Background Dominant and recessive variants in the KIF1A 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.
Methods In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3–65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders.
Results 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.
Conclusion The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A 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 KIF1A 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.
- central nervous system diseases
- cerebellar diseases
- genetic heterogeneity
- neurodegenerative diseases
Statistics from Altmetric.com
FN and MG contributed equally.
Contributors FN, MG, EMV, GZ and ESB established the project. FN and MG collected the data. FN and MG wrote the first draft of the manuscript, tables and figures. MG, LT, FS, LB and AS performed molecular analyses. All the remaining authors clinically diagnosed and followed up the patients. All the authors revised the manuscript for important intellectual content and approved the final version.
Funding This work was supported from grants from the Italian Ministry of Health (Ricerca Finalizzata NET-2013–02356160, Ricerca Corrente 2020 to IRCCS Fondazione Mondino), European Research Council (ERC Starting Grant 260888), Italian Ministry of University and Research (Progetto Dipartimenti di Eccellenza to Dept. of Molecular Medicine, University of Pavia) and Pierfranco and Luisa Mariani Foundation (PADAPORT project).
Map disclaimer The depiction of boundaries on this map does not imply the expression of any opinion whatsoever on the part of BMJ (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. This map is provided without any warranty of any kind, either express or implied.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Ethics approval This study has been notified to the Ethics Committee of the Bambino Gesù Children's Hospital (approval number 590).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.