Clinical characteristics of affected females with a PCDH19 pathogenic variant
The clinical spectrum of CE varies significantly, even amongst individuals in the same family (including mother-daughter, sister-sister, and monozygotic twin pairs) and non-related individuals with the same PCDH19 variant.
Epilepsy
The median age of seizure onset is 10 months (range 1 to 70 months), with 95% of cases beginning before 25 months of age.
Seizures are often focal and include focal impaired awareness seizures (FIAS), focal motor seizures and focal to bilateral tonic-clonic seizures (FBTC) but can progress quickly to bilateral tonic-clonic seizures. Ictal fear is an initial feature in ~80% of seizures with screaming reported in ~60%. FAIS are prominent in the first few years and can have subtle semiology with a fearful expression, behavioural arrest accompanied by an arrest, loss of muscle tone, hypopnea, cyanosis, and desaturation. The motor semiology is often tonic and more common in older girls. Seizures can arise independently from either hemisphere. Tonic-clonic seizures are common in infancy, occurring in clusters and often triggered by fever. Generalised absence, myoclonic, and atonic seizures are rare but there are no reports of epileptic spasms. The more severe cases have a developmental and epileptic encephalopathy.
For 95% of individuals, seizures cluster and are often triggered by fever and illness, and, less commonly, by vaccination. Clusters typically comprise of many seizures per day over several days for up to a week. The severity of the clusters varies from several brief seizures per day with normal interictal state to hourly seizures, or status epilepticus requiring intensive care management. Video monitoring shows that most (71%) seizures occur during sleep. Although girls can have months of seizure freedom between clusters, the epilepsy is often pharmaco-resistant and it can be difficult to both abort a cluster of seizures and prevent clusters and sporadic seizures from occurring in the first decade of life. In adolescence, seizures often improve, with at least 30% of girls becoming seizure free. The age of seizure onset does not predict seizure outcome.
Intellectual disability
Infants are usually developmentally normal at seizure onset, although some are delayed from birth. Regression often occurs with seizure clusters. Initially, development subsequently improves with a return to normal between clusters. Over time, with subsequent clusters, return to previous levels of function may not occur. Intellectual outcome varies from normal (~30%) to severe or profound intellectual disability (~15%), with most individuals having mild to moderate cognitive difficulties (~55%) with predominant language impairment.
Early seizure onset (≤ 12 months of age) is associated with more severe intellectual disability. As delayed development prior to the onset of seizures is observed in ~15% of infants and seizure persistence is not correlated with intellectual outcome, it is likely that PCDH19 pathogenic variants have an independent effect on seizures and cognition, which may be additive. In a set of identical twins with the same variant, the sister who had more frequent, intense and longer clusters had a significantly worse cognitive and behavioural outcome than the sister who had fewer seizures. This is consistent with a developmental and epileptic encephalopathy. Although the association of early seizure onset with more severe intellectual disability may reflect the underlying severity of the disorder in that individual, it is likely that the early, frequent seizure activity also contributes to poorer cognitive outcomes.
Psychiatric comorbidities
Many females with PCDH19 pathogenic variants develop significant mental health disorders. Autism spectrum disorder is often diagnosed in childhood. Although seizures typically improve by the second decade of life, behavioural difficulties become the main feature in adolescence and significantly impact the quality of life for both the individual and their family. These difficulties affect over half of females and males and, in addition to autistic features, include aggression, obsessions, depression, hyperactivity, panic attack, hysteria/ somatoform disorder, anxiety, impulsivity, disinhibition, and dysexecutive syndrome. Autistic features and executive dysfunction are the most prominent, occurring in approximately 60% of individuals. Reports describe that 22% of individuals have multiple psychiatric comorbidities that predominantly include combinations of autistic, aggressive, hyperactive, and/or obsessive features. Psychosis occurs in about 20% of women, beginning in adolescence or adult life.
EEG and neuroimaging findings
EEGs are often normal between seizure clusters but may show focal slowing and interictal focal or multifocal epileptiform discharges between and, more frequently, during seizure clusters. Focal discharges are typically located in the frontal and temporal regions. Focal discharges can have a diffuse field in up to 25% of EEGs with true generalised spike wave or polyspike wave occurring infrequently and in patients who also have focal discharges.
The ictal EEG shows seizures arise from the temporal (83%), frontal (6%), parieto-occipital (6%), or central (5%) regions. Within a cluster, seizures can start independently from either hemisphere or have bilateral onset. In 20% of seizures, interhemispheric asynchrony is observed with seizures originating in one hemisphere and migrating to involve only the other hemisphere.
Neuroimaging is usually normal, although there is a report of focal cortical malformation in 5 individuals with PCDH19 pathogenic variants.
Differential diagnosis
At presentation, the main differential diagnoses include a self-limited infantile epilepsy syndrome, focal structural epilepsy, and Dravet syndrome (DS). There is some clinical overlap between CE and DS, as both syndromes present at a similar age, with seizures often triggered by fever. However, the syndromes are quite distinguishable: a younger age of onset in DS (mean 5 months) compared with CE (mean 14 months); often presenting with hemiclonic status epilepticus in DS compared to clusters of brief FIAS or TCS with ictal fear in CE; and generalised spike wave often seen later in DS but uncommon in CE.
It can be difficult to differentiate CE from self-limited focal infantile epilepsy at presentation. For example, sporadic or familial PRRT2 self-limited focal infantile epilepsy presents at a similar age with clusters of brief focal seizures. With time, the features of the syndromes diverge with continuing normal development and seizure resolution in most PRRT2 epilepsies and developmental slowing and continuing seizure clusters in CE.
Clinical characteristics of “mosaic” males with a de novo PCDH19 pathogenic variant
At least ten males have been reported with de novo PCDH19 pathogenic variants. All had a normal complement of sex chromosomes. It was confirmed that each male was mosaic, with some cells containing the PCDH19 pathogenic variant and some containing wildtype PCDH19. This mixed population of PCDH19 mutant and wildtype cells is termed cellular mosaicism and arises from a pathogenic variant that occurs after fertilisation, but during early development. The mosaic cellular expression resembles an affected heterozygous female who has two X chromosomes, one with mutant and one with wildtype PCDH19.
These mosaic males have a similar clinical profile to heterozygous females. Nine of the ten reported mosaic males have comorbid psychiatric features including behavioural disturbances (i.e., aggression and rigidity), attention-deficit hyperactivity disorder, anxiety, obsessive-compulsive disorder, and oppositional defiant disorder.
An additional five males have recently been described, with intellectual function ranging from normal to severely impaired. Executive dysfunction, autistic features, hyperactivity, and social problems were also common.
Clinical characteristics of hemizygous males with a germline PCDH19 pathogenic variant
As transmitting males do not have epilepsy or significant cognitive difficulties, they are considered unaffected. However, it has been noted that they may exhibit behavioural features reminiscent of a broader autism-like phenotype or obsessive-compulsive features. Five transmitting males have been described with inflexible, rigid personalities, and obsessive traits.