Novel KIF1A Variant in a Patient with Cerebellar Atrophy and Ataxia: A Case Report

Pathogenic variants in KIF1A are associated with a spectrum of neurological disorders collectively known as KIF1A-associated neurological disorders (KAND). We present the case of a 57-year-old female with lifelong dysarthria, gait instability, and progressive ataxia, diagnosed with cerebellar ataxia in her late 40s. Brain MRI revealed diffuse cerebellar atrophy. Genetic testing identified a novel heterozygous KIF1A (NM_004321.6) variant, c.1788_1790delinsACG (p.His596_Pro597delinsGlnArg), which is absent from population databases and predicted to be deleterious by multiple in silico tools. Unlike most pathogenic KIF1A variants that cluster within the motor domain, this variant lies outside this region. In silico structural modeling suggests this substitution likely affects local protein architecture through two concurrent changes: the substitution of histidine 596 with glutamine represents a modest change to the local biochemical environment, while the replacement of the conformationally restrictive proline 597 with arginine removes the characteristic cyclic structure that constrains the peptide backbone. Family history was notable for cerebellar atrophy in the mother and similar neurological symptoms in the maternal brother, suggesting possible autosomal dominant inheritance. The identification of this novel KIF1A variant outside the motor domain expands our understanding of KAND's genetic basis and suggests that non-motor domain variants may be associated with slowly progressive neurological symptoms.