Clinical manifestations

Presentation and course

Epilepsy is reported in more than 90% of patients with PCDH19 mutations (11). Seizure onset typically occurs during infancy, reported around age 8 to 14 months. Seizures are characterized by recurrent febrile events and severe seizure clusters, which are most commonly focal in onset (06; 18; 20; 11). Seizures are classically highly sensitive to fever; about 50% of patients present with a febrile seizure or seizure cluster (05; 01). Individual seizures are often brief, lasting less than a minute. However, seizure clusters can last hours to days, with multiple seizures per cluster and multiple clusters per day (06; 01; 20; 11; 10). Some patients have severe seizure clusters that lead to status epilepticus, ultimately resulting in the use of intravenous benzodiazepine and admission to an intensive care unit. Individual patients typically have multiple seizure types, with focal onset seizures being the most common. Motor manifestations are most frequent, especially tonic events. Rarely, patients will have myoclonic seizures. Nonmotor seizures, including behavioral arrest, atypical absences, loss of tone, and hypopnea, have been reported as well. A fearful expression is a commonly reported initial ictal manifestation (01; 20). Although there is a wide range of seizure types and severity, patients will most commonly develop intractable epilepsy, with seizures or seizure clusters occurring every week to month (20). Ultimately, seizure frequency and severity typically improve with age, and about 25% of patients experience seizure freedom by their late teenage years or early adulthood (11).

Comorbidities of PCDH19-clustering epilepsy include intellectual disability, developmental impairment, and neuropsychiatric symptoms. Intellectual disability is reported in approximately 50% to 75% of patients, ranging from mild to severe impairments (18; 05; 11). Developmental impairment is reported in approximately 60% to 85% of patients, and cases of developmental regression have been described as well. The onset of developmental delay is most common in the first year of life--after patients have presented with their first lifetime seizure. Communication and motor skills are most affected (11; 17). Neuropsychiatric disorders are common as well, including autism, ADHD, aggression, and obsessive behaviors. Autism is noted in about 28% to 69% of patients (15; 06; 18; 01; 20). Of note, cognitive outcomes are not clearly associated with epilepsy severity (06; 05; 01; 20), although one study associated earlier age of seizure onset and increased seizure number within a cluster with more severe autism symptoms and seizure onset before 1 year of age with the development of more severe intellectual disability (11).

Prognosis and complications

As patients with PCDH19-clustering epilepsy age into their teenage and young adult years, seizures become the less prominent phenotype, and the disease is primarily characterized by neuropsychiatric conditions including ADHD, autism, and cognitive or developmental impairment (04; 06; 18; 08; 17).

Biological basis

Etiology and pathogenesis

Protocadherin19 is a transmembrane protein that is a member of the cadherin family of calcium-dependent cell adhesion molecules and specifically belongs to the nonclustered delta2 protocadherin subfamily (14; 07; 16). Proteins in this protocadherin subfamily are strongly expressed in the developing nervous system, and mutations in this class of protein have been associated with neurodevelopment disorders, intellectual disability, autism, microcephaly, and epilepsy (02; 16). Protocadherin19 is highly expressed in human neural stem cells and progenitor cells as well as in the developing brain, and it is most highly expressed in the hippocampus, cortex, and amygdala (09; 03). Protocadherin19 is involved in several functions that are critical for cortical development, including cellular migration, adhesion, regulation of gene expression, and synaptogenesis (17). Furthermore, protocadherin19 is known to be expressed during cortical development, suggesting a potential role in neuronal synaptogenesis and plasticity (09; 16). Loss of function of the protocadherin19 gene in animal studies has shown abnormal neurogenesis (09; 03).

It is hypothesized that pathologic communications in PCDH19 heterogeneous cell populations disrupt the typical development of neuronal connections and synaptogenesis. Heterogenous cell populations likely are the result of random X-inactivation in those with heterozygous or mosaic mutations, and this heterogeneity causes interference in cell-to-cell signaling, which disrupts intracellular communication. The resulting disorganization of cortical networks likely predisposes the neuronal networks to dysfunction and epileptic activity (05; 09).

