Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review

Background Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement. Methods In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes. Results Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit. Conclusions This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.

Automated summary

Background: Monoallelic variants in the KIF1A gene are associated with various clinical phenotypes involving the central and peripheral nervous system. Methods: In a multicenter study, 28 index cases with heterozygous variants in KIF1A were analyzed for clinical, genetic, and neuroradiological features. Results: Nine novel monoallelic variants and one copy number variation encompassing KIF1A were identified. Mutations mainly occurred de novo and in the motor domain, with most patients showing a spectrum of ataxia-spasticity disorders and some presenting secondary impairment of oxidative metabolism. Ubiquinol supplementation therapy showed subjective benefit in a subset of patients. Conclusions: This study expanded our understanding of KIF1A-related disorders, highlighting the heterogeneous nature of manifestations and the potential therapeutic role of ubiquinol supplementation in certain patients.