Long-term clinical observation of patients with heterozygous KIF1A variants

Aritomo Kawashima, Kaori Kodama, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Miki Ikeda, Yu Katata, Noriko Togashi, Chihiro Ohba, Eri Imagawa, Kazuhiro Iwama, Takeshi Mizuguchi, Masahiro Kitami, Yu Aihara, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Hirotomo Saitsu, Naomichi MatsumotoKazuhiro Haginoya

Research output: Contribution to journalArticlepeer-review


KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4–44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype–genotype correlation.

Original languageEnglish
JournalAmerican Journal of Medical Genetics, Part A
StateAccepted/In press - 2024
Externally publishedYes


  • KIF1A
  • cerebellar atrophy
  • optic radiation
  • peripheral neuropathy
  • spastic paraplegia


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