Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review

Abstract

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low–average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management.

Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant—Our Experience and Systematic Review of the Literature

“…Olson et al reported 14 cases that included relevant data [ 7 ]. Chou et al published a review of cases they identified from databases that included English, Chinese, and Japanese articles [ 22 ]. They included 29 patients in their review and described three patients of their own.…”

“…Chou et al [ 22 ] also performed a literature review of articles published in English, Chinese, and Japanese. In March 2023, they published an article reviewing 31 cases of the heterogenous missense variant PACS2 p.Glu209Lys and one case of the heterogenous missense variant PACS2 pGlu211Lys.…”

“…One case included in their review and originally published by Valenzuela et al [ 17 ] had inherited the p.Glu209Lys variant from the mother, who also presented the characteristic phenotype of this mutation. Most patients in their review were females (63%), and the onset of most epileptic seizures occurred in the perinatal period, with only one case reporting an onset at 2 months old [ 22 ]. We included in our review and in Table 1 only patients that presented the p.Glu209Lys PACS2 gene mutation and did not include PACS2 p.Glu211Lys missense mutations.…”

“…Motor developmental delay and walking difficulties were frequently reported by different authors [ 1 , 7 , 15 , 22 ] without an involvement of the peripheral nervous system [ 30 ]. Some patients presented with a wide-based gait [ 7 , 22 ]. This was also noted in our patient.…”

“…This was also noted in our patient. Ocular abnormalities and the presence of nystagmus were also described [ 7 , 22 ]. This neurological sign was also present in our patient.…”