Novel de novo mutations in KIF1A as a cause of hereditary spastic paraplegia with progressive central nervous system involvement

摘要

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness. Recently, the first de novo mutations in KIF1A were identified in patients with an early onset severe form of complicated HSP. We report two additional patients with novel de novo mutations in KIF1A hereby expanding the genetic spectrum of KIF1A-related HSP. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential MRIs, therefore linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in Patient 1 and Patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199R), respectively. Therefore our report contributes to the expanding the genotypic and phenotypic spectrum of HSP caused by mutations in KIF1A.