A Novel De Novo Missense Mutation in KIF1A Associated with Young-Onset Upper-Limb Amyotrophic Lateral Sclerosis

Abstract

We investigate the etiology of amyotrophic lateral sclerosis (ALS) in a 35-year-old woman presenting with progressive weakness in her left upper limb. Prior to sequencing, a comprehensive neurological work-up was performed, including neurological examination, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Six months before evaluation, the patient experienced weakness and atrophy in her left hand, accompanied by brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Trio genome sequencing identified a likely pathogenic de novo variant in the KIF1A gene (NM_001244008.2): c.574A>G, p.(Ile192Val). Pathogenic variants in KIF1A have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). This report describes a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.

Keywords: KIF1A; amyotrophic lateral sclerosis; de novo mutation; genome sequencing.

Figure 1

Identification of KIF1A mutation. (A) Pedigree of the affected family. (B) Sanger sequencing of the c.574A>G mutation for the proband and her parents. The de novo heterozygous c.574A>G mutation in the KIF1A gene is indicated by an arrow. (C) Amino acid sequence comparison of the KIF1A motor domain and orthologous proteins from various species. Identical amino acids to the human KIF1A sequence are shown in bold. The missense mutation is indicated by an arrow on top of the mutated amino acid Isoleucine (I) 192 highlighted in yellow.

Figure 2

Brain MRI of a 35-year-old woman with ALS harboring a de novo probably pathogenic c.574A>G KIF1A mutation. Coronal (A) and axial (B) FLAIR sequences revealed asymmetrical hypersignal of the corticospinal tracts (black arrow indicating the right corticospinal tract). Axial SWI sequence (C) displayed linear hyposignal of the right precentral gyrus (black arrow). Abbreviations: FLAIR: Fluid-attenuated inversion recovery, SWI: Susceptibility weighted imaging.