While proline-rich transmembrane protein 2 (PRRT2) variants have been reported in association with self-limited infantile epilepsy (SeLIE), their relevance to adult epilepsy remains largely uncharacterized. Therefore, we investigated the prevalence of PRRT2 variants in an adult epilepsy cohort to broaden their phenotypic spectrum. In a cohort of adult patients with epilepsy who underwent whole-exome sequencing (WES), individuals harboring PRRT2 variants were identified and selected for further analysis. Amino acid conservation among species, combined with functional verification of mutant proteins, was performed to assess the pathogenicity of novel PRRT2 variants. Furthermore, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) were conducted in patients carrying PRRT2 variants. Two novel missense variants (c.643C > A/ p.P215T and c.932G > A/ p.R311Q) were demonstrated to impair protein expression, indicating a likely haploinsufficiency mechanism. Nine cases were identified carrying PRRT2 variants, including the c.649dupC hotspot variant and two missense variants. The age of seizure onset was predominantly during infancy or adolescence, with epilepsy persisting or relapsing into adulthood. Drug-resistant epilepsy was observed in two cases, whereas others were primarily controlled through sodium channel blockers. Unlike previously reported normal interictal EEG findings in PRRT2-related disorders, epileptiform discharges were recorded in the majority of patients. fMRI revealed reduced thalamocortical connectivity, indicating disrupted brain network integration. This study expands the genotypic and phenotypic spectrum of PRRT2-related disorders, links its variants to epileptiform discharges, and reveals impaired network integration in PRRT2-associated epilepsy.

Infantile epileptic spasms syndrome (IESS) and self-limited infantile epilepsy (SeLIE) are both genetically heterogeneous disorders during infancy with distinct prognoses. To better define the genetic spectrum of IESS, we performed a comparative genetic analysis using SeLIE cases as a reference group. We performed whole-exome sequencing in a Chinese cohort comprising 54 parent-offspring trios with IESS and 37 trios or quartets with SeLIE. Causal pathogenic or likely pathogenic variants were identified in 61% (56/92) of patients, distributed across 20 different genes. Among these, 10 (29%) variants were novel. A definitive genetic diagnosis was achieved in 37% (20/54) of IESS patients, involving 17 distinct genes, indicating a high degree of genetic heterogeneity. In contrast, SeLIE patients had a much higher diagnostic yield of 95% (36/38), with variants concentrated in only four genes. By comparing de novo mutations in protein-coding regions between the IESS and SeLIE cohorts, we identified both shared and potentially novel variants. Notably, there was a trend toward an increased burden of de novo loss-of-function variants in IESS compared to SeLIE. Among IESS patients, 51.9% (28/54) responded to initial hormonal therapy, while 38.9% (21/54) failed to respond. These integrative genomic analyses provide new insights into the pathogenesis of IESS, underscoring a more complex and heterogeneous genetic landscape in IESS compared to SeLIE. This study investigated the genetic architecture of two infantile epilepsy syndromes: IESS and SeLIE. We demonstrated that IESS has a more heterogeneous genetic background, whereas SeLIE is associated with more specific variants. These findings provide novel insights into the genetic underpinnings of IESS.

Pathogenic heterozygous variants in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been recently identified as the major cause of familial infantile convulsion and choreoathetosis syndrome (OMIM#602,066), a spectrum of autosomal dominant paroxysmal neurological disorders, including self-limited infantile epilepsy (SeLIE) and infantile convulsion that can be isolated (IC) or associated with paroxysmal kinesigenic dyskinesia (PKD/IC). Incomplete penetrance of PRRT2 variants and variable phenotypes without developmental impairment have been widely reported in previous studies of this syndrome, but no studies to date have documented global development delay (GDD) with growth retardation (GR) occurred in a family with multiple phenotypes of this syndrome. Here, using family-based whole-exome sequencing, we identified a pathogenic heterozygous PRRT2 variant (NM_145239.3: c.718C > T, p.Arg240*) in a 3-generation Chinese family of infantile convulsion and choreoathetosis syndrome. The variant was detected in five family members, of which two (pedigree III.1 and III.3) were diagnosed with PKD/IC, one (pedigree III.2) presented uncontrolled generalized/focal seizures with GDD and GR; the GR of this patient was aggravated with the progression of the epileptic condition; she was then diagnosed with IC and developmental impairment, one (pedigree II.2) was diagnosed with SeLIE, and one (pedigree II.3) was phenotypically unaffected and recognized as an obligate carrier. In conclusion, we reported a PRRT2-related syndrome family harboring multiple phenotypic features, including uncontrolled seizures with developmental impairment, which may potentially expand PRRT2-related clinical spectrum. Moreover, our findings suggest that children with PRRT2-related seizures/convulsions, especially those who suffer from uncontrolled multiple seizure types, should be aware of potential risks of having developmental impairment aggravation and need timely and effective antiepileptic medications.

