Epilepsy & Behavior 154 (2024) 109730

Contents lists available at ScienceDirect

Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

PCDH19-clustering epilepsy, pathophysiology and clinical significance

Safoura Kowkabi a, b, *, Majid Yavarian c, Reza Kaboodkhani b, Mahmood Mohammadi a,
Reza Shervin Badv a
a
Child Neurology Division and Children’s Epilepsy Monitoring Unit, Children’s Medical Centre, Tehran University of Medical Sciences, Tehran, Iran
b
Shiraz University of Medical Sciences, Shiraz, Iran
c
Hematology Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability
Protocadherin 19 (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to
Seizure epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hy­
Genetics
pothesis of cellular interference was described as a key pathogenic mechanism. According to that, males do not
Dravet-like
develop the disease because of the uniform expression of PCDH19 (variant or wild type) unless they have a
Pathogenesis
somatic variation.
We conducted a literature review on PCDH19-CE pathophysiology and concluded that other significant
mechanisms could contribute to pathogenesis including: asymmetric cell division and heterochrony, female-
related allopregnanolone deficiency, altered steroid gene expression, decreased Gamma-aminobutyric acid re­
ceptor A (GABAA) function, and blood–brain barrier (BBB) dysfunction. Being aware of these mechanisms helps
us when we should decide which therapeutic option is more suitable for which patient.

1. Introduction seen [5].

PCDH19-CE is an X-linked epilepsy disorder associated with ID and
behavioral disturbances, which caused by PCDH19 gene variations. The
hallmark clinical features of PCDH19-CE are recurrent clusters of focal
or generalized seizures, triggered by febrile or afebrile illnesses and
continue for days to weeks despite multiple treatments, but they do not
recur regularly. Seizures start at the age of 6–36 months and reduce
during adolescence, but neuropsychiatric dysfunctions and behavioral
disturbances such as attention-deficit hyperactivity disorder (ADHD),
autism-spectrum disorders (ASD), obsessive–compulsive disorder
(OCD), and executive dysfunction remain. Therefore, PCDH19 patho­
genic variations produce both developmental and epileptic encepha­
lopathy [1–3]. Mild to profound ID is evident in approximately 70 % of
the cases, which displays a direct association with early seizure onset,
while about 30 % of patients have normal cognition [1,4–6]. Early
seizure onset interferes with glucose metabolism and new synapse for­
mation in the developing frontal cortex. Disrupting the frontal cortex in
this critical period could be responsible for ID [1]. Contrary to that, an
association between seizure onset and seizure outcome has not been
Males are generally involved more severely than females in X-linked
variations, thanks to the protective healthy allele on the second X
chromosome in females. In contrast, PCDH19 variation leads to epilepsy
in heterozygous girls, not in hemizygous boys and the inheritance
pattern is unusual [7–11]. The hypothesis of cellular interference, which
explains the mosaicism of wild and variant cells, was described as a key
pathogenic mechanism. According to that, males do not develop the
disease because of the uniform expression of PCDH19 (variant or wild
type) unless they have somatic variation and mosaicism [12–14]. Other
suggested hypotheses for the pathogenesis of PCDH19-CE include:
Altered cell division (Cellular heterochrony), female-related allopreg­
nanolone deficiency, altered steroid gene expression, decreased Gamma-
aminobutyric acid receptor A (GABAA) function, and blood–brain bar­
rier (BBB) dysfunction [1,9].
Here we review the available evidence of suggested pathophysiology
for this genetic epilepsy, and discuss them separately with existed evi­
dence for or against them.

* Corresponding author at: Child Neurology Division and Children’s Epilepsy Monitoring Unit, Children’s Medical Centre, Tehran University of Medical Sciences,
Tehran, Iran.
E-mail addresses: Kowkabis@gmail.com (S. Kowkabi), yavarian@sums.ac.ir (M. Yavarian).

https://doi.org/10.1016/j.yebeh.2024.109730
Received 19 January 2024; Received in revised form 7 February 2024; Accepted 27 February 2024
Available online 22 March 2024
1525-5050/© 2024 Elsevier Inc. All rights reserved.

Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
S. Kowkabi et al.
2. Review
2.1. Method and result
A literature review of published and unpublished researches after
2000 on PCDH19-CE pathophysiology was conducted and searched in
Google Scholar and PubMed by using these search terms: ((((PCDH19
OR protocadherin 19)) AND ((epilepsy OR seizure))) AND ((mechanism
OR pathogenesis OR Pathophysiology))) [all field] without language
restriction. All in vitro, animal and MRI studies and case reports which
obtained through theses search terms were included with out any
exclusion. At first, 1175 papers were selected. After reading abstracts
and in certain cases full texts, we ended up with the most relevant pa­
pers. Additional related non duplicated papers were also added via
reference lists of identified studies. At last, 85 relevant full text papers
and theses were collected which were studied thoroughly.
2.2. Discussion
PCDH19 is a membrane calcium-dependent cell adhesion glycopro­
tein of the protocadherin (PCDH) family. Protocadherin is the largest
subgroup within the cadherin superfamily. Cadherins are single-pass
transmembrane cell adhesion proteins, whose extracellular domains
mediate calcium-dependent cell–cell interactions [15,16].
PCDH19 is highly expressed in the central nervous system, especially
in the limbic system and cortex. It acts on the regulation of various
functions: neurulation, proliferation, homotypic cell adhesion, neurite
self-avoidance, axon guidance, and synaptogenesis. Elimination of
PCDH19 revealed disruption of the columnar organization and neural
circuit formation with a subsequent defect in visually guided behaviors
in zebrafish optic tectum [17–21]. PCDH19 protein is composed of six
extracellular cadherin (EC1-6) repeats with conserved calcium binding
sequences (homologous of those of classical cadherins), a trans­
membrane region, and a conserved cytoplasmic domain (cytoplasmic
Fig. 1. Role of PCDH19 in cell division. Schemata of a neural rosette enclosed by mitotic neural progenitor cells (NPCs). PCDH19 marks the spindle poles during
mitosis and determines the orientation of metaphase plane. A. Presence of one metaphase plane parallel and the other one perpendicular to neural rosette leads to
formation of one neuron and three NPCs in normal conditions B. In variant PCDH19, two metaphase planes parallel to the neural rosette increases asymmetric
divisions, differentiation and neurogenesis with formation of two neurons and two NPCs.
Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
Epilepsy & Behavior 154 (2024) 109730
motif CM 1 and CM2). PCDH19 gene is located on Xq22.1 and consists of
six exon coding sequences. Exon 1 encodes the whole extracellular and
transmembrane region, as well as a small part of the cytoplasmic
domain. The rest of the cytoplasmic domain is encoded by exons 2–6.
Exons 5 and 6 encode CM1 and CM2, respectively [12,15].
2.3. Role of PCDH19 in cell division
A hypothetic role for PCDH19 in the orientation of cleavage plane of
neural progenitor cells NPCs) was suggested in some researches. It was
shown that PCDH19 marks the spindle pole during mitosis in human-
PSCs, and contributes to positional information and control of sym­
metric versus asymmetric cell division [22]. PCDH19 located at one pole
is responsible for determining the position of cells relative to the
neighboring cells. During mitosis, PCDH19 positioned at two poles of
mitotic spindle regulates the type of cell division. Mutated PCDH19
leads to cell autonomous effect, which increases asymmetric divisions,
accelerates differentiation and neurogenesis and decreases brain size.
Higher number of asymmetric divisions was detected in PCDH19-
variant neural rosettes, which augmented in mixed conditions. In mixed
environment (both normal and variant PCDH19 together), two cells
divide and form a multiple mitotic structure. In other words, the coex­
istence of normal and variant PCDH19 in mixed environment results in a
non-cell-autonomous effect other than the cell-autonomous effect seen
in PCDH19 variant neural rosettes. This leads to the generation of
altered dividing cells, which exacerbates neurogenesis phenotype
(Fig. 1) [15,23]. Homogeneous synchronous differentiation of NPCs is
crucial for normal cortical brain development. Wild type and variant
PCDH19 cells are different cells both at the transcript level and at the
cellular behaviors (differentiation and migration) and this diversity
leads to various neuronal circuits during cortical development by cell
autonomous effects (asynchronous differentiation) and non-cell auton­
omous effects (altered cell–cell interactions). This means that, difference
in production time of neurons originating from wild type and variant
S. Kowkabi et al. Epilepsy & Behavior 154 (2024) 109730

NPCs contributed to downstream heterochrony, subtle abnormalities in
neuronal networks and epileptic seizure [24]. Drugs effective on
microtubule polymerization and mitosis were suggested to slow down
the cell cycle and counteract the accelerated differentiation [15].
2.4. Role of PCDH19 in cell adhesion
Cell adhesion ability is important in the formation of germ layers,
cell rearrangement, migration, sorting, neurite outgrowth, axon path­
finding, and synaptic formation in neurons during development.
Although cadherin plays an important role in strong cell–cell adhesion
through homophilic interactions, PCDH acts as a mediator of homophilic
or heterophilic cell–cell adhesion [16,20,25]. While PCDH19 by itself is
weakly adhesive, a robust adhesion was observed in the complex of
PCDH19 and N-cadherin (N-cad; CDH2), which was featured by the
dominant role of PCDH19. It means that the PCDH19-Ncad complex
only binds to other PCDH19-Ncad complexes via PCDH19 homophilic
binding. It was observed that variations disrupting N-cad homophilic
binding did not affect PCDH19- Ncad complex, but the cis complex be­
tween PCDH19-Ncad was inhibited by variations in PCDH19. Therefore,
it was proposed that PCDH19-Ncad complex does a switch between
distinct binding specificities. The adhesive interface of PCDH19-Ncad
was different from that of N-cad, and the homophilic adhesive ability
of N-cad was masked when added to PCDH19 [26] (Fig. 2).
2.5. The idea of cellular interference and altered cell–cell interaction
PCDHs are involved in neuronal diseases such as autism, epilepsy,
schizophrenia, and cognitive impairment [18,25,27]. In 1971, Juberg
and Hellman reported a new form of epilepsy with only female
occurrence and in 2008, Dibbens discovered protocadherin 19 gene
variations. Now PCDH19 is among the six most relevant genes in epi­
lepsy [14,28,29,30].
PCDH19-CE is a monogenic epilepsy syndrome. Phenotypes range
from mild epilepsy to epileptic encephalopathy, resembling the spec­
trum of epilepsy syndromes from genetic epilepsy with febrile seizures
plus to Dravet syndrome [12,31]. The inheritance pattern is unique for
an X-linked gene, and is described as X-linked dominant with male
sparing. Heterozygous females are affected, whereas hemizygous males
are not. It has been proposed that the mosaicism of wild and variant
PCDH19 cells in females leads to scrambling of the neuronal circuits in
the brain of affected individuals. Rare cases of affected mosaic males and
one male case with Klinefelter syndrome (47, XXY) were described as
supporting evidence for this aforementioned theory of cellular inter­
ference as the pathogenic mechanism [9,16,32–36]. However, reported
cases of heterozygous females without epilepsy and hemizygous males
with autism challenge this hypothesis as the unique pathogenesis
[37,38].
2.6. Supporting evidence for the idea of cellular interference
2.6.1. Studies on mice models
By evaluation of PCDH19 null mice, Pederick et al revealed impaired
migration of some neurons without apparent morphological defects.
They proposed that PCDH19 is extensively expressed but not required
for brain development in itself [16]. Two years later, he evaluated
heterozygous female mice and showed that mosaic expression of
PCDH19 led to incompatible adhesion affinities between wild and null
cells and altered network activity. While complete removal of PCDH19
terminated this abnormal cell sorting. They indicated the adhesion role

Fig. 2. Role of PCDH19 in cell adhesion between two neurons A. A robust adhesion is seen between complexes of PCDH19-Ncad, which is featured by the dominant
role of PCDH19 in wild type female or male B. Strong cell–cell adhesion occurs through Ncad homophilic interaction in PCDH19-Hemizygous males C. Impaired
adhesion in PCDH19-Heterozygous females with mismatch between PCDH19 + and PCDH19 − neurons and D. Altered adhesion between PCDH19 missense variant
cell and normal cell.

Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
S. Kowkabi et al.
of PCDH19 in developing cortex and the way, segregation of these
mosaic cells was associated with its unusual inheritance [8]. During
nervous system development, each neuron contacts genetically
compatible neurons to make functional synapse. In the lack of match
neurons, PCDH19 mosaic cells extend their neurites as an adaptive
mechanism to reach another genetically compatible cell. Evaluating
mosaic neuronal culture of a mouse model demonstrated alteration of
excitatory synaptic contacts and higher network activity. It was pro­
posed that mosaic expression of PCDH19 leads to disruption of neural
networks that are essential for cognition and behavior. This likely occurs
at the boundaries of positive and negative PCDH19 cells leading to
network fragmentation, disruption of the negative feedback circuit,
higher excitation and increased risk of seizure [39]. Another mosaic
mice model of hippocampus again characterized disturbed network
activity and connectivity [40]. It is also compatible with more severe
behavioral disturbances observed in the heterozygous female mice than
knockout males [41].
2.6.2. Studies on stem cells
Induced pluripotential stem cells (iPSCs), derived from heterozygous
females and mosaic males with pathogenic variations in exon 1, showed
aberrant morphologies and increased excitability in cortical-like neu­
rons. The results suggested that PCDH19 was important in self-
avoidance and dendritic tiling and its disruption might cause
abnormal spreading of electrical signals and hyperexcitability [42]. By
using artificial mosaic environment of missense PCDH19 variations in
heterozygous female mouse brain, some aberrantly cell aggregates and
segregated patterns of wild and null cells were observed which
encountered higher seizure susceptibility [43].
2.6.3. Mismatch in PCDH19-Ncad cis-complexes
As the majority of PCDH19 variations located in the extracellular
domain of the protein, it was suggested that the variations altered
PCDH19 homophilic interactions and cell–cell adhesion. In wild type
female or male mice, PCDH19-Ncad cis-interaction contributed trans-
synaptic signaling through PCDH19 homophilic matching. In PCDH19-
Hemizygous males, Ncad did this action through Ncad homophilic
matching. But in PCDH19-Heterozygous females with mismatch be­
tween PCDH19 + and PCDH19 − neurons, PCDH19-Ncad cis-complex
could not trans-synaptically bind Ncad. This mismatch impaired pre­
synaptic development, and led to cognitive impairment. (Fig. 2) Inhi­
bition of PCDH19-Ncad cis-complex with a competitive peptide,
probably unmasks Ncad and restores Ncad homophilic matching in
heterozygous female mice [44].
2.6.4. Structural MRI abnormalities
Quantitative MRI of 20 heterozygous females and mosaic males
demonstrated bilateral reduction of gyrification in limbic cortical areas
and diffusivity abnormalities in the underlying white matter. These
abnormalities were more pronounced in patients with earlier seizure
onset, worse psychiatric and cognitive impairment [45]. A male with
cortical dysplasia was also reported who revealed a mosaic truncating
variant in exon 1 [46]. In line with this observed MRI abnormalities, a
cohort of five mosaic patients with PCDH19-CE illustrated the presence
of malformation of cortical development and recommended searching
for structural lesions [47].
2.6.5. Disrupted slow wave sleep (SWS)
An electrophysiological model of mosaic mice with PCDH19-CE
displayed hyperexcitability and disrupted slow wave sleep (SWS). SWS
is important in memory consolidation and cognitive function by
restoring synaptic strength of the network through synaptic down
scaling. Sleep also homogenizes the firing rate. They observed highly
variable neuronal activity and unstable network, due to the lack of this
homogenizing effect in mosaic mice. Epileptiform bursts were seen in
adolescents as a consequence of variable activity with a group of
Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
Epilepsy & Behavior 154 (2024) 109730
hyperactive neurons generating hypersynchronous activity during SWS.
While behavioral and cognitive problems were observed in adults due to
loss of SWS, as a compensatory mechanism for hypersynchronous ac­
tivity seen in adolescents. This age dependent loss of SWS in mosaic mice
is considered as different function of PCDH19 in a mature circuit versus
a developing one [48–51].
2.7. PCDH19-GABA interaction
Defects in GABAergic transmission predispose brain to seizure,
cognitive and behavioral problems. GABAA receptor is inhibitory in
adults, while it is depolarizing and excitatory in immature brains which
contain high intracellular chloride concentration. PCDH19 down­
regulation during embryonic and the first postnatal period disturbs
neuronal migration, maturation and increases seizure probability.
PCDH19 intracellular C-terminal domain binds intracellular loop of
GABAA and modulates its surface availability and currents [52]. GABAA
structure is preserved following PCDH19 downregulation, but its func­
tion is impaired by subunit changes. In other words, receptor open time
is shorter and this reduces receptor current flow. Reduction of surface
GABAA and its open time inhibit GABA tonic current which leads to
neuronal hyperexcitability, epilepsy, cognitive, behavioral and sleep
problems [53].
In line with this observed GABAergic effects, ASD-like behavior and
subclinical hyperexcitability were noticed in a knockout-PCDH19 mouse
model as consequences of GABAergic defect [54]. Furthermore, among
antiepileptic medications, clobazam and bromide, which are GABAA
modulators, showed the best result in contrast with the controversial
results of voltage gated sodium channel blockers [55,56].
2.8. PCDH19-neurosteroids interaction:
Adhesion molecules are regulated by sex steroids; besides they
participate in sexual differentiation of the brain. Evaluation of the skin
fibroblasts of affected females, affected mosaic males, and transmitting
males showed the deficiency of neurosteroid allopregnanolone, a
metabolite of progesterone and one of the most potent modulators of
extra synaptic GABAA. Lower expression level of aldo-
ketoreductase1C2, 3 (AKR1C2, 3), a neurosteroid metabolizing
enzyme which converts 5-hydroxy progesterone (5αDHP) to allopreg­
nanolone, was observed as the underlying cause of allopregnanolone
deficiency. A gender-biased pattern of expression in AKR1C3 was
detected as hemizygous transmitting males showed higher expression
level (maybe it has a protective role not to show PCDH19 related
symptoms), while affected females had lower level of AKR1C3 mRNA
and protein and in consequence lower allopregnanolone level. Seizure
active period in PCDH19-CE females falls between post mini-puberty
(0–6 months) and pre-puberty (12 years). In that period, effective sex
hormone levels including allopregnanolone are low (Fig. 3). Neuro­
steroids such as allopregnanolone and its synthetic analog ganaxolone
have antiepileptic properties, which underlines the importance of
AKR1C3 involvement in PCDH19-CE pathogenesis. All these findings
emphasize on the role of low neurosteroid level, in particular allopreg­
nanolone, during early development in the pathogenesis of PCDH19-CE
and its therapeutic target. That is the same as seizure generation in
catamenial epilepsy which relates to neurosteroid withdrawal [57,58].
Decreased level of allopregnanolone was not resolved after adrenocor­
ticotropin hormone (ACTH) stimulation, which means a reduced ca­
pacity for hormonal synthesis in PCDH19-CE. Cortisol levels were also
different, indicating dysfunctional steroidogenesis in the adrenal glands.
Reduced production of allopregnanolone and other neurosteroids were
hypothesized to be responsible for imbalance in anticonvulsant and
proconvulsant hormones. Restoring steroidogenesis and normal adre­
nocortical function by ACTH is supposed effective in the treatment [59].
In line with the effect of neurosteroids, a phase 2 clinical trial of oral
ganaxolone showed a greater reduction in the frequency of PCDH19-
S. Kowkabi et al. Epilepsy & Behavior 154 (2024) 109730

