Heterozygous <i>KIF1A</i> variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

Abstract

Dominant and recessive variants in the <i>KIF1A</i> gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous <i>KIF1A</i> variants, and extensively review the available literature to improve current classification of <i>KIF1A</i>-related disorders. Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. The present study further enlarges the clinical and mutational spectrum of <i>KIF1A</i>-related disorders by describing a large series of patients with dominantly inherited <i>KIF1A</i> pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that <i>KIF1A</i> screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.