-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of .

Background And Objectives: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in . 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 LoF in ZTTK syndrome and hemiplegic migraine remains unknown.

Methods: We identified a patient with a pathogenic variant in 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 knockdown on mRNA expression of the , , , and genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of on knockdown was further examined by RT-PCR using primers targeting specific exons.

Results: 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 knockdown significantly reduces mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in , , and mRNA expression was not observed. We further identified that knockdown leads to failure in intron 2 removal from pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2.

Discussion: 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 caused by LoF as a mechanism causing hemiplegic migraine. Examination of the gene may be indicated in individuals with recurrent hemiplegic migraine.