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

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A Correction to this article was published on 16 February 2023

A Correction to this article was published on 15 October 2021

This article has been updated

Abstract

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.

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Acknowledgements

We thank Catherine J. Wrenn for expert editing of the manuscript and critical advice on tables and figures. We are indebted to our colleagues who referred patients with spastic-ataxia for gene screening.

Funding

This research was partially supported by Grants MITO-NEXT and MINDFUL CC-2019-2366613 (to FMS), RC 5 × 1000 2020–2021 (to AT, RB, and AR), and RF-2019-12370112 (to AT and MTB) from the Italian Ministry of Health. We also acknowledge the financial support of DECODE-EE Tuscany Region Call for Health 2018 (to RG).

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Authors and Affiliations

  1. IRCCS Stella Maris Foundation, Calambrone, via dei Giacinti 2, 56128, Pisa, Italy

    Stefania Della Vecchia, Alessandra Tessa, Rosa Pasquariello, Guja Astrea, Roberta Battini, Anna Rita Ferrari, Diego Lopergolo, Chiara Ticci, Anna Rubegni & Filippo Maria Santorelli

  2. Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy

    Claudia Dosi

  3. Kode Solutions, Lungarno Galileo Galilei 1, 56125, Pisa, Italy

    Jacopo Baldacci

  4. Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, 80131, Naples, Italy

    Antonella Antenora, Giovanna De Michele & Alessandro Filla

  5. Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, 23842, Lecco, Italy

    Maria Teresa Bassi & Elena Panzeri

  6. Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, 56125, Pisa, Italy

    Roberta Battini

  7. Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, 40100, Latina, Italy

    Carlo Casali & Ettore Cioffi

  8. Neurology Unit and Neurogenetics Laboratories, Meyer Children University Hospital, University of Florence, 50139, Florence, Italy

    Greta Conti, Renzo Guerrini & Federico Melani

  9. Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, DINOGMI, University of Genoa, Genoa, Italy

    Chiara Fiorillo

  10. Child Neurology Unit, Pediatric Neurophysiology Laboratory, Department of Pediatrics, Azienda USL-IRCCS Di Reggio Emilia, 42122, Reggio Emilia, Italy

    Carlo Fusco & Carlotta Spagnoli

  11. Clinical Neurogenetics, Department Neurosciences, Az. Osp. Città della Salute e della Scienza di Torino, 1026, Torino, Italy

    Salvatore Gallone

  12. Neuromuscular Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, 23842, Lecco, Italy

    Chiara Germiniasi

  13. Department of Neurology, Azienda Ospedaliera San Camillo Forlanini, 00152, Rome, Italy

    Shalom Haggiag

  14. Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy

    Diego Lopergolo & Andrea Mignarri

  15. Scientific Institute IRCCS E. Medea, Unità Operativa Conegliano, 31015, Treviso, Italy

    Andrea Martinuzzi

  16. Neuromuscular Pediatric Unit, IRRCS Istituto delle Scienze Neurologiche di Bologna, 40139, Bologna, Italy

    Antonella Pini

  17. Medical Genetics Unit, University of Siena, Azienda Ospedaliera Universitaria Senese, 53100, Siena, Italy

    Anna Maria Pinto & Alessandra Renieri

  18. Department of Metabolic and Muscular, Meyer Children’s University Hospital, 50139, Florence, Italy

    Francesca Pochiero, Elena Procopio & Chiara Ticci

  19. Neurofisiopathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy

    Guido Primiano, Cristina Sancricca & Serenella Servidei

  20. Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842, Lecco, Italy

    Romina Romaniello

  21. Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore, 00168, Rome, Italy

    Serenella Servidei

Authors
  1. Stefania Della Vecchia
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  2. Alessandra Tessa
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  3. Claudia Dosi
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  8. Maria Teresa Bassi
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  9. Roberta Battini
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  22. Diego Lopergolo
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  39. Filippo Maria Santorelli
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Contributions

Conceptualization: [SDV, AT, AR, CD, FMS]; Acquisition data: [SDV, AT, AR, CD, AA, RP, GA, MTB, RB, CC, EC, GC, GDM, ARF, AF, CF, CF, SG, CG, RG, SH, DL, FM, AMa, AMi, AP, AMP, FP, GP, EP, RR, AR, CSan, SS, CSp, CT]. Methodology: [SDV, AT, CD, AR]; Formal analysis and investigation: [SDV, AT, CD, AR, JB, RP]; Writing—original draft preparation: [SDV, AT, CD, AR, JB, FMS]; Writing—review and editing: [SDV, AT, AR, FMS]; Critical revision: [SDV, AT, AR, CD, RP, GA, MTB, RB, CC, EC, GC, GDM, ARF, AF, CF, CF, SG, RG, EPa, DL, FM, AM, AP, AMP, FP, GP, EPr, AR, SS, CS, CT, FMS]; Funding acquisition: [FMS]; Resources: [FMS, RG]; Supervision: [FMS, AT]. All authors fully comply with and approve the version to be published.

Corresponding authors

Correspondence to Alessandra Tessa or Filippo Maria Santorelli.

Ethics declarations

Conflicts of interest

The authors declare no conflict of interest.

Ethical standards

This study was approved by the Tuscany Regional Pediatric Ethics Committee and written informed consent was obtained from the patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Appendix

. Detailed genetic information on KIF1A variants reported in our cohort. (XLSX 13 KB)

Figure S1

. Family pedigrees. Figure S2. (A) Pie chart and histogram showing the clinical manifestations in our cohort of 28 patients. The relative Human Phenotype Ontology codes are given in brackets. (B) Histogram showing the neuroradiological findings (MRI) in 27 members of our cohort. The relative Human Phenotype Ontology codes are given in brackets. Figure S3. (A) Histogram showing the clinical manifestations of the patients with congenital ataxia in our cohort (n=6). The relative Human Phenotype Ontology codes are given in brackets. GDD: Global developmental delay. ID: Intellectual disability. (B) Histogram showing the neuroradiological findings in the patients with congenital ataxia in our cohort (n=6). The relative Human Phenotype Ontology codes are given in brackets. Figure S4. Myo-pathological changes in patients with KIF1A mutations: a) Hematoxylin and eosin staining demonstrating marked variation in fiber size in Pt9. b) Oil Red O Stain showing mild lipid storage in Pt5. (PDF 1167 KB)

Supplementary file3 (DOCX 39 KB)

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Vecchia, S.D., Tessa, A., Dosi, C. et al. Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review. J Neurol 269, 437–450 (2022). https://doi.org/10.1007/s00415-021-10792-3

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