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

Cross-Sectional Studies DNA Copy Number Variations Heterozygote Humans Kinesins / genetics Mutation Phenotype Spastic Paraplegia, Hereditary / genetics

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

Journal

Journal of neurology

ISSN: 1432-1459

Titre abrégé: J Neurol

Pays: Germany

ID NLM: 0423161

Informations de publication

Date de publication:
Jan 2022

Historique:

received: 22 07 2021

accepted: 01 09 2021

revised: 01 09 2021

pubmed: 7 9 2021

medline: 11 1 2022

entrez: 6 9 2021

Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND BACKGROUND

METHODS 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 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 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.

Identifiants

DOI: 10.1007/s00415-021-10792-3 PMID: 34487232

pubmed: 34487232

doi: 10.1007/s00415-021-10792-3

pii: 10.1007/s00415-021-10792-3

doi:

Substances chimiques

KIF1A protein, human 0

Kinesins EC 3.6.4.4

Types de publication

Journal Article Multicenter Study Systematic Review

Langues

eng

Sous-ensembles de citation

Pagination

437-450

Subventions

Organisme : ministero della salute

ID : MITO-NEXT

Organisme : ministero della salute

ID : RF-2019-12370112

Commentaires et corrections

Type : ErratumIn

Informations de copyright

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