Pathogenic variants in the PRRT2 gene cause self-limited infantile epilepsy (SeLIE). Recently, atypical epilepsy phenotypes have been described. We explore the phenotypic spectrum of PRRT2-related epilepsy through international collaboration. All children with epilepsy and either a pathogenic PRRT2 variant or 16p11.2 microdeletion encompassing the PRRT2 gene were included in this retrospective study. Details related to the epilepsy, comorbidities, genetic results, EEG/neuroimaging findings, and treatments are summarized. Forty children were identified, and 24 were male (n = 24/40, 60%). The median age at seizure onset was 5 months (IQR 4, 6) (range 2-150 months). Bilateral tonic-clonic (BTC) (n = 22/40, 55%) and focal motor seizures with impaired awareness evolving to BTC seizures (n = 9/40, 23%) were most common. Thirty-six children (n = 36/40, 90%) had pathogenic PRRT2 variants; 3 were homozygous, and 33 were heterozygous. Four children (n = 4/40, 10%) had 16p11.2 microdeletion. SeLIE was most common, diagnosed in 32 children with heterozygous PRRT2 variants (n = 32/33, 97%), 3 children with homozygous PRRT2 variants (n = 3/3, 100%), and 3 children with 16p11.2 microdeletion (n = 3/4, 75%). Atypical phenotypes were observed in 3 children with heterozygous PRRT2 variants; 1 child evolved from SeLIE to infantile epileptic spasms, another developed spike-wave activation in sleep, and 1 developed focal epilepsy in adolescence. Medically refractory genetic generalized epilepsy and intellectual disability were diagnosed in 1 child with a whole-gene PRRT2 deletion and 16p11.2 microdeletion. All children with homozygous PRRT2 variants had SeLIE with movement disorders. Thirty-seven children (n = 37/40, 93%) were treated with antiseizure medications, and sodium channel blockers were effective in most (20/27 responded, 74%). The median age at seizure freedom was 9 months (IQR 3, 10) (range 3-168 months). Pathogenic PRRT2 variants are commonly associated with SeLIE. However, additional epilepsy phenotypes may be observed with heterozygous PRRT2 variants. In individuals with heterozygous PRRT2 variants, corresponding chromosomal microarray may be helpful to assess for concomitant 16p11.2 microdeletion, given the phenotypic overlap between the 2 conditions. Collection of additional cases is needed, however, to better understand the spectrum of epilepsy phenotypes associated with 16p11.2 microdeletion encompassing the PRRT2 gene and homozygous and compound heterozygous PRRT2 variants. Currently, precise genotype-phenotype relationships are lacking.

Self-limited infantile epilepsy (SeLIE) is one of the most common epileptic syndromes encountered in infancy. The rapid control of seizures and determining the etiology will help the clinician and the family. Care providers need to be aware of the implications, etiology, and management. In our study, the aim is to evaluate the characteristics and response to treatment in children with SeLIE and to raise awareness about early diagnosis and treatment options. A total of 72 infants and children diagnosed with SeLIE were retrospectively analyzed to evaluate their clinical and prognostic data. The average age at the time of diagnosis of patients was 7.6 ± 4 months, and the onset of seizures was 7 ± 3.7 months, and 54.1% were boys in the study group. Of the patients with normal neurodevelopmental steps, 38 (52.7%) had focal elementary motor seizures, 17 (23.6%) had focal impaired consciousness seizures with observable manifestation, 16 (22.2%) had bilateral tonic-clonic seizures of unknown onset, and 1 had focal to bilateral tonic-clonic seizure initially. The most common anti-seizure medication chosen as the first-line treatment was levetiracetam in our study cohort, but the highest seizure-free rate was achieved by initiating carbamazepine. If focal seizures occur in clusters in an afebrile infant with normal neuromotor development and normal neuroimaging, SeLIE should be considered as a possible diagnosis. Sodium channel blockers, with shown high treatment success, should be considered as the first-line medication for favorable outcomes in SeLIE.