Another proposed theory for pathogenesis suggests that protocadherin19 mutations disrupt critical neurosteroid pathways (03; 17). Protocadherin19 is known to be involved in regulating steroid receptor activity, and it is hypothesized that there is disruption of the nuclear hormone receptor (NHR) gene expression due to PDHC19 mutations. It is known that neurosteroids play a role in epileptogenesis through a proposed mechanism of influencing neurotransmission by altering chloride influx of GABA-A receptors (03; 17). The role of neurosteroids in epilepsy has been previously described; estrogen has known proconvuslant properties, and androgens, progesterone, and progesterone metabolites have anticonvulsant properties. Furthermore, hormonal fluctuations are known to influence catamenial epilepsy. This theory that neurosteroid pathway disruption leads to epileptogenesis is supported by an improvement of seizures after school-age years, which is after patients go through pubertal development (20). Furthermore, this hypothesis suggests a potential therapeutic role for ganaxolone, a synthetic analog of allopregnanolone, which is a potent GABA-A receptor modulator, thus, functioning as a neurosteroid-like agent (03). Ongoing clinical trials are evaluating the efficacy of ganaxolone in patients with PCDH19-clustering epilepsy.

Finally, protocadherin19 has also been demonstrated to influence the GABA-A receptor directly (03; 17), and this altered modulation in GABA-A receptor function may also contribute to the development of epilepsy in these patients.

Heredity

The PCDH19 gene is located on the long arm of chromosome X and encodes the protein protocadherin 19 (14). It is located in a region that is targeted in random X inactivation (17). The PCDH19 gene consists of six exons. Exon 1 is the largest and encodes for the entire extracellular domain of the protocadherin 19 protein. The remaining exons 2 through 6 encode for the intracellular domain of the protein (07; 16). There are more than 175 cases of PCDH19-related epilepsy reported the literature with more than 90% of mutations in exon 1 (07). The majority of cases are sporadic, including de novo mutations (07; 11; 17). Various mutation types have been reported, all of which result in loss of function of the protein. These mutation types include frameshift, nonsense, missense, in-frame duplications, deletions, insertions, and splicing variants. The most commonly reported mutations are missense substitutions involving exon 1, which abolish the cell-to-cell adhesion function of PCDH19. Other pathologic variants commonly result in a premature termination codon (05; 09). There is no clear phenotypic difference based on mutation type or genotype (20; 11; 03; 17).

PCDH19-clustering epilepsy is an X-linked disease with a unique inheritance pattern in which heterozygous females and mosaic males are symptomatic, whereas homozygous females and hemizygous males are unaffected. The mechanism of this inheritance pattern is poorly understood; however, it is hypothesized to be secondary to interference in cell-to-cell signaling between wild-type cells and cells with PCDH19 mutations. In cell-to-cell interference, it is the mosaicism of the cell population that results in pathologic cell communication (04; 06; 05; 14; 09; 20; 17). This theory has been further supported by studies showing homogeneous groups of PCDH19-positive or PCDH19-negative cells do not develop the disease (04).

Of note, there is variable penetrance of the clinical phenotype, as family members, including twins with the same mutations, have been reported to have a wide range of symptoms, from asymptomatic to epileptic encephalopathy (10). This is hypothesized to be due to variation in X inactivation in these patients (15).

Genetic counseling is especially important given this complex inheritance pattern. There are cases of inheritance from asymptomatic parents, most commonly asymptomatic hemizygous fathers, with no family history of epilepsy or neuropsychiatric disorders, including autism or developmental delay. However, asymptomatic male carriers who do not have seizures and have normal cognition may have subtle psychiatric phenotypes on further investigation. Conversely, females without a mosaic mutation may transmit the mutation to unaffected males (04; 05; 10).

Epidemiology

PCDH19-clustering epilepsy has a reported incidence of 1 in 20,600 females (03).

Prevention

Although most cases are sporadic (06; 10), genetic counseling has a significant role. Female patients with PCDH19 mutations have a 50% risk of transmitting their mutation, but only their female offspring will likely be symptomatic, thus presenting a 25% risk of passing on the disease (06). Furthermore, hemizygous unaffected male offspring have a risk of passing on the disease to their female offspring as well. Of note, the SRPX22 gene is near PCDH19 on the long arm of the X chromosome; thus, certain mutations may also involve this gene, which is associated with Rolandic epilepsy, oral and speech dyspraxia, polymicrogyria, and developmental disability (06).

