Expanding the Neurological Phenotype of ZTTK Syndrome: A Case of Recurrent Acute Confusional Migraine

Acute confusional migraine (ACM) is an uncommon pediatric migraine variant characterized by transient confusion and agitation, nonspecific electroencephalographic changes, and normal bloodwork and neuroimaging. We present the first case of ACM in a child with Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM: 617140), a rare multisystem disorder caused by a pathogenic variant in the SON gene, clinically characterized by global developmental delay, intellectual disability, hypotonia, distinctive craniofacial dysmorphic features, and structural brain anomalies. Emerging evidence suggests that SON haploinsufficiency may contribute to a broader neuroinflammatory phenotype, potentially increasing susceptibility to cortical excitability, which is one of the proposed causes of ACM. We hypothesize a direct mechanistic link whereby SON-related splicing defects lower the cortical excitability threshold, predisposing individuals to episodic hyperexcitability syndromes such as ACM. This report expands the known neurological phenotype of ZTTK syndrome. Given the nature of the communication impairments among patients with ZTTK syndrome, ACM symptoms may be underreported or mistaken for epileptic events. Future studies are needed to validate this association and elucidate the underlying molecular pathways.