Objective: To describe the clinical and functional characterization of a patient with childhood-onset dystonia carrying the KIF5A:p.Arg422Cys variant.

Background: KIF5A encodes a neuronal kinesin essential for axonal transport [1]. KIF5A pathogenic variants are classically associated with hereditary spastic paraplegia (SPG10), Charcot-Marie-Tooth type 2 (CMT2), neonatal intractable myoclonus (NEIMY), and amyotrophic lateral sclerosis (ALS), exhibiting high phenotypic heterogeneity [2]. Recent reports suggest that KIF5A variants may also cause dystonia [3], but cases of early-onset dystonia remain unreported.

Method: Neurological evaluation, neuroimaging (brain MRI, DAT-scan), and laboratory studies were performed. Genetic analysis was performed via clinical exome sequencing. Functional studies using patient-derived fibroblasts assessed KIF5A–α-tubulin interaction by proximity ligation assay.

Results: A 54-year-old right-handed male with normal neurodevelopment and no family history of neurological disease, presented with dystonia at the age of 7, initially affecting the right upper limb and cervical musculature. During adolescence, he developed cervical tremor, and in the last decade, axial dystonia impairing gait. He showed inadequate response to oral pharmacological treatment for dystonia. Physical examination revealed dystonia of the right arm, left torticollis, and axial dystonia with leftward trunk deviation, along with bilateral action and head tremor, without evidence of polyneuropathy, paraparesis, myoclonus or motor neuron disease. MRI and DAT-scan were unremarkable. Exome sequencing identified a heterozygous KIF5A:p.Arg422Cys variant, which is predicted as VUS. Functional analysis demonstrated impaired KIF5A binding to α-tubulin, consistent with a deleterious effect on the protein function. Segregation studies in family members are ongoing.

Conclusion: We report the first case of early-onset dystonia associated with a KIF5A variant, supported by functional evidence and expanding the clinical spectrum of KIF5A-related disorders. Functional and phenotypic data suggest a deleterious effect, but ACMG pathogenicity criteria [4] cannot be fully met until segregation studies are completed. This case underscores the importance of combining clinical, genetic, and functional genomics in rare movement disorders when the candidate variant is predicted to be a VUS or is not associated with the clinical phenotype.

References: 1. Cozzi M, Tedesco B, Ferrari V, et al. One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases. Cell Communication and Signaling. 2025;23(1):287. doi:10.1186/s12964-025-02277-x
2. Ferese R, Suppa A, Campopiano R, et al. New variants and genotype–phenotype correlation in KIF5A mutation: the contribution of a large Italian cohort. J Med Genet. 2025;62(10):641-646. doi:10.1136/jmg-2025-110801
3. Dulski J, Pant DC, Hoffman-Zacharska D, Kwaśniak-Butowska M, Wszolek ZK, Sławek J. KIF5A variant in familial dystonia: A clinicogenetic study of a large Roma kindred. Parkinsonism Relat Disord. 2025;135(March 2025):10-14. doi:10.1016/j.parkreldis.2025.107825
4. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. 2015;17(5):405-424. doi:10.1038/gim.2015.30

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/childhood-onset-dystonia-linked-to-kif5ap-arg422cys-case-report-and-functional-characterization/