TSEN54 Gene-Related Pontocerebellar Hypoplasia Type 2 in a Newborn with Refractory Myoclonic Seizures

Abstract

Neonates are vulnerable to epileptic seizures. Eighty percent of neonatal seizures occur in the first 1 or 2 days of life. The most common cause of neonatal seizures is hypoxic ischemic encephalopathy. Brain malformations can also be an important cause of seizures. Herein, we present a case of an infant who experienced severe myoclonic seizures with little response to anti-seizure medications from the first day of life. The infant had refractory myoclonic seizures associated with pontocerebellar hypoplasia (PCH) and a mutation in transfer ribonucleic acid splicing endonuclease 54 (TSEN54). This case was reviewed and approved by the Institutional Review Board of Keimyung University Dongsan Hospital (IRB No. 2022-04-017). The requirement for informed consent was waived by the board. A female infant was born at 38 weeks of gestation by cesarean section due to breech presentation at a local hospital. She had a birth weight of 2,840 g (25th to 50th percentile), length of 45 cm (10th to 25th percentile), and head circumference of 31 cm ( < 10th percentile). Although her Apgar scores were 7 and 9 at 1 and 5 minutes, respectively, the baby suffered from severe seizures and respiratory distress from the first day of life. Therefore, she was transferred to a university hospital. A neurological examination revealed generalized myoclonic seizures with respiratory distress, hypertonia of the extremities, joint stiffness of both elbows, and increased deep tendon reflexes. Initial electroencephalography (EEG) showed frequent ictal EEG patterns with 6 to 7 Hz rhythmic activities beginning at P3, P4, and T6 independently. Radiologic studies (Fig. 1) showed a flat ventral pons and a small cerebellum. This baby had no specific findings in studies for metabolic disorders or genetic screening tests associated with early myoclonic seizures in infancy. To determine the genetic cause of PCH, targeted exome sequencing was performed when she was 1 month of age. Finally, two variants of the TSEN54 gene, c.919G > T and c. 623G > A, were found, representing compound heterozygosity. These two variants were confirmed by Sanger sequencing (Fig. 2), and no other copy number variation was found in the diagnostic exome sequencing study. The c.919G > T mutation (NM_ 207346.2:c.919G > T, p.Ala307Ser, rs1139941 52) has been already reported as the most common TSEN54 variant found in PCH patients [1,2], and has been classified as a pathogenic variant in the ClinVar database. It is very rare in large population databases, such as gnomAD (https:// gnomad.broadinstitute.org/), where it has a minor allele frequency (MAF) of 0.09%, and KorepISSN 2635-909X • eISSN 2635-9103 Ann Child Neurol 2022;30(3):152-154 https://doi.org/10.26815/acn.2022.00178