De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.
Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.|Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
Chihiro
C
Ohba
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
Kazuhiro
K
Haginoya
Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.|Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
Hitoshi
H
Osaka
Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
Kazuo
K
Kubota
Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
Akihiko
A
Ishiyama
Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
Takuya
T
Hiraide
Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
Hirofumi
H
Komaki
Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
Masayuki
M
Sasaki
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Satoko
S
Miyatake
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Mitsuko
M
Nakashima
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Yoshinori
Y
Tsurusaki
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Noriko
N
Miyake
Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
Fumiaki
F
Tanaka
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Hirotomo
http://orcid.org/0000-0003-0723-0960
H
Saitsu
Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
Naomichi
N
Matsumoto
D019943:Amino Acid Substitution; D002526:Cerebellar Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016547:Kinesins / Q000235:genetics*; D035002:Lower Extremity / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009128:Muscle Spasticity / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense; D014786:Vision Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
C094065:KIF1A protein, human; D016547:Kinesins