KIF1A-related disorders in children: A wide spectrum of central and peripheral nervous system involvement

Area of Science:

• Neurology
• Genetics
• Pediatrics

Background:

• KIF1A-related disorders (KRD) are rare genetic neurological conditions.
• The phenotypic spectrum of KRD has expanded since their initial description in 2011.
• Childhood-onset KRD involves complex central and peripheral nervous system manifestations.

Purpose of the Study:

• To delineate the clinical, neurophysiological, and radiological spectrum of childhood-onset KRD.
• To report on a case series of individuals with KRD from a single tertiary center.
• To identify novel mutations and characterize the range of disease severity.

Main Methods:

• Retrospective case-notes review of children and young people with KRD.
• Analysis of clinical presentations, neurophysiological findings, and brain MRI results.
• Genetic analysis to identify KIF1A mutations.

Main Results:

• Twelve individuals from 10 families with KRD were identified, harboring eight different mutations, including four novel ones.
• Two patients presented with severe phenotypes: congenital contractures, spasticity/dystonia, dysautonomia, sensorimotor polyneuropathy, optic atrophy, white matter changes, and respiratory insufficiency.
• Ten patients exhibited a milder spectrum with movement disorders, dysautonomia, sensory axonal neuropathy, optic atrophy, learning/behavioral difficulties, and variable white matter changes; epilepsy was common in severe cases.

Conclusions:

• KIF1A-related disorders encompass a wide range of neurological presentations in childhood.
• Both severe and milder forms of KRD involve combined central and peripheral nervous system deficits, including autonomic dysfunction.
• This case series underscores the heterogeneity of KRD and the importance of comprehensive neurodiagnostic evaluation.