Fig. 3. Diagram illustrates seizure active period in PCDH19 clustering epilepsy, which falls between post mini-puberty (0–6 months) and pre-puberty (12 years). As
the effective sex hormone levels start to decline, the risk of seizure is dramatically increased.

clustering seizures in the group that received ganaxolone compared to the importance of NHRs signaling is again underlined [59,61]. Another
the placebo group; however, this outcome did not reach statistical sig­ significantly dysregulated gene is Oxytocin Receptor gene (OXTR).
nificance [60].’. Reduced OXTR expression was introduced in schizophrenia and ASD
that are the comorbidities of PCDH19-CE. The role of OXTR in brain
development is assumed to be through GABA switch from depolarizing
2.9. PCDH19-gene expression regulation:
to hyperpolarizing during postnatal period [57,62,63].
Therefore, PCDH19 participates in more than one cellular pathway
A gene expression regulatory function was suggested for PCDH19, as
and behaves as a signaling molecule linking cell adhesion and migration
the genes adjusted by estrogen, progesterone, and androgen receptors
to gene expression regulation. In line with this bridging role of PCDH19
were observed dysregulated in patients’ skin fibroblasts. PCDH19 was
from synapse to gene expression in nucleus, N-methyl-D-aspartate re­
identified in the perinuclear and nucleoplasmic region of cells, in close
ceptor (NMDAR) mediated proteolytic cleavage of PCDH19 was detec­
contact with a nuclear protein NONO as its interactor. NONO is a cor­
ted within the transmembrane or inner membrane surface. This cleavage
egulatory of steroid nuclear hormone receptors (NHRs) like estradiol
produced a C-terminal fragment (CTF) with ability to enter the nucleus
receptors (ERs) and PCDH19-NONO interaction regulates NHRs with the
and inhibit the expression of immediate-early genes (IEGs), which pre­
subsequent effect on gene transcription. Silencing NONO expression in
vents runaway excitation and hyperactivity. While an increase in IEG
human adrenocortical cells decreased cortisol biosynthesis in response
expression and excitation following PCDH19 downregulation and CTF
to ACTH. It is assumed that impaired PCDH19-NONO-ACTH axis leads
reduction were observed. Any alteration during this path could be
to fever related seizures in PCDH19-CE. As previously indicated AKR1C
associated with neurological disorders such as epilepsy. Whole-gene
(the gene responsible for producing allopregnanolone) was down
deletions and truncating variants by preventing PCDH19 cleavage and
regulated in PCDH19-CE, which is consistent with gene expression
CTF production, and extracellular missense point mutations and het­
regulatory function of PCDH19. Low AKR1C3 gene expression affects
erozygous gene mutations by impairing adhesion might modulate pro­
allopregnanolone, testosterone, and estradiol (E2) levels. Estradiol re­
teolytic cleavage (Fig. 4) [64,65]. An unpublished paper showed that a
ceptor (ER) expression is adjusted by estrogen level; ER expression is low
distinct protease processed PCDH19 into an extracellular fragment and
when estrogen is low and vice versa. Wild type PCDH19 through NONO
two intracellular C-terminal fragments (CTF1 and CTF2). CTF2 was
acts on ERa-mediated gene expression, which is more enhanced in the
carried to the nucleus by a transport protein, to modulate the expression
presence of estrogen, contrary to the lack of this function in PCDH19-CE
of genes [1,66].
(Fig. 4). It is assumed that all PCDH19 variations are loss of function,
which impair ERa-mediated gene expression. ERa and its ligand estra­
diol (E2) get involved in various diseases including epilepsy, psychiatric 2.10. PCDH19- BBB and immune mechanism:
and behavioral disorders. Although estrogen is proconvulsant like in
catamenial epilepsy, some evidence of anticonvulsant role of it in special There are reports of immune system involvement and successful
occasions exist. Just as the seizure onset and offset of PCDH19-CE pa­ treatment with steroid in the acute phase of PCDH19-CE. A case of new
tients lie within the low and high estrogen period respectively (Fig. 3). In onset refractory status epilepticus (NORSE) was introduced with a
a different way, PCDH19 variations result in lower ERa transcription and pathogenic variant in PCDH19 and a cytokine storm following routine
affect the patients during low estrogen period. Considering this and also vaccination. Treatment with Anakinra resulted in cytokine and seizure
previously indicated allopregnanolone deficiency in PCDH19-CE girls, reduction. Two therapeutic mechanisms for steroid in PCDH19-CE were

Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
S. Kowkabi et al. Epilepsy & Behavior 154 (2024) 109730

Fig. 4. PCDH19-mediated gene expression regulation. At first, N-methyl-D-aspartate receptor (NMDAR) mediated proteolytic cleavage of PCDH19 occurs in the
transmembrane or inner membrane surface. This cleavage produces a C-terminal fragment (CTF) with ability to enter the nucleus. In the nucleus, CTF interacts with a
nuclear protein NONO, and regulates steroid nuclear hormone receptors (NHRs) like estradiol receptors (ERs) with the subsequent effect on gene transcription (e.g.,
AKR1C, OXTR, …). AKR1C is responsible for producing steroid hormones like allopregnanolone, testosterone and estradiol. A reciprocal interaction is seen between
estradiol receptor (ER) expression and estrogen level; ER expression is low when estrogen is low and vice versa. Also, CTF inhibits the expression of immediate-early
genes (IEGs), which prevents runaway excitation and hyperactivity. Lack of PCDH19 in hemizygous males might cause excitation, hyperactivity and loss of its
regulatory effect on steroid gene transcription through lack of the C-terminal fragment.

proposed:(1) steroid improves BBB susceptibility resulting from
PCDH19 variations (2) steroid acts as an antiepileptic agent, via
enhancing both tonic and phasic GABAA mediated Inhibition [67–70].
PCDH19 is expressed in BBB and its mutation causes BBB vulnerability.
Moreover, systemic inflammation can disrupt BBB, exacerbate its pri­
mary dysfunction, and predispose patient to seizure recurrence. Seizure
clusters will further alter BBB by inducing brain inflammation. Along
with the BBB alteration, seizure period in PCDH19-CE falls in the age of
BBB instability. Anti-neuronal antibodies detected in PCDH19-CE, were
nonspecific and represent a non-specific sensitization to degraded
neuronal proteins leaking into the bloodstream from the compromised
BBB by recurrent seizure. Considering all these findings, Higurashi et al
proposed restoration of BBB integrity as the likely mechanism of corti­
costeroid action in PCDH19-CE. In other words, seizures might be trig­
gered by disruption of BBB and alleviated by corticosteroid [17].
hemizygous male mice [72]. In the same way, network hyperexcitability
was detected in both mosaic and non-mosaic mutant zebrafish. Non-
mosaic mutants displayed reduced inhibitory interneurons which
could be the cellular basis of their hyperexcitability. This research
emphasized on interneuron- mediated mechanisms and suggested ben­
zodiazepines and barbiturates as more effective than other medications
by modifying inhibitory GABAergic activity [73]. Evaluation of the
functional imaging of zebrafish PCDH19 mutant larvae revealed
enhanced clustering and altered brain network assembly [74]. There are
some reported cases of ASD in hemizygous males, which suggest the role
of other mechanisms than cellular interference. Asymptomatic carrier
mothers are another contradiction [38,75,76]. Loss of PCDH19-
mediated adhesion or dysregulation of intracellular proteins was
described as the pathogenic mechanism for autism-like phenotypes in
hemizygous-PCDH19 KO male mice [77].

2.11. Challenging evidence against cellular interference model: 2.12. The role of modifiers:

Heightened seizure susceptibility was observed in PCDH19-
Knockout and Heterozygous female mice. While knockout females
should behave the same as wild type according to the cellular interfer­
ence model. It was suggested that other mechanisms, possibly gender-
related, might work such as differences in neurosteroid metabolism
[71]. Behavioral test was also impaired in heterozygous female and
A small cohort showed that cellular interference could not explain all
phenotypic severities of mosaic males. Mosaic males with missense
variants had higher level of blood mosaicism and more severe epileptic
phenotype than others [9]. However, blood mosaicism is not probably
equal to the brain mosaicism [78]. Another cohort suggested the pres­
ence of modifiers for describing variable presentation. The percentage of

Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
S. Kowkabi et al.
mutant allele close to 50 % in the brain of mosaic symptomatic males
was introduced as a modifier, which determines more scrambling than
too high or too low percentage of mutant allele in asymptomatic males.
While mutant allele ratio near to 50 % was seen in asymptomatic mosaic
females which ruled out mosaicism and suggested other modifiers like X
chromosome inactivation as a modifier in females [13]. Herein, total
skewed pattern of X inactivation simulates a hemizygous form with less
sever phenotype in females [79]. An asymptomatic female with the same
variant as her affected sister was reported who had extremely X-chro­
mosome inactivation in peripheral blood [80]. Another female with
PCDH19-CE was seen with duplication variant in exon 5, who had an
asymptomatic carrier mother [76].
Furthermore, variations with more change in adhesiveness were
suggested to correlate with more severe symptoms [81]. The great ma­
jority of missense variations in the PCDH19 were reported in exon 1
(86.7 %), the largest exon encoding the extracellular adhesive domain of
protein. These variations might interfere with homophilic adhesion of
the protein or prevent interaction in cis with other cadherins, such as
Ncad. The most frequent pathogenic variants are missense (45.4 %),
followed by frameshift (27.3 %) and nonsense (19.6 %) [1,12,35].
Penetrance of PCDH19 for female is 80––85 % [82].
PCDH19 has various functions through extracellular and intracel­
lular domains [83]. The intracellular domains anchor on the cytoskel­
eton and regulate intracellular signaling pathways [12]. Till now, few
variations have been reported in the intracellular domain of the protein,
possibly affect sorting or intracellular signaling [18]. At first, the hy­
pothesis of cellular interference was proposed for describing the path­
ophysiology of this disorder. Since then, a broad range of clinical
variability was seen, even in identical, monozygotic twins [84,85].
Now, the balance is shifting from accepting cellular interference
model as the sole pathogenic mechanism to counting on different
mechanisms for the pathogenesis [15,17,31].
The majority of PCDH19 variations were reported in exon 1. Exon 1
is the largest exon which encodes the extracellular adhesive domain of
protein. As it was described before, every mismatch in the extracellular
region of neighboring cells, whether through a heterozygous female or
mosaicism in male, scrambles cells adhering and disrupts all after going
cascades of PCDH19 function. The chance of mutation in females with
two X chromosomes is likely more than males with just one X chromo­
some. Additionally, each mutation in exon 1 in women is expected to
disrupt adhesiveness via random X inactivation and cell sorting, while it
is unlikely in men, thanks to the presence of only one X chromosome and
therefore only one cell types (mutant or wild), unless there is somatic
mutation. This might be the cause of female predominant involvement,
otherwise PCDH19 variations could be pathogenic in each gender and
pathogenic mechanism probably depends on which part of the gene is
mutated.
A genotype–phenotype correlation was showed by Shibata et al.
They observed earlier seizures and sever intellectual disability with
missense and truncating variants located from EC1 to EC4, compared to
milder phenotypes seen with truncating variants located from EC5 to the
cytoplasmic domain [86]. It was revealed that domains EC1 to EC4
contain minimal part for homophilic adhesion of PCDH19 and that
missense variations located here, alter the homophilic binding of
PCDH19 [87].
Therefore, it is assumed that variations located in exon 2–6 and
encode the cytoplasmic domains disrupt intracellular gene pathways,
while variations in exon 1 encoding domains EC1 to EC4 largely disrupt
adhesion and neuronal network activity, combined with following
intracellular cascades dysregulation. It is worth enough when we decide
about therapeutic plan. If variations takes place in exon 2–6, advising
medications with effect on intracellular pathways like neurosteroids and
GABAergics might make sense, but variations in exon 1 are likely more
problematic through its additive adhesion defects. However, the role of
modulators such as X chromosome inactivation, differences in gene
expression and age-related steroid levels should be considered too.
Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
Epilepsy & Behavior 154 (2024) 109730
Adhesion is one of the mechanisms of PCDH19 function, however other
outstanding functions make this gene noticeable. This leads to problem
in identifying a therapeutic agent for all patients.
Concerning the age-depending pattern of seizures, the age-related
pathogenic mechanisms are assumed: 1) whose sufficiency increases
with age or 2) to them, body need decreases with age. Seizure happens
when steroid hormones drop after mini-puberty in the first year of life
which nearly coincides with the time to change of GABA function from
excitatory to inhibitory. If GABA does not work properly during this
transition phase (for example due to the effect of PCDH19 variations on
GABA), it may not show a through inhibitory function. Moreover,
decreased allopregnanolone levels in PCDH19 variations (due to down
regulation of AKR1C gene in PCDH19-CE) during this period of drop in
in-utero sex steroids may act as a predisposing factor to hyperexcit­
ability. All these changes, besides immature BBB at this age and fever
triggered seizures argue for the lack of proper innate anticonvulsive
mechanisms during this susceptible period.
The presence of ID and behavioral disturbances even without seizure
indicates the role of PCDH19 in neurodevelopment, which might be
through its positional information and direct effect of spindle pole on
symmetric neurogenesis, differentiation, and synaptic connections or
indirectly via its role on GABA excitatory function in primary neural
development.
We conducted a multi-dimensional review of suggested pathogenic
mechanisms in PCDH-CE, considering all effects of gene variations on
biological functions (from disrupted adhesion and neurogenesis to im­
