PCDH19-related epilepsy: a rare but recognisable clinical syndrome in females

Abstract

Protocadherin 19 (PCDH19)-related epilepsy (OMIM 300088) is a distinctive clinical syndrome limited to females. We describe a 17-year-old girl who presented to a regional epilepsy clinic with a history of recurrent febrile seizures in infancy. Genetic analysis of the gene revealed a novel heterozygous mutation within a highly conserved region of the gene. Patients with mutations present with clusters of seizures associated with fever. While fever-induced seizures are common to children with and mutations, there are certain clinical features that distinguish these genetic syndromes from each other. mutation demonstrates an unusual form of transmission such that only heterozygous females develop the phenotype. De novo mutations account for most cases although the inheritance is sometimes familial patterns of inheritance. Hemizygous males are typically unaffected. Identification of the mutation provides patients and their families with an explanation for their clinical presentation, important prognostic information and an opportunity for genetic counselling.

Early and long‐term electroclinical features of patients with epilepsy and PCDH19 mutation

“…Key words: early-onset epilepsy, intellectual disability, Dravet syndrome, EFMR, PCDH19, afebrile focal seizures, fever-sensitive seizures Epilepsy associated with protocadherin 19 (PDH19) mutation is associated with a large electroclinical spectrum, from "self-limited" epilepsies to epileptic encephalopathies Depienne et al, 2009Specchio et al, 2011a;Depienne and LeGuern, 2012;Higurashi et al, 2012;Marini et al, 2012;Lyons et al, 2017). PCDH19 is a non-clustered delta 2 protocadherin belonging to the cadherin family, which are calciumdependent adhesion proteins.…”

A Novel Pathogenic Variant (c.592_599del) in PCDH19 in a Korean Family with Epilepsy

“…There have been reports of effective levetiracetam use, including in these siblings, which should be studied further [4]. Fever-sensitive seizures and prominent seizure clustering in varied patterns with short duration ( < 5 minutes) in girls younger than 1 year, as in our cases, can provide clues for PCDH19-related epilepsy to clinicians [1,4,5].…”

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

“…Protocadherins preferentially interact with cells expressing the same combination of protocadherins and these non‐homogeneous cell populations are likely to disrupt cell sorting or cell–cell interactions, possibly leading to abnormal synaptic connections (Depienne et al., ; Pederick et al., ). This mode of inheritance means that every daughter of a hemizygous male is expected to be a heterozygous carrier, and therefore, has a high risk of being affected; however, every child of heterozygous female has a 50% chance of inheriting the pathogenic allele, although only the daughters will be affected (Lyons et al., ).…”

“…The main clinical features of PCDH19 variants are fever‐triggered early onset seizures that occur in clusters (Lyons et al., ). The combination of febrile seizures and intellectual disability in this syndrome resembles Dravet syndrome.…”

“…It is a membrane protein consisting of six extracellular cadherin repeats, one transmembrane domain, and one c‐terminal intracellular tail, which has two conserved motifs (CM1 and CM2; Redies, Vanhalst, & Roy, ). This gene is composed of six exons, with the large exon 1 encoding all six extracellular repeats required for the calcium dependent cell adhesion (Lyons, Marnane, Reavey, Williams, & Costello, ).…”