Tobiasz A, Hager M, Dębowska J, Jaunich A, Paprocka J. Tough to treat: What we know about managing PCDH19-related epilepsy - Systematic review. Seizure. 2025 Aug 26;132:98-109. doi: 10.1016/j.seizure.2025.08.030. Epub ahead of print. PMID: 40934839.
Abstract
Background: PCDH19-related epilepsy is a rare, X-linked developmental and epileptic encephalopathy that primarily affects heterozygous females. It is caused by pathogenic variants in the PCDH19 gene, encoding protocadherin-19, a calcium-dependent adhesion protein involved in neurodevelopment. The disorder's hallmark is cellular interference, leading to brain mosaicism and clinical features including early-onset clustered focal seizures, cognitive impairment, and frequent comorbidity with autism.
Objective: This review synthesizes current evidence on treatment approaches for PCDH19-related epilepsy, covering conventional anti-seizure medications, adjunctive therapies, and non-pharmacological interventions, while highlighting emerging strategies and research gaps.
Methods: A systematic literature search was conducted in PubMed and Scopus (January 2008 - April 2025).
Results: 27 studies were included, involving patients with genetically or clinically confirmed PCDH19-related epilepsy and reported treatment outcomes. The condition is often pharmacoresistant, with highly variable responses. Levetiracetam, especially when initiated early, showed the most consistent seizure reduction, followed by clobazam and potassium bromide. Topiramate and stiripentol showed potential in isolated reports. Carbamazepine was often ineffective or worsened seizures. Adjunctive agents - including corticosteroids, ganaxolone - had variable efficacy; ganaxolone showed promise in recent trials. Non-pharmacological interventions, like vagus nerve stimulation, ketogenic diet, and temporal lobectomy, reduced seizures in some cases but lacked standardized evidence.
Conclusions: Treatment remains challenging due to clinical heterogeneity and limited high-quality data. Early, individualized, multimodal approaches appear most beneficial. There is a need for genotype-informed, multicenter trials and standardized outcome measures to guide evidence-based care.
Hu W, Zhao F, Ren Y, Zhang H, Li X. Abdominal pain as a novel manifestation in children with PCDH19-related epilepsy: A case report. Medicine (Baltimore). 2025 Jan 10;104(2):e41211. doi: 10.1097/MD.0000000000041211. PMID: 39792735; PMCID: PMC11730840.
Abstract
Rationale: PCDH19-related epilepsy manifested various clinical features, including febrile epilepsy, with or without intellectual disability, and psych-behavioral disorders. However, there are few studies demonstrating abdominal pain as the first symptom.
Patient concerns: A 3-year-old Chinese girl presented with clustered seizures of fever sensitivity accompanied by abdominal pain.
Diagnoses: After ultrasonography ruled out abdominal organic lesions, electroencephalographic (EEG) identified abdominal pain was a seizure feature. Trio whole-exome sequence demonstrated a de novo and heterozygous PCDH19 missense mutation (NM_001184880: c.824A>G, P.Y275C), which was confirmed by Sanger sequence. The final diagnosis were "PCDH19-related epilepsy; abdominal pain."
Interventions: At first, she was treated ineffectively by levetiracetam and valproate. Finally, she was provided with topiramate (TPM).
Outcomes: The patient had gained seizure-free, and the follow-up EEG discharges were reduced.
Lessons: Abdominal pain is a rare autonomic symptom in the setting of seizures. This report describes abdominal pain as a novel manifestation of PCDH19-related epilepsy and might expand its phenotypes spectrum. It also alerts us to perceive the abdominal pain characterized by seizures and early conduct EEG examination to clarify the nature of abdominal pain.
Feng W, Wang Z, Wang X, Chen S, Chen X, Chen C, Deng J, Zhuo X, Wang J. Phenotypic and genotypic characteristics of children with PCDH19 clustering epilepsy in China. Seizure. 2024 Oct;121:95-104. doi: 10.1016/j.seizure.2024.07.023. Epub 2024 Jul 31. PMID: 39146709.
Abstract
Purpose: PCDH19 gene variants, termed PCDH19 clustering epilepsy, represent a distinct etiology of epilepsy. This study aimed to elucidate the clinical manifestations and explore the genotypes and phenotypes of children affected by PCDH19 clustering epilepsy.
Methods: This retrospective study included medical history, magnetic resonance imaging, video-electroencephalography, and genetic analysis of patients diagnosed with PCDH19 Clustering Epilepsy at the Neurology Department of Beijing Children's Hospital from 2015 to 2023. Chi-square tests and logistic regression analyses were conducted to study the factors associated with developmental delay in patients.
Results: The age at seizure onset ranged from 5 to 61 months among all 30 patients (median 14 months; IQR 9.25-22.5 months). Among the 30 patients, 29 were female and 1 was male. Clusters of seizures and fever-triggered seizures were observed, with the most prevalent seizure types being focal to bilateral tonic-clonic seizures (FBTCS). Seizures were successfully controlled in 15 patients. Unfortunately, one patient experienced a sudden unexpected death in epilepsy (SUDEP). Additionally, 14 patients had hereditary mutations, 14 had de novo mutations, 1 had both hereditary and de novo mutations, and 1 male patient had a mosaic component mutation of 0.64 due to a somatic mutation. Developmental delays were identified in 17 patients (56.7 %), and 6 patients (20 %) were diagnosed with autism spectrum disorder (ASD). Among the 17 patients, 9 experienced developmental delays before the onset of epilepsy, while 8 were initially normal but later developed developmental delays during disease progression. Statistical analysis revealed that the presence of drug-resistant epilepsy was an independent risk factor for the occurrence of developmental delays (P = 0.020, OR = 9.758, 95 % CI (1.440-66.111)).
Conclusion: In this study, 13 new potential rare pathogenic variations in PCDH19 clustering epilepsy were identified. The clinical features observed in patients are consistent with known phenotypic features, and we found that patients with drug-resistant epilepsy are more likely to have developmental delays. The severity of the phenotype in patients with PCDH19 variants ranged from drug-responsive seizures to refractory epilepsy.
Kowkabi S, Yavarian M, Kaboodkhani R, Mohammadi M, Shervin Badv R. PCDH19-clustering epilepsy, pathophysiology and clinical significance. Epilepsy Behav. 2024 May;154:109730. doi: 10.1016/j.yebeh.2024.109730. Epub 2024 Mar 22. PMID: 38521028.
Abstract
PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hypothesis of cellular interference was described as a key pathogenic mechanism. According to that, males do not develop the disease because of the uniform expression of PCDH19 (variant or wild type) unless they have a somatic variation. We conducted a literature review on PCDH19-CE pathophysiology and concluded that other significant mechanisms could contribute to pathogenesis including: asymmetric cell division and heterochrony, female-related allopregnanolone deficiency, altered steroid gene expression, decreased Gamma-aminobutyric acid receptor A (GABAA) function, and blood-brain barrier (BBB) dysfunction. Being aware of these mechanisms helps us when we should decide which therapeutic option is more suitable for which patient.
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