Objective: To deeply characterize the clinical and genetic spectrum of ANK2-related hyperkinetic movement disorders and expand their recognized link to myoclonus-dystonia phenotype.

Background: The ANK2 gene encodes ankyrin-B, a multifunctional scaffold protein essential for the localization and regulation of ion channels in excitable cells. While historically linked to cardiac arrhythmias and neurodevelopmental disorders [1,2], a recent report briefly associated ANK2 variants with myoclonus-dystonia [3]. This study aims to comprehensively expand upon this emerging genotype-phenotype association.

Method: Clinical data, neuroimaging, and family histories were prospectively collected from affected individuals. Genetic analyses were performed using targeted movement disorder gene panels and whole-exome sequencing (WES).

Results: We identified six patients from three unrelated families carrying likely pathogenic ANK2 variants. This includes two previously unreported protein-truncating variants (c.3804dup; c.10682-2A>G) and one missense variant (c.4279C>T). Three individuals exhibited a distinct myoclonus‑dystonia phenotype, consisting of action‑induced dystonic tremor of the upper limbs and stimulus‑sensitive myoclonic jerks involving the head and trunk. These cases further substantiate the recently reported association between ANK2 variants and myoclonus‑dystonia [3], providing additional clinical and genetic evidence that extends the spectrum of ANK2‑related movement disorders. The remaining three carriers manifested variant movement disorder presentations, including isolated dystonic tremor, subtle cervical dystonia, or spasticity with cognitive impairment. Notably, two unrelated individuals exhibited congenital renal abnormalities (solitary kidney and parapelvic cysts), suggesting possible extraneurological involvement of ankyrin‑B dysfunction.

Conclusion: This study expands the phenotypic spectrum of ANK2 mutations to myoclonus-dystonia and related hyperkinetic movement disorders. Our findings emphasize the critical role of ankyrin-B in neuronal function and motor control and advocate for the consideration of ANK2 variants in patients presenting with early-onset dystonia and myoclonus.

References: 1. Mohler PJ, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421(6923):634-639.
2. Smith KR, et al. Ankyrin-B dysfunction predisposes to epilepsy and autism spectrum disorder. Nat Commun. 2019;10(1):1-11.
3. Zech M. Combined genomics and proteomics unveils elusive variants with potential monogenic dystonia relevance. Brain. 2025;148(8):2827-2838.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ank2-mutations-associated-with-a-myoclonus-dystonia-phenotype-expanding-the-neurological-spectrum-of-ankyrin-b-dysfunction/