pairments of BBB and intracellular signaling), on electrophysiological
aspects (disruption of SWS), on neuroimaging findings and brain
structure, and also on clinical manifestations.
3. Conclusion
PCDH19 is an important gene with diverse extracellular and intra­
cellular functions and interactions that its effects are more prominent
during a distinct period of life, considering changes in its interactors and
modulators during this specific period. It is speculated that PCDH19
variations can be epileptogenic regardless of gender with or without
cellular interference, but pathogenic mechanism differs in each patient.
Managing its interactors and modulators might be promising for
treatment.
Employing induced-pluripotent stem cell (iPSC) or animal models,
with distinct variations in exons encoding extracellular domains or
intracellular ones, on homozygous and heterozygous females and
hemizygous males provides opportunities for more precise evaluation
and treatment.
Funding statement
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Safoura Kowkabi: Writing – original draft, Investigation, Concep­
tualization. Majid Yavarian: Writing – review & editing. Reza
Kaboodkhani: Writing – review & editing. Mahmood Mohammadi:
Supervision. Reza Shervin Badv: Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
S. Kowkabi et al.
Acknowledgments
The authors would like to thank Mohammad Kaboodkhani for his
invaluable cooperation in figures and software
References:
[1] Kolc KL, Sadleir LG, Scheffer IE, et al. A systematic review and meta-analysis of 271
PCDH19-variant individuals identifies psychiatric comorbidities, and association of
seizure onset and disease severity. Mol Psychiatry 2019;24(2):241–51. https://doi.
org/10.1038/s41380-018-0066-9.
[2] Johannessen M, Kjellsen IM, Malt E. Behavioral and neuropsychological profile of a
male patient with mosaic PCDH19 mutation. Epilepsy Behav Rep 2022;19:100559.
https://doi.org/10.1016/j.ebr.2022.100559.
[3] Depienne C, Trouillard O, Bouteiller D, et al. Mutations and deletions in PCDH19
account for various familial or isolated epilepsies in females. Hum Mutat 2011;32:
E1959–75. https://doi.org/10.1002/humu.21373.
[4] Kozina AA, Okuneva EG, Baryshnikova NV, et al. Two novel PCDH19 mutations in
russian patients with epilepsy with intellectual disability limited to females: a case
report. BMC Med Genet 2020;21(1):209. https://doi.org/10.1186/s12881-020-
01119-6.
[5] Trivisano M, Pietrafusa N, Terracciano A, et al. Defining the electroclinical
phenotype and outcome of PCDH19-related epilepsy: a multicenter study. Epilepsia
2018;59(12):2260–71. https://doi.org/10.1111/epi.14600.
[6] Kolc KL, Sadleir LG, Depienne C, et al. A standardized patient-centered
characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy.
Transl Psychiatry 2020;10(1):127. https://doi.org/10.1038/s41398-020-0803-0.
[7] Gross C. Interference resolved: sorting out picky protocadherins in epilepsy.
Epilepsy Curr 2018;18(3):189–90. https://doi.org/10.5698/1535-7597.18.3.189.
[8] Pederick DT, Richards KL, Piltz SG, et al. Abnormal cell sorting underlies the
unique X-linked inheritance of PCDH19 epilepsy. Neuron 2018;97(1):59–66 e5.
https://doi.org/10.1016/j.neuron.2017.12.005.
[9] Terracciano A, Trivisano M, Cusmai R, et al. PCDH 19 -related epilepsy in two
mosaic male patients. Epilepsia 2016;57(3):e51–5. https://doi.org/10.1111/
epi.13295.
[10] Kolc KL, Moller RS, Sadleir LG, et al. PCDH19 pathogenic variants in males:
expanding the phenotypic Spectrum. Advances in Experimental Medicine and
Biology 2020;1298:177–87. https://doi.org/10.1007/5584_2020_574.
[11] Zhou W, Ouyang Y, Ji Y, et al. Genetic variants and phenotype analysis in a five
generation chinese pedigree with PCDH female limited epilepsy. Front Neurol
2023;14:1107904. https://doi.org/10.3389/fneur.2023.1107904.
[12] Yang L, Liu J, Su Q, et al. Novel and de novo mutation of PCDH19 in girls clustering
epilepsy. Brain Behav 2019;9(12):e01455.
[13] Liu A, Yang X, Yang X, et al. Mosaicism and incomplete penetrance of PCDH19
mutations. J Med Genet 2019;56(2):81–8. https://doi.org/10.1136/jmedgenet-
2017-105235.
[14] Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations cause
female-limited epilepsy and cognitive impairment. Nat Genet 2008;40(6):776–81.
https://doi.org/10.1038/ng.149.
[15] Borghi R, Magliocca V, Petrini S, et al. Dissecting the role of PCDH19 in clustering
epilepsy by exploiting patient-specific models of neurogenesis. J Clin Med 2021;10
(13):2754. https://doi.org/10.3390/jcm10132754.
[16] Pederick DT, Homan CC, Jaehne EJ, et al. Pcdh19 loss-of-function increases
neuronal migration in vitro but is dispensable for brain development in mice. Sci
Rep 2016;6(1):26765. https://doi.org/10.1038/srep26765.
[17] Higurashi N, Takahashi Y, Kashimada A, et al. Immediate suppression of seizure
clusters by corticosteroids in PCDH19 female epilepsy. Seizure 2015;27:1–5.
https://doi.org/10.1016/j.seizure.2015.02.006.
[18] Gerosa L, Francolini M, Bassani S, et al. The role of protocadherin 19 (PCDH19) in
neurodevelopment and in the pathophysiology of early infantile epileptic
Encephalopathy-9 (EIEE9). Dev Neurobiol 2019;79(1):75–84. https://doi.org/
10.1002/dneu.22654.
[19] Cooper SR, Emond MR, Duy PQ, et al. Protocadherins control the modular
assembly of neuronal columns in the zebrafish optic tectum. J Cell Biol 2015;211
(4):807–14. https://doi.org/10.1083/jcb.201507108.
[20] Emond MR, Biswas S, Jontes JDJDb. Protocadherin-19 is essential for early steps in
brain morphogenesis. Dev Biol 2009;334(1):72–83. https://doi.org/10.1016/j.
ydbio.2009.07.008.
[21] Biswas S, Emond MR, Jontes JD. Protocadherin-19 and N-cadherin interact to
control cell movements during anterior neurulation. J Cell Biol 2010;191(5):
1029–41. https://doi.org/10.1083/jcb.201007008.
[22] Compagnucci C, Petrini S, Higuraschi N, et al. Characterizing PCDH19 in human
induced pluripotent stem cells (iPSCs) and iPSC-derived developing neurons:
emerging role of a protein involved in controlling polarity during neurogenesis.
Oncotarget 2015;6(29):26804–13. https://doi.org/10.18632/oncotarget.5757.
