Genomic sequencing and animal-model studies have begun to define a strong neurodevelopmental basis of dystonia.¹ In addition, neurodevelopmental defects are also thought to represent factors contributing to the manifestation of Parkinson's disease (PD) and parkinsonian syndromes.^2-4 Knowledge about single-gene disorders presenting with neurodevelopmental dystonia and/or parkinsonism is still limited, hindering individualized patient care and comprehensive mechanistic understanding.

We have enrolled a male proband demonstrating adult-onset generalized dystonia combined with akinetic-rigid symptoms in our research program aiming to unravel the etiologies of dystonic syndromes.¹ The proband's movement-disorder features started at the age of 46 years, without prior medication intake. He developed dystonic posturing of the lower extremities left>right, and subsequently also posturing of both arms and the trunk with intermittent lateroflexion/camptocormia. These symptoms were followed by manifestation of postural instability, swallowing difficulties, and muscle stiffness. Over time, dystonia became less prominent, whereas slowness of movements and gait dysfunction worsened. Examination at the age of 52 years revealed constant dystonia affecting predominantly the left arm associated with marked parkinsonism (Video S1). During childhood, the proband had experienced gross-motor and speech delays but he had never visited special pediatric services. He showed mild coarse facial features (Video S1) but no evidence of significant cognitive impairment (Montreal Cognitive Assessment [MoCA] score 27/30), autism, or cardiac abnormalities, consistent with the heterogeneous nature of NAA15-related disease.⁵ There was no family history of neurological disorders. Evaluations including blood biochemistry, metabolic screenings, and genetic testing for spinocerebellar ataxias (SCA 1,2,3,6) and LRRK2-associated PD yielded unremarkable results. Chromosomal microarray analysis was unrevealing. Brain imaging could not be performed because the patient did not tolerate the procedure due to abnormal postures. A trial of L-dopa/carbidopa produced improvement with decreased tone, although no sustained response was seen.

By trio whole-exome sequencing,¹ the proband was found to carry a de novo pathogenic nonsense variant in NAA15: NM_057175.5:c.382C>T, p.Arg128*. The same variant has previously been identified in two unrelated patients (one published⁶ and one from our in-house pediatric cohorts) with classic neurodevelopmental-disease features but no movement disorder. No alternative genetic causes were observed upon in-depth analysis of the exome data (including ExomeDepth-based copy number variation [CNV] assessment), especially no potentially pathogenic variants in established dystonia/parkinsonism-related genes.

NAA15 encodes N-alpha-acetyltransferase-15, an essential component of the N-terminal-acetyltransferase-complex-A mediating the attachment of acetyl-groups to the N-termini of various substrate proteins.⁵ N-terminal acetylation has significant impact on protein properties such as folding, complex formation, and activity, and dysfunction of this process has been associated with both neurodevelopmental and neurodegenerative pathological effects including alterations in the stability of α-synuclein.⁷ NAA15-related disease has been characterized as an infantile-/childhood-onset disorder that presents with variable combinations of milestone delay, intellectual impairment, and dysmorphia.⁵ To date, abnormal (limb dystonic) movements have been reported in only a single affected child.⁵

Our case study expands the phenotype of NAA15-related disease and serves to enhance awareness of the natural history of this syndrome which can involve adult-onset movement-disorder presentations. Moreover, the findings add NAA15 to the growing list of genes whose variants can underlie both typical pediatric neurodevelopmental conditions and phenotypes with parkinsonism/dystonia-parkinsonism later in life.^{3, 4} Notable, yet only recently emerging examples of this group of neurodevelopmental genes include NR4A2, PLXNA1, PPP2R5D, WARS2, and YY1, which are associated in certain adult cases with dopa-responsive dystonia-parkinsonism, atypical parkinsonian syndromes with dystonia, and parkinsonism resembling PD (Table 1). Further elucidation of this novel class of genetically determined entities is important to gain broader insights into pathogenesis and stratify patients according to etiological subtype and treatment response. We encourage additional collaborative research to improve identification of the spectrum and outcomes of neurodevelopmental gene-linked dystonia-parkinsonism, with the eventual goal of designing more efficient therapies.

