Maroofian Reza, Spoto Giulia, Moualek Dalila, Zaki Maha S, Biswas Asthik, D'Arco Felice, Biglari Sajjad, Nikuei Pooneh, Gleeson Joseph G, Tazir Meriem, Ali Pacha Lamia, Houlden Henry
Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK.
Department of Biomedical Sciences, Dental Sciences & Morpho-Functional Imaging, University of Messina, Messina, Italy.
Mov Disord. 2025 Nov;40(11):2531-2537. doi: 10.1002/mds.30324. Epub 2025 Aug 4.
ANK3 encodes ankyrin-G, a key scaffolding protein essential for neuronal function. While both monoallelic and biallelic ANK3 variants have been linked to neurodevelopmental disorders (NDDs), existing evidence for their pathogenicity and clinical correlation remains limited and heterogeneous.
To delineate the clinical features associated with biallelic ANK3 predicted loss-of-function (pLOF) variants.
We employed exome sequencing, Sanger validation, detailed clinical phenotyping, and extensive international data sharing to identify patients with biallelic ANK3 variants.
We describe five individuals from three unrelated consanguineous families with segregating homozygous ANK3 pLOF variants. These patients presented with a relatively consistent phenotype comprising developmental delay, intellectual disability, hypotonia, variable epilepsy, and cerebellar signs including ataxia, tremor, and dysarthria. Among the three patients for whom brain magnetic resonance imaging was available, cerebellar atrophy was observed, predominantly affecting the superior vermis and cerebellar hemispheres. These clinical findings align with murine models lacking the cerebellar ankyrin-G isoform, which similarly exhibit ataxic features and high cerebellar ANK3 expression.
Our findings support a recognizable NDD with non-progressive cerebellar ataxia linked to biallelic ANK3 pLOF variants. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
ANK3基因编码锚蛋白G，这是一种对神经元功能至关重要的关键支架蛋白。虽然单等位基因和双等位基因ANK3变异均与神经发育障碍（NDDs）有关，但其致病性和临床相关性的现有证据仍然有限且不一致。
描述与双等位基因ANK3预测功能丧失（pLOF）变异相关的临床特征。
我们采用外显子组测序、桑格验证、详细的临床表型分析以及广泛的国际数据共享来识别携带双等位基因ANK3变异的患者。
我们描述了来自三个不相关近亲家庭的五名个体，他们携带分离的纯合ANK3 pLOF变异。这些患者表现出相对一致的表型，包括发育迟缓、智力残疾、肌张力减退、可变的癫痫发作以及小脑体征，如共济失调、震颤和构音障碍。在可进行脑磁共振成像的三名患者中，观察到小脑萎缩，主要影响小脑上蚓部和小脑半球。这些临床发现与缺乏小脑锚蛋白G亚型的小鼠模型一致，该模型同样表现出共济失调特征和小脑ANK3高表达。
我们的研究结果支持一种可识别的与双等位基因ANK3 pLOF变异相关的非进行性小脑共济失调的神经发育障碍。© 2025作者。由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版的《运动障碍》。
