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 PCDH19 gene revealed a novel heterozygous mutation within a highly conserved region of the gene. Patients with PCDH19 mutations present with clusters of seizures associated with fever. While fever-induced seizures are common to children with PCDH19 and SCN1A mutations, there are certain clinical features that distinguish these genetic syndromes from each other. PCDH19 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.
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A 17-year-old right-handed girl with active epilepsy presented to a regional epilepsy clinic to transition from paediatric to adult services. She was born 5 days post-term by forceps-assisted delivery and there were no perinatal complications. Her initial motor development was normal: she smiled at 3 weeks, sat by 4 months and walked at 9 months of age. At 11 months, she presented with a seizure in the context of a febrile illness. A subsequent striking aspect of her history was the occurrence of innumerable fever-induced seizures that varied in semiology. Some were characterised by motor arrest, unresponsiveness followed by generalised stiffness and tremulousness without a clonic component. Others began with a scream, followed by tonic posturing of both arms with a symmetrical tonic–clonic phase. She had clusters of up to 40 seizures once or twice a month. Most individual seizures lasted less than 1 min. Following the onset of seizures, her development plateaued, particularly her linguistic skills. She could not participate in mainstream primary school because of mild learning difficulties, particularly receptive and expressive language deficits. By age 16, she was found to meet criteria for autism-spectrum disorder, based on her difficulty with social communication and interaction, inflexibility in thinking and behavioural rigidity. There was no family history of epilepsy or intellectual disability and both her parents were normal. Her neurological examination was unremarkable and she was not dysmorphic. She was treated successfully with levetiracetam 1500 mg daily. Previous trials of antiseizure medications were either poorly tolerated (carbamazepine, topiramate) or ineffective (sodium valproate, lamotrigine, diazepam). She was never treated with corticosteroids.
At age 17, an MR scan of brain was normal. An electroencephalogram (EEG) showed right occipital slowing with intermittent spikes. A previous awake EEG at age 11 showed bilateral posterior temporal slowing and infrequent sharp waves within both posterior temporal regions (best seen at electrodes T5 and T6). Neither photic stimulation nor hyperventilation activated any significance abnormalities.
Because of her striking history of fever-induced seizures, often in clusters, we undertook genetic testing at the West of Scotland Genetic Services, Glasgow. Sequence analysis of the PCDH19 gene revealed a novel heterozygous missense variant c1615G>C. This resulted in a substitution of glycine with arginine at position 539, a highly conserved and functionally significant region of the PCDH19 protein in the fifth extracellular cadherin domain. In silico analysis indicated that it was likely to be pathogenic. The mutation had not been previously reported in the gnomAD database of 123 136 exome sequences.1 Analysis using Polyphen 2.0 found the mutation to be probably damaging.2 Sequence analysis of her parents did not find the c1615G>C variant.
This case illustrates the characteristic clinical features of PCDH19-associated epilepsy, namely recurrent febrile seizures and severe clusters of seizures in early childhood in females that improve with age. PCDH19-related epilepsy, also called ‘epilepsy female-restricted with mental retardation’ (EFMR, OMIM 300088) is a rare disorder, first fully characterised in 2008,3 4 although the EFMR phenotype was described in 1971.5
The key clinical characteristics of this rare epilepsy syndrome are the early onset (mean age 9–10 months6) of fever-associated seizures and prominent seizure clusters.7 Patients develop several different seizure types, most commonly tonic–clonic or tonic, but occasionally atonic and absence seizures. Most patients have a focal onset of their seizures.8 About two-thirds of patients have some intellectual disability but its severity varies and some patients are intellectually normal. Developmental regression after the onset of seizures is common, but not universal. Behavioural problems are also common. Obsessive or aggressive behaviours can occur, and autism is a common feature. Delay in language acquisition is a particular feature.9 Initially, the syndrome was considered to resemble Dravet’s syndrome, due to the febrile seizures and associated intellectual disability. However, subsequently a distinct phenotype has emerged (see table 1). The distinguishing features of protocadherin 19 (PCDH19)-related epilepsy include limitation to females; briefer individual seizures compared with those in Dravet’s syndrome; they also have fewer myoclonic and clonic seizures, less clinical photosensitivity and more prominent emotional or affective features, such as fearful screaming during seizures.8
PCDH19-related epilepsy follows an unusual pattern of X-linked female exclusive inheritance.10 The PCDH19 gene, located on the long arm of the X chromosome, codes for PCDH19, a transmembrane protein belonging to the cadherin family of calcium-dependent cell-adhesion molecules. Epilepsy is seen exclusively in patients with a mixed population of cells with mutant and wild-type PCDH19, possibly due to interference in cell-to-cell signalling, thus affecting females exclusively. Hemizygous males are largely unaffected. This unique mode of inheritance means that every female child of a male who carries a disease-causing variant is expected to be affected. Every child of a female with a disease-causing mutation has a 50% chance of inheriting the pathogenic allele, although only female offspring will be affected (see figure 1). Mutations are generally novel (≈70%).7 Most mutations in PCDH19-related epilepsy are, like this one, located on exon 1, which is unusually large and codes for the entire extracellular portion of the protein.
In terms of treatment, there is evidence that pulsed corticosteroids may terminate clusters of seizures in the initial phase.10 Retrospective studies of antiepileptic therapies have found that clonazepam and bromide were the most effective treatments 3 months after starting treatment.11 The decrease in pharmacoresistance with increasing age is well documented, and seizure freedom can often be achieved in adolescence and adulthood.12
PCDH19 mutations are an unusual but important cause of infantile onset epilepsy in females. A confirmed pathogenic mutation provides useful prognostic information and facilitates appropriate genetic counselling where the unique features of the syndrome can be relayed to families. However, determining whether a novel mutation is pathogenic can be difficult. With increasing testing, the range of genetic variants will continue to expand and correlation with the clinical syndrome is essential. Mutations are more likely to be relevant in patients with the typical clinical features of early onset seizures, which occur in clusters and are triggered by fever.
Transitioning from paediatric to adult services provides an opportunity to assess patients afresh and, potentially, to take advantage of diagnostic and clinical advances since their initial presentation.
PCDH19-related epilepsy is an infantile-onset syndrome of clusters of seizures that are fever associated, focal in onset and treatment resistant, associated with cognitive, behavioural and autism-spectrum disorders; it has a specific phenotype distinct from Dravet’s syndrome.
Clinicians should be aware of the typical clinical presentation and test for genetic epilepsies where appropriate; when novel gene variants are detected, correlation with the clinical syndrome and testing other family members is essential.
Seizures in PCDH19-related epilepsy are often initially resistant to treatment but the response to medications improves with increasing age.
A diagnosis of PCDH19-related epilepsy helps to predict the clinical course and genetic risk, particularly important given the unusual mode of inheritance.
Parental testing is essential, as the variant may be inherited from an asymptomatic father or, occasionally, a mother with a mild or subclinical phenotype.
Contributors SL and MM wrote the article with editing from DC. ER and NW performed the genetic analysis and edited the article. DC is the patient's consultant neurologist.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Rhys Thomas, Cardiff, UK.
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