Differential diagnosis

Confusing conditions

Patients with PCDH19-clustering epilepsy share a similar phenotype to patients with Dravet syndrome in some features, including early febrile seizures and rapid development of intractable epilepsy with multiple seizure types. There is also a similar neuropsychiatric component with behavioral disturbances, cognitive regression, and developmental and language delays. In fact, many reports of PCDH19 mutations are identified in patients with a clinical diagnosis of Dravet syndrome and a negative workup for SCN1A mutations (06; 01). However, unlike those with Dravet syndrome, patients with PCDH19-clustering epilepsy infrequently have myoclonic and absence seizures, and they do not typically present with prolonged seizures (lasting longer than 15 minutes) but rather with seizure clusters (08; 14). Patients with PCDH19-clustering epilepsy typically have a slightly older age of onset (8 to 14 months of age), unlike Dravet syndrome, which may present earlier (around 6 months old). Patients with PCDH19-clustering epilepsy often have a better prognosis regarding seizure outcomes, with many patients having prolonged seizure cessation in their teenage or young adult years. Also, developmental delays, including motor and cognitive impairment, tend to be less severe in patients with PCDH19-clustering epilepsy than in patients with Dravet syndrome (08; 20). Of note, patients with Dravet syndrome classically develop ataxia and an abnormal gait, which is not a common feature of those with PCDH19-clustering epilepsy (08). Finally, Dravet syndrome is inherited in an autosomal dominant fashion, whereas PCDH19-clustering epilepsy is an X-linked mutation and is female-predominant (10).

Because PCDH19-clustering epilepsy classically presents with sudden onset, intractable epilepsy in the setting of fever, many patients initially undergo an evaluation for encephalitis (18).

Associated or underlying disorders

• Intractable epilepsy
• Developmental delay or regression
• Autism

Diagnostic workup

Electroencephalogram results often show focal features, including slowing, spikes, polyspikes, and spike-and-wave complexes. Focal findings are most common in the temporal and frontal regions. Cases have been reported with occipital, parieto-occipital, and central foci as well. Patients may also have interictal generalized background slowing or multifocal abnormalities. Approximately half of the patients have normal interictal EEGs (13; 20). Studies have shown EEGs normalizing in follow-up studies, which is consistent with the typical improvement in seizure severity with time (18; 01). The presence of interictal EEG abnormalities is not associated with the degree of intellectual disability or autism diagnosis (20).

Magnetic resonance imaging studies are normal in the majority of patients (13; 09), although a few abnormalities have been reported, including microcephaly, cortical dysplasia, heterotopias, and hippocampal atrophy (09). One study identified changes in cortical surface area in 20 patients with PCDH19-clustering epilepsy using quantitative neuroimaging studies (12). There were significant reductions of cortical surface area of the whole brain, specifically within regions of the limbic network, including the amygdala and hippocampus. Furthermore, these changes were more pronounced in patients who had worse autistic manifestations, more severe cognitive impairment, and earlier age of seizure onset (12).

Management

After seizure onset, patients with PCDH19-clustering epilepsy will typically show rapid development of intractable epilepsy requiring polytherapy. Seizures have been reported to respond best to clobazam, phenytoin, levetiracetam, phenobarbital, and potassium bromide (13; 01; 20). Stiropentol (in addition to clobazam or valproic acid) has also been reported as having successful outcomes in a few patients (01; 20). Interestingly, despite the tendency for seizures to be focal, carbamazepine has been reported to have poor efficacy (13; 14). Other antiseizure medications with mixed responses include lamotrigine, valproic acid, and topiramate (06; 14; 01). Pulse steroids (for example, intravenous methylprednisolone) have been reported as successful treatments for stopping acute seizure clusters (08; 14). A prospective phase 2 trial evaluating the efficacy of oral ganaxolone for seizure reduction in patients with PCDH19-clustering epilepsy was recently completed. This randomized, double-blind placebo-controlled trial found that ganaxolone was associated with a reduction in seizure frequency, but it did not reach statistical significance (19).

Outcomes

Ultimately, pharmacoresistance decreases as age increases, and many patients may experience seizure freedom in adolescence and adulthood.

Special considerations

Pregnancy

There are no reported data on precautions to be taken in fertile women or the impact of pregnancy specific to PCDH19-clustering epilepsy. In general, genetic counseling should be offered, and the risk-benefit assessment of antiseizure medication administration during pregnancy should be discussed.

Anesthesia

There are no reported data on precautions for general anesthesia and postprocedure management for PCDH19-clustering epilepsy.