Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship between SON LoF in ZTTK syndrome and hemiplegic migraine remains unknown.

We identified a patient with a pathogenic variant in SON who shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediated SON knockdown on mRNA expression of the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of PRRT2 on SON knockdown was further examined by RT-PCR using primers targeting specific exons.

Recurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed that SON knockdown significantly reduces PRRT2 mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in CACNA1A, ATP1A2, and SCN1A mRNA expression was not observed. We further identified that SON knockdown leads to failure in intron 2 removal from PRRT2 pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2.

This report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation of PRRT2 caused by SON LoF as a mechanism causing hemiplegic migraine. Examination of the SON gene may be indicated in individuals with recurrent hemiplegic migraine.

Zhu-Tokita-Takenouchi-Kim (ZTTK) 综合征 (OMIM 617140) 是最近发现的一种神经发育障碍，由SON中的杂合性功能丧失 (LoF) 变异引起。由于 SON 蛋白作为 RNA 剪接调节剂发挥作用，已表明 ZTTK 综合征的某些临床特征可归因于异常的 RNA 剪接。在 ZTTK 综合征患者中观察到几种神经系统特征，包括癫痫发作/癫痫和其他脑电图异常。然而，ZTTK 综合征中的SON LoF 与偏瘫性偏头痛之间的关系仍然未知。

我们确定了一名患有SON致病性变异的患者，该患者表现出 ZTTK 综合征的典型临床特征，并经历过偏瘫性偏头痛的反复发作。为了定义临床特征，对偏瘫性偏头痛发作期间和之后的脑部 MRI 和脑电图进行了表征。为了确定该临床表现的分子机制，我们通过定量 RT 研究了小干扰 RNA (siRNA) 介导的SON敲低对已知与偏瘫性偏头痛相关的CACNA1A、ATP1A2、SCN1A和PRRT2基因mRNA 表达的影响-PCR。PRRT2在SON上的前体 mRNA 剪接使用靶向特定外显子的引物通过 RT-PCR 进一步检查敲低。

本例患者偏瘫性偏头痛的反复发作通常发生在轻度闭合性头部损伤之后，并且反复发作发生在这些发作最严重的时候。在发作期间发现短暂的半球皮质间质水肿和不对称脑电图减慢。我们的 siRNA 实验表明，SON敲低显着降低了U87MG 和 SH-SY5Y 细胞系中的PRRT2 mRNA 水平，尽管未观察到CACNA1A、ATP1A2和SCN1A mRNA 表达的降低。我们进一步确定SON敲低导致内含子 2 从PRRT2移除失败pre-mRNA，导致过早终止密码子阻断功能完整的全长 PRRT2 的产生。

该报告将复发性偏瘫性偏头痛确定为 ZTTK 综合征的一种新临床表现，进一步描述了这一临床特征，并为SON LoF引起的PRRT2下调作为引起偏瘫性偏头痛的机制提供了证据。在患有复发性偏瘫性偏头痛的个体中可能需要检查SON基因。