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).
