Objective: In this case, we present a novel mutation in the regulatory region for CUX-2 that is associated with clinical PNKD.

Background: Paroxysmal nonkinesigenic dyskinesias (PNKD) are characterized by acute attacks of chorea and dystonia triggered by factors unrelated to physical activity, such as stress or caffeine. PNKD has previously been linked to mutations in the MR-1 gene, also known as the PNKD gene, which encodes three proteins implicated in synaptic transmission. To our knowledge, no connection has been made between PNKD and mutations in the CUX-2 gene.

Method: We present an 18-year-old male with a variant of uncertain significance (VUS) in the regulatory region of the CUX-2 gene (c.-4 C>T) and clinical PNKD.

Results: Our patient has a history of paroxysmal episodes of dystonia when he becomes excited, during which his eyes roll upwards, his jaw locks, and he is unable to eat or speak. While episodes initially lasted several hours, they now last 15-20 minutes following management with oxcarbazepine, clonazepam, and clonidine. Attempts to wean off oxcarbazepine resulted in return of episode severity and frequency. Notably, both continuous and ambulatory EEG have shown no abnormalities during these episodes and MRI Brain and MRI Sella have shown no structural abnormalities. A Comprehensive Dystonia gene panel did not reveal any mutations associated with paroxysmal movement disorders, but whole exome sequencing showed a novel variant in the regulatory region of the CUX-2 gene.

Conclusion: While mutations in the MR-1/PNKD gene have been identified as major drivers in the development of PNKD, the genetic etiology of PNKD is still not yet fully understood. Likewise, mutations in the regulatory region of CUX-2 have not been thoroughly investigated, with most studies focusing on the gene’s coding regions instead. The CUX-2 gene produces a transcription factor that regulates the development of dendrites and synapses and has been associated with epilepsy and seizures. Genetic disorders initially linked to epilepsy have been increasingly implicated in paroxysmal movement disorders as well. Our patient with clinical PNKD and a CUX-2 mutation highlights the need for further investigation into the mutations of the regulatory region of CUX-2 and the role they play in PNKD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-cux2-mutation-identified-in-patient-with-clinical-paroxysmal-nonkinesigenic-dyskinesia/