In movement disorders, there are many non-motor symptoms that are a fundamental part of the clinical entity, such as obsessive–compulsive behaviours in tics and Tourette syndrome and psychiatric disturbances in chorea and Huntington disease. The manifestation of movement disorders secondary to ATP1A3 mutations spectrum is rapidly expanding. It is now well recognized that the ATP1A3 mutation is responsible for various entities, such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-Parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss, and relapsing encephalopathy with cerebellar ataxia. The presence of psychiatric disorders in these diseases is not uncommon, for example, in RDP depression is reported in 50% of patients and psychotic disturbances in 20%. In 2016, our group described two sporadic patients with an ATP1A3 mutation, with a phenotype overlapping clinical features in the phenotype of RDP and AHC, and with severe psychiatric symptoms such as psychotic ideation and anorexic behaviour. Interestingly, Chaumette et al. reported two unrelated patients with two distinct pathogenic de novo variants of an ATP1A3 mutation with AHC and childhood-onset schizophrenia (COS). Furthermore, using whole exome sequencing, from a cohort of 17 unrelated COS cases they identified one case with a missense mutation in ATP1A3 and three other cases with missense variants in the FXYD gene family. FXYD similarly to ATP1A3 encodes for proteins that modulate the ATP-dependant pump function. These data confirm that psychiatric disorders are strictly related to the gene mutation itself. Over the last few years, paediatric neurologists have increasingly regarded psychiatric disorders, in particular autism, as co-occurring with other neurological disorders. Autistic features such as repetitive behaviours and interests, and deficit in social cognition and social communication, are symptoms that have been reported as being associated with AHC. Uchitel et al. describe the presence of severe social impairments in patients with AHC. The patients were evaluated with the Social Responsiveness Scale, Second Edition (SRS-2) questionnaire and they found that many patients had impaired social skills involving multiple domains. The authors suggested that social impairments and autistic features are an important manifestation of AHC, and are part of the disease itself. They believe that these findings are consistent with current understandings of the pathophysiology of AHC and ASD, both involving GABAergic disfunction. It has also been demonstrated in animal models that the ATP1A3 mutation causes psychiatric disorders, such as hyperactivity, increased anxiety, and reduced sociability. ATP1A3 is ubiquitously expressed in central nervous system neurons, causing a dysfunction of the cerebellum-basal ganglia-cortex circuit, explaining both the motor and nonmotor symptoms. The problem that remains is how to understand if external elements can play a role in determining the outcome of the disease and the evolution toward more severe phenotypes. Unfortunately, Uchitel et al. did not find any correlation between high SRS-2 scores and the onset of other AHC symptoms, such as paroxysmal events and epileptic seizures. On the other hand, in other known neurological syndromes due to specific gene mutations, such as SCN1A and PCDH19, a correlation between earlier age at onset and more severe phenotype has been reported. It is indeed crucial to identify specific factors that may predict the outcome and influence the prognosis in order to achieve earlier and better treatment. The Uchitel et al. paper has the scientific merit to have highlighted the presence of ASD in patients with ACH and the consequent need for screening, early diagnosis, and early, personalized rehabilitation.

中文翻译：

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运动障碍中的非运动症状：不仅仅是眼睛

在运动障碍中，有许多非运动症状是临床实体的基本组成部分，例如抽动和图雷特综合征中的强迫行为以及舞蹈病和亨廷顿病中的精神障碍。继发于 ATP1A3 突变谱的运动障碍的表现正在迅速扩大。现在已经众所周知，ATP1A3 突变是导致各种疾病的原因，例如儿童交替性偏瘫 (AHC)、快速发作性肌张力障碍-帕金森综合征 (RDP)、小脑性共济失调、反射消失、pes cavus、视神经萎缩和感音神经性听力损失，和复发性脑病伴小脑共济失调。在这些疾病中存在精神障碍并不少见，例如，在 RDP 中，50% 的患者有抑郁症，20% 的患者有精神障碍。2016 年，我们小组描述了两名散发 ATP1A3 突变的患者，其表型与 RDP 和 AHC 表型的临床特征重叠，并且具有严重的精神症状，例如精神病意念和厌食行为。有趣的是，Chaumette 等人。报道了两名不相关的患者，他们有两种不同的 ATP1A3 突变的致病性从头变异，患有 AHC 和儿童期精神分裂症 (COS)。此外，使用全外显子组测序，他们从 17 个不相关的 COS 病例队列中确定了一个病例在 ATP1A3 中有错义突变，另外三个病例在 FXYD 基因家族中有错义变异。FXYD 与 ATP1A3 类似，编码调节 ATP 依赖性泵功能的蛋白质。这些数据证实精神疾病与基因突变本身密切相关。过去几年来，儿科神经学家越来越多地认为精神疾病，特别是自闭症，与其他神经系统疾病同时发生。自闭症特征，如重复的行为和兴趣，以及社交认知和社交沟通的缺陷，是据报道与 AHC 相关的症状。乌奇特尔等人。描述 AHC 患者存在严重的社会障碍。使用社会反应量表第二版 (SRS-2) 问卷对患者进行评估，他们发现许多患者在涉及多个领域的社交技能受损。作者认为社交障碍和自闭症特征是 AHC 的重要表现，并且是疾病本身的一部分。他们认为这些发现与目前对 AHC 和 ASD 病理生理学的理解一致，两者都涉及 GABA 能功能障碍。在动物模型中也证明了 ATP1A3 突变会导致精神障碍，例如多动症、焦虑增加和社交能力下降。ATP1A3 在中枢神经系统神经元中普遍表达，导致小脑-基底神经节-皮质回路功能障碍，解释运动和非运动症状。剩下的问题是如何理解外部因素是否可以在决定疾病的结果和向更严重的表型演变方面发挥作用。不幸的是，Uchitel 等人。没有发现高 SRS-2 评分与其他 AHC 症状（如阵发性事件和癫痫发作）的发生之间存在任何相关性。另一方面，在其他已知的由特定基因突变引起的神经系统综合征中，如 SCN1A 和 PCDH19，据报道，较早的发病年龄与更严重的表型之间存在相关性。确定可能预测结果和影响预后的特定因素确实至关重要，以便实现更早更好的治疗。Uchitel 等人。论文具有科学价值，强调了 ACH 患者中 ASD 的存在以及随之而来的筛查、早期诊断和早期个性化康复的需要。确定可能预测结果和影响预后的特定因素确实至关重要，以便实现更早更好的治疗。Uchitel 等人。论文具有科学价值，强调了 ACH 患者中 ASD 的存在以及随之而来的筛查、早期诊断和早期个性化康复的需要。确定可能预测结果和影响预后的特定因素确实至关重要，以便实现更早更好的治疗。Uchitel 等人。论文具有科学价值，强调了 ACH 患者中 ASD 的存在以及随之而来的筛查、早期诊断和早期个性化康复的需要。