Female-restricted epilepsy with intellectual disability

The hallmark of the disorder is clustered seizures lasting hours to days, often triggered by fever, with onset on average around 15 months of age (reported range 1-70 months). Seizure types span focal, generalised tonic-clonic, tonic, atonic, absence, and myoclonic events. The clinical spectrum is wide, ranging from genetic epilepsy with febrile seizures plus to severe developmental and epileptic encephalopathy. Cognitive function varies from normal to severe intellectual impairment, with autistic behaviour the most prevalent neurobehavioural comorbidity, frequently accompanied by hyperactivity, attention deficit, and sleep disturbance. Substantial intra- and interfamilial phenotypic variability is well documented. Seizures typically attenuate during adolescence, and a subset of affected individuals become seizure-free; non-epileptic features then dominate the disability burden in adulthood.

The estimated prevalence is 1/20,000-1/25,000 in female live births. A Hungarian multicentre cohort reported a lower figure of approximately 1/100,000, presumed to reflect under-ascertainment.

Pathogenic variants in a single gene, PCDH19 (Xq22.1), underlie the disorder. PCDH19 encodes protocadherin 19, a calcium-dependent cell-adhesion glycoprotein involved in neuronal connectivity and signal transduction. Loss-of-function variants act through a cellular-interference mechanism: random X-chromosome inactivation in heterozygous females generates two neuronal populations (one expressing wild-type and one expressing mutated protocadherin 19), whose abnormal interaction at cell-cell contacts disrupts cortical organisation and GABAergic signalling. This mechanism
explains why hemizygous males with a germline variant are typically spared, whereas heterozygous females and males with somatic mosaicism develop the disorder.

The disorder shows an X-linked inheritance pattern with a sex-limited expression unique among X-linked conditions: heterozygous females and mosaic males are affected, whereas hemizygous males carrying a germline variant are typically unaffected. Each daughter of an affected female has a 50% risk of inheriting the variant, and each son of an affected female has a 50% risk of inheriting the variant; phenotypic expression in carriers is variable. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established by molecular genetic testing identifying a germline pathogenic variant in PCDH19; no specific clinical diagnostic criteria, biochemical marker, or imaging finding establishes the diagnosis. Clinical features supporting molecular work-up include infantile-onset clustered seizures, fever sensitivity, and the female-restricted inheritance pattern with neurodevelopmental comorbidity.

Main differential diagnoses include:

• : earlier seizure onset (often before 7 months) with prolonged hemiclonic or generalised seizures provoked by fever or hot water, and progressive cognitive decline; SCN1A
• CDKL5 deficiency disorder: early-infantile seizure variant of the Rett spectrum with refractory seizures from the first months of life and severe global developmental delay; CDKL5
• : apparently normal early development followed by regression with characteristic stereotypic hand movements; epilepsy affects roughly 60-80% of patients, typically appearing after the regression stage; MECP2

• Establishing the molecular diagnosis confirms the clinical suspicion and ends the diagnostic odyssey.
• Identification of the causative variant is a prerequisite for individualised clinical management of seizures and neurodevelopmental comorbidities; specific management decisions remain with the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive and carrier testing of at-risk relatives is technically possible and can inform reproductive decision-making in consultation with human genetics.

• Marques PT, Kaka N, Zulfiqar Ali Q, Rong M, Bui E, Andrade DM. Women with genetic epilepsies. Neurol Genet. 2025;11(1). PMID: .
• Kovacs M, Fogarasi A, Hegyi M, Siegler Z, Kelemen A, Mellar M, et al. Multicenter retrospective study of patients with PCDH19-related epilepsy: the first Hungarian cohort. Epileptic Disord. 2024;26(5):685-693. PMID: .
• Dell’Isola GB, Vinti V, Fattorusso A, Tascini G, Mencaroni E, Di Cara G, et al. The broad clinical spectrum of epilepsies associated with protocadherin 19 gene mutation. Front Neurol. 2021;12:780053. PMID: .