[23] Alaverdian D, Corradi AM, Sterlini B, et al. Modeling PCDH19 clustering epilepsy
by neurogenin 2 induction of patient- derived induced pluripotent stem cells.
Epileptic Disord 2023;25(3):371–82. https://doi.org/10.1002/epd2.20065.
[24] Homan CC, Pederson S, To T-H, et al. PCDH19 regulation of neural progenitor cell
differentiation suggests asynchrony of neurogenesis as a mechanism contributing
to PCDH19 girls clustering epilepsy. Neurobiol Dis 2018;116:106–19. https://doi.
org/10.1016/j.nbd.2018.05.004.
[25] Kim SY, Yasuda S, Tanaka H, et al. Non-clustered protocadherin. Cell Adh Migr
2011;5(2):97–105. https://doi.org/10.4161/cam.5.2.14374.
Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
Epilepsy & Behavior 154 (2024) 109730
[26] Emond MR, Biswas S, Blevins CJ, et al. A complex of Protocadherin-19 and N-
cadherin mediates a novel mechanism of cell adhesion. J Cell Biol 2011;195(7):
1115–21. https://doi.org/10.1083/jcb.201108115.
[27] Mancini M, Bassani S, Passafaro MJC. Right place at the right time: how changes in
protocadherins affect synaptic connections contributing to the etiology of
neurodevelopmental disorders. Cells 2020;9(12):2711. https://doi.org/10.3390/
cells9122711.
[28] Orland MD, Giampietro PFJTJoP. 50 Years Ago in The Journal of Pediatrics:
Unique X-Linked Mutation Associated with Female-Specific Epilepsy and
Intellectual Disability. J Pediatr. 2021; 238:144. https://doi.org/10.1016/j.
jpeds.2021.08.047.
[29] Symonds JD, McTague A. Epilepsy and developmental disorders: next generation
sequencing in the clinic. Eur J Paediatr Neurol 2020;24:15–23. https://doi.org/
10.1016/j.ejpn.2019.12.008.
[30] Juberg RC, Hellman CD. A new familial form of convulsive disorder and mental
retardation limited to females. J Pediatr 1971;79(5):726–32. https://doi.org/
10.1016/s0022-3476(71)80382-7.
[31] Dell’Isola GB, Vinti V, Fattorusso A, et al. The broad clinical Spectrum of epilepsies
associated with protocadherin 19 gene mutation. Front Neurol 2021;12:780053.
https://doi.org/10.3389/fneur.2021.780053.
[32] Perez D, Hsieh DT, Rohena L. Somatic mosaicism of PCDH19 in a male with early
infantile epileptic encephalopathy and review of the literature. Am J Med Genet A
2017;173(6):1625–30. https://doi.org/10.1002/ajmg.a.38233.
[33] Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic
encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but
mainly affects females. PLoS genetics. 2009;5(2): e1000381. https://doi.org/
10.1371%2Fjournal.pgen.1000381.
[34] Romasko EJ, DeChene ET, Balciuniene J, et al. PCDH19-related epilepsy in a male
with klinefelter syndrome: additional evidence supporting PCDH19 cellular
interference disease mechanism. Epilepsy Res 2018;145:89–92. https://doi.org/
10.1016/j.eplepsyres.2018.06.008.
[35] Thiffault I, Farrow E, Smith L, et al. PCDH19-related epileptic encephalopathy in a
male mosaic for a truncating variant. Am J Med Genet A 2016;170(6):1585–9.
https://doi.org/10.1002/ajmg.a.37617.
[36] Tan Y, Hou M, Ma S, et al. Chinese cases of early infantile epileptic
encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic
male-case report. BMC Med Genet 2018;19(1):1–8. https://doi.org/10.1186/
s12881-018-0621-x.
[37] Moncayo JA, Ayala IN, Argudo JM, et al. Understanding protein Protocadherin-19
(PCDH19) syndrome: a literature review of the pathophysiology. Cureus 2022;14
(6):e25808.
[38] Chouery E, Makhlouf J, Daoud Khatoun W, et al. PCDH19 in males: are hemizygous
variants linked to autism? Genes (Basel) 2023;14(3):598. https://doi.org/10.3390/
genes14030598.
[39] Mincheva-Tasheva S, Nieto Guil AF, Homan CC, et al. Disrupted excitatory synaptic
contacts and altered neuronal network activity underpins the neurological
phenotype in PCDH19-clustering epilepsy (PCDH19-CE). Mol Neurobiol 2021;58
(5):2005–18. https://link.springer.com/article/10.1007/s12035-020-02242-4.
[40] Giansante G, Mazzoleni S, Zippo AG, et al. Neuronal network activity and
connectivity are impaired in a conditional knockout mouse model with PCDH19
mosaic expression. Mol Psychiatry 2023. https://doi.org/10.1038/s41380-023-
02022-1.
[41] Galindo-Riera N, Newbold SA, Sledziowska M, et al. Cellular and behavioral
characterization of Pcdh19 mutant mice: subtle molecular changes, Increased
Exploratory Behavior and an Impact of Social Environment. eNeuro 2021;8(4).
https://doi.org/10.1523/ENEURO.0510-20.2021.
[42] Plummer X. Mechanisms of Embryonic and Adult Neurogenesis in the Development
of Epilepsy. (Doctoral dissertation) 2019. https://hdl.handle.net/2027.42/151436.
[43] 임지수. Molecular and functional characterization of PCDH19 mutations in
epilepsy in females with mental retardation (EFMR): Graduate School, Yonsei
University; 2019. [UCI]I804:11046-000000521629.
[44] Hoshina N, Johnson-Venkatesh EM, Hoshina M, et al. Female-specific synaptic
dysfunction and cognitive impairment in a mouse model of PCDH19 disorder.
Science 2021;372(6539):eaaz3893.
[45] Lenge M, Marini C, Canale E, et al. Quantitative MRI-based analysis identifies
developmental limbic abnormalities in PCDH19 encephalopathy. Cereb Cortex
2020;30(11):6039–50. https://doi.org/10.1093/cercor/bhaa177.
[46] Rungsung I, Bhowmik AD, Dalal A. Truncation variation in the protocadherin 19
(PCDH19) gene exhibiting mosaicism in a manifesting heterozygous male. Genetic
Clinics 2021;14(2):5–7.
[47] Kurian M, Korff CM, Ranza E, et al. Focal cortical malformations in children with
early infantile epilepsy and PCDH 19 mutations: case report. Dev Med Child Neurol
2018;60(1):100–5. https://doi.org/10.1111/dmcn.13595.
[48] Bolsterli BK, Schmitt B, Bast T, et al. Impaired slow wave sleep downscaling in
encephalopathy with status epilepticus during sleep (ESES). Clin Neurophysiol
2011;122(9):1779–87. https://doi.org/10.1016/j.clinph.2011.01.053.
[49] Mohammadi M, Kowkabi S, Asadi-Pooya AA, et al. Hemi-ESES associated with
agenesis of the corpus callosum and normal cognition. Epilepsy Behav Case Rep
2019;11:96–8. https://doi.org/10.1016/j.ebcr.2019.01.005.
[50] Lamers D, Landi S, Mezzena R, et al. Perturbation of cortical excitability in a
conditional model of PCDH19 disorder. Cells 2022;11(12):1939. https://doi.org/
10.3390/cells11121939.
[51] Vlaskamp DR, Bassett AS, Sullivan