enrichment of KIF5A loss-of-function mutations in FALS patients was confirmed by a large whole exome sequencing study comprising 1138 index FALS cases and 19 494 controls (Nicolas et al., 2018). In both studies, pathogenic mutations clustered predominantly in the C-terminal cargo binding domain of KIF5A and are predicted to affect splicing of exon 27. The disease course of FALS patients carrying C-terminal KIF5A mutations is rather heterogeneous. While in our cohort the median survival of KIF5A loss-of-function mutation carriers was 40.5 months (n = 8), Nicolas et al. reported a median survival of 117 months (n = 17). Remarkably, three patients with C-terminal KIF5A mutation in the latter cohort survived more than 18 years. By comparison, the median survival time of ALS patients is ∼20–36 months in countries with European ancestry (Chiò et al., 2009) or 31 months in southern Germany (Rosenbohm et al., 2017). FALS patients carrying C-terminal KIF5A loss-of-function mutations showed asymmetric affection of upper and lower motor neurons consistent with a classical ALS phenotype.

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