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Ottaviani, D.* ; Bacchin, R.* ; Pjeçi, A.* ; Malaguti, M.C.* ; Longo, C.* ; Sarubbo, S.* ; Giometto, B.* ; Dzinovic, I. ; Zech, M. ; Di Fonzo, A.* ; Monfrini, E.*

CACNA1C-related channelopathy presenting with adult-onset combined dystonia-parkinsonism: A novel neurological presentation.

Am. J. Med. Genet. A, DOI: 10.1002/ajmg.a.70168 (2026)
DOI PMC
Pathogenic variants in CACNA1C have been associated with cardiac arrhythmias and neurodevelopmental disorders, occasionally accompanied by movement disorders. Here we report the case of a 66-year-old female patient with combined dystonia-parkinsonism carrying a pathogenic CACNA1C variant. Neurological examination revealed painful tremulous cervical dystonia, blepharospasm, divergent strabismus, hypomimia, and mild dystonic posturing of left hand, action tremor, and bradykinesia of the upper limbs. Botulinum toxin type A injections provided only partial relief of cervical dystonia, so the patient underwent bilateral Deep Brain Stimulation of Globus Pallidus Internus (GPi-DBS), which resulted in dystonia improvement. Genetic analysis identified an extremely rare heterozygous nonsense variant in the CACNA1C gene (NM_199460.3: c.481C > T; NP_955630.3: p.Arg161*), predicted to introduce a premature stop codon resulting in early protein truncation. Haploinsufficiency is a known disease mechanism for this gene. This variant has previously been reported in two individuals with neurodevelopmental phenotypes. Based on ACMG guidelines, the variant was classified as pathogenic. Our findings suggest that CACNA1C variants may be associated with adult-onset movement disorders, even in the absence of a prior history of neurodevelopmental disease. This case broadens the phenotypic spectrum within CACNA1C-related disorders. GPi-DBS may represent a valuable therapeutic option in selected cases.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cacna1c‐related Disorder ; Gpi‐dbs ; Combined Dystonia‐parkinsonism ; Dystonia ; Globus Pallidus Internus Deep Brain Stimulation ; Parkinsonism
ISSN (print) / ISBN 1552-4825
e-ISSN 1552-4833
Journal American Journal of Medical Genetics, Part A
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Fondazione Regionale per la Ricerca Biomedica