PCDH19関連症候群

OBJECTIVE: To explore the clinical features and molecular genetic characteristics of epilepsy related to fever sensitivity caused by various types of gene mutations, and to analyze the relationships of genotype and clinical phenotype with clinical treatment efficacy. METHODS: This retrospective study was conducted on 30 cases of children with abnormal genetic testing related to febrile sensitivity epilepsy treated in Wuxi Children's Hospital between June 2016 and April 2023. All 61 children who met the inclusion criteria underwent whole exome sequencing (WES); clinical features were compared between the 30 gene-positive patients and the 31 gene-negative patients. Genetic testing results and clinical data of the 30 positive cases were summarized and the children were divided into "effective" and "ineffective" groups according to the efficacy of clinical treatment for comparisons. RESULTS: Among the 30 gene-positive children, the onset of epilepsy occurred early, with 20 cases occurring within 1 year after birth, and 17 cases having developmental delay. Thirty cases of pathogenic genes related to epilepsy were detected with mutations in the SCN1A gene (13 cases), PCDH19 (4 cases), ADGRV1 (3 cases), and CACNB4 (2 cases) as well as one case each of mutations in SCN2A, PRRT2, CACNA1A, CACNA1E, CACNA1H, KCNA2, CHD2, and KIAA2022, which was identified as a novel gene mutation related to epilepsy. The final diagnosis was 11 cases (36.7%) of Dravet syndrome, four cases (13.3%) of PCDH19-related epilepsy, four cases (13.3%) of generalized epilepsy with febrile seizures plus, one case (3.3%) of Epilepsy with myoclonic-atonic seizures, two cases (6.7%) of focal epilepsy, and eight cases (26.7%) of other types of epilepsy. There were differences between the 'effective' and 'ineffective' groups in the different pathogenic levels of American College of Medical Genetics and Genomics (ACMG) classification, mutation type (gene) and the onset age group (≤1 year group) (p < 0.05), while there were no differences in sex, presence or absence of status epilepticus, and ion channel efficacy (p > 0.05). Comparison between the positive and negative groups revealed that patients in the positive group had a significantly earlier age at onset (p < 0.05), a higher frequency of status epilepticus (p < 0.05), and a higher rate of developmental delay after onset (p < 0.001). CONCLUSION: Febrile sensitivity-related epilepsy in children is primarily caused by SCN1A, PCDH19, and ADGRV1 mutations, manifesting mainly as Dravet syndrome and PCDH19-related epilepsy. The novel KIAA2022 mutation expands the gene spectrum of this condition. Early age at onset, status epilepticus, and developmental delay are clinical red flags for genetic etiology, supporting early genetic testing in infants ≤1 year to guide precision treatment.

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.

OBJECTIVE: Provide the perspective of caregivers planning for adulthood in people with developmental and epileptic encephalopathies (DEEs). RESULTS: Family members (N = 134) of people with DEE (1-44 years old) responded to an anonymous, internet-based survey to assess the needs of DEE families. Respondents included parents/guardians (n = 121, 90.3 %) and adult siblings ≥18y (n = 13, 9.7 %). Diagnoses included Dravet syndrome (n = 71), Lennox-Gastaut syndrome (n = 38), PCDH19-related epilepsy syndrome (n = 8), CDKL5 deficiency disorder (n = 5), SYNGAP1-related DEE (n = 5), STXBP1-related DEE (n = 3), Dup15q syndrome (n = 2), infantile spasms and NPRL2 seizure disorder (dual diagnosis, n = 1), and Fragile X syndrome (n = 1). Constant safety monitoring was required for many people with DEE (82.1 %). Between 81.3 % and 92.5 % of people with DEE experienced developmental delays, intellectual disability, delayed language and speech issues, and movement and/or balance issues. Overall, 29 (21.6 %) respondents reported having adequate access to long-term adult care planning information. Medical, legal, and financial planning was completed by 22 (18.2 %) to 46 (38.0 %) parent/guardian respondents. Most adult siblings (12/13, 92.3 %) planned to receive responsibility for future care of their sibling with DEE. Respondents accessed relevant information via disease-specific patient organizations (81.3 %), other patients and/or caregivers (67.9 %), social media (53.7 %), primary care physicians (40.3 %), nurses (14.2 %), and neurologists (1.5 %). Respondents indicated concern as the people with DEE transition into adulthood. SIGNIFICANCE: Caregivers of adults with DEE are often family members, including adult siblings. Caregivers/families may benefit from receiving additional support to facilitate future planning of transition to adult care. The healthcare system may require changes to facilitate successful medical transition.

Some epilepsy syndromes are more common in female individuals. Often, these syndromes have an underlying genetic variant involving the X chromosome that is typically lethal in male individuals, resulting in a higher female prevalence. However, some of the idiopathic generalized epilepsies such as juvenile myoclonic epilepsy are conditions with complex inheritance, with thousands of variants in genes throughout the genome. But they can also have a predominance in female individuals. In this study, we performed a narrative review of PubMed and Scopus using the following entries: "epilepsy in women," "genetic epilepsy in female individuals," "epilepsy genetics in women," "female-specific epilepsy genetics," "epilepsy and genetic mutations in female individuals." The findings were synthesized and described according to clinical characteristics, underlying genetic mechanisms, and treatment considerations for these epilepsy syndromes manifesting largely in female individuals. The epilepsy syndromes reviewed here include Rett syndrome, CDKL5 deficiency disorder, PCDH19-related epilepsy, subcortical band heterotopia, periventricular heterotopia, Aicardi syndrome, and juvenile myoclonic epilepsy. Recognizing these epilepsy syndromes and understanding their underlying genetic etiology helps provide a tailored treatment approach early in the course of the disease. It can also assist with genetic counselling for family members who plan to have children.

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.