基因组测序和动物模型研究已经开始确定肌张力障碍的强大神经发育基础。¹此外，神经发育缺陷也被认为是导致帕金森病 (PD) 和帕金森综合征表现的因素。^2-4对表现为神经发育性肌张力障碍和/或帕金森症的单基因疾病的了解仍然有限，阻碍了个体化患者护理和全面的机制理解。

我们在我们的研究计划中招募了一名男性先证者，该男性先证者表现出成人发作的全身性肌张力障碍并伴有运动不能强直症状，旨在阐明肌张力障碍综合征的病因。^1个先证者的运动障碍特征始于 46 岁，之前没有服药。他出现左下肢 > 右下肢肌张力障碍姿势，随后双臂和躯干姿势出现间歇性侧屈/前凸。这些症状之后是姿势不稳、吞咽困难和肌肉僵硬的表现。随着时间的推移，肌张力障碍变得不那么明显，而运动缓慢和步态障碍恶化。52 岁时的体格检查显示持续性肌张力障碍主要影响与明显帕金森症相关的左臂（视频 S1）。在童年时期，先证者经历过粗大运动和言语发育迟缓，但他从未去过特殊的儿科服务机构。NAA15相关疾病。⁵无神经系统疾病家族史。包括血液生化、代谢筛查和脊髓小脑性共济失调 (SCA 1,2,3,6) 和LRRK2相关 PD 基因检测在内的评估结果平平无奇。染色体微阵列分析没有透露任何信息。无法进行脑成像，因为患者由于姿势异常而无法耐受该程序。左旋多巴/卡比多巴的试验产生了音调降低的改善，尽管没有看到持续的反应。

通过 trio 全外显子组测序，¹发现先证者在NAA15中携带新的致病性无义变异：NM_057175.5:c.382C>T, p.Arg128*。先前已在两名不相关的患者（一名已发表⁶和一名来自我们内部的儿科队列）中发现了相同的变异，这些患者具有典型的神经发育疾病特征但没有运动障碍。在深入分析外显子组数据（包括基于 ExomeDepth 的拷贝数变异 [CNV] 评估）后，没有观察到其他遗传原因，尤其是在已建立的肌张力障碍/帕金森病相关基因中没有发现潜在的致病变异。

NAA15编码 N-α-乙酰转移酶 15，它是 N 末端乙酰转移酶复合物 A 的重要组成部分，介导乙酰基与各种底物蛋白 N 末端的连接。⁵ N-末端乙酰化对折叠、复合物形成和活性等蛋白质特性具有显着影响，并且该过程的功能障碍与神经发育和神经退行性病理影响相关，包括 α-突触核蛋白稳定性的改变。⁷ NAA15相关疾病的特征是一种婴儿期/儿童期发病的疾病，表现为里程碑延迟、智力障碍和畸形的不同组合。^5个迄今为止，只有一名受影响的儿童报告了异常（肢体肌张力障碍）运动。^5个

我们的案例研究扩展了NAA15相关疾病的表型，并有助于提高对该综合征的自然史的认识，该综合征可能涉及成人发作的运动障碍表现。此外，这些发现将NAA15添加到越来越多的基因列表中，这些基因的变异可能是典型的儿科神经发育状况和晚年帕金森症/肌张力障碍-帕金森症表型的基础。^{3, 4}这组神经发育基因值得注意但最近才出现的例子包括NR4A2、PLXNA1、PPP2R5D、WARS2和YY1，这在某些成人病例中与多巴反应性肌张力障碍-帕金森症、伴有肌张力障碍的非典型帕金森综合征和类似 PD 的帕金森症有关（表 1）。进一步阐明这一类新的遗传决定的实体对于更广泛地了解发病机制和根据病因亚型和治疗反应对患者进行分层非常重要。我们鼓励进行更多的合作研究，以改进对神经发育基因相关肌张力障碍-帕金森症的范围和结果的识别，最终目标是设计更有效的疗法。