Abstracts

Rationale: The polynucleotide kinase 3'-phosphatase (PNKP) gene plays a key role in DNA repair. Dysfunction in this gene causes significant increase in apoptosis in both dividing and postmitotic neurons. PNKP mutations are associated with MCSZ syndrome (microcephaly, seizures, and developmental delay), ataxia-oculomotor apraxia-4, and progressive cerebellar atrophy and polyneuropathy. However, there are only a few case reports in the literature regarding the clinical phenotype resulting from PNKP mutations, and only a few mutations in this gene have been identified. Methods: A retrospective review was conducted on patients seen at the UT Pediatric Epilepsy clinic between 2007 and 2015. 298 patients with genetic testing were identified. The clinical, imaging, and EEG data of these patients were compiled into a database. From this database, we identified 7 patients with PNKP mutations. Results: The ages of our 7 patients ranged from 9 months to 20 years, with a mean age of 11.7 years old. Our cohort included 5 males and 2 females. 6 of our 7 patients were Caucasian and 1 patient was African American. The mean follow-up duration was 5.4 years (range 3 months to 11 years). Our cohort included 2 pairs of siblings. All 7 patients had intractable epilepsy. 3 of the patients had normal motor development and either learning or intellectual disabilities; 1 patient had mild motor delay, and 3 patients had severe global developmental delay and were non-verbal or had minimal speech. 2 siblings had microcephaly, seizures and severe developmental delay (MCSZ syndrome) and 1 patient had progressive cerebellar atrophy, severe developmental delay and symptoms of dysautonomia. 5 of the patients had a novel missense mutation, p.R139H, which has not been reported as benign or pathogenic. All 5 patients were heterozygous for this mutation. The other 2 patients (siblings) were compound heterozygotes with a pathogenic frameshift duplication p.T424Gfs48X and a variant frameshift duplication p.A441QfsX28. The p.T424Gfs48X reduces or eliminates the PNKP DNA kinase activity, leading to faulty DNA repair. The p.A441QfsX28 mutation is posited to cause a loss of function, similar to the previous frameshift mutation. These 2 patients presented with the full MCSZ phenotype. Conclusions: Cumulatively, our cohort of 7 patients had 3 different mutations of the PNKP gene. 2 of these mutations (p.R139H and p.A441QfsX28) are novel, and were reported as variants of unknown significance (VUS) and the third mutation (p.T424Gfs48X) is a known pathogenic variant. Our data indicate that the p.A441QfsX28 mutation is pathogenic and causes the MCSZ phenotype (both patients with this mutation had compound heterozygosity with the pathogenic variant). Patients with the p.R139H mutation were heterozygous, and it is unclear if this mutation is contributing to their phenotype. 5 of our 298 patients with epilepsy were found to have this mutation, suggesting that it may contribute to the pathophysiology of their epilepsy. Our study contributes to expanding understanding of the PNKP gene and its potential role in epilepsy. Funding: None