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

Stefania Della Vecchia, Alessandra Tessa, Claudia Dosi, Jacopo Baldacci, Rosa Pasquariello, Antonella Antenora, Guja Astrea, Maria Teresa Bassi, Roberta Battini, Carlo Casali, Ettore Cioffi, Greta Conti, Giovanna De Michele, Anna Rita Ferrari, Alessandro Filla, Chiara Fiorillo, Carlo Fusco, Salvatore Gallone, Chiara Germiniasi, Renzo GuerriniShalom Haggiag, Diego Lopergolo, Andrea Martinuzzi, Federico Melani, Andrea Mignarri, Elena Panzeri, Antonella Pini, Anna Maria Pinto, Francesca Pochiero, Guido Primiano, Elena Procopio, Alessandra Renieri, Romina Romaniello, Cristina Sancricca, Serenella Servidei, Carlotta Spagnoli, Chiara Ticci, Anna Rubegni, Filippo Maria Santorelli

Research output: Contribution to journalArticlepeer-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.

Original languageEnglish
Pages (from-to)437-450
Number of pages14
JournalJournal of Neurology
Issue number1
Publication statusPublished - 2022


  • CoQ10
  • Hereditary ataxia
  • Hereditary spastic paraparesis
  • KIF1A neuroimaging
  • KIF1A phenotype
  • Psychiatric manifestation in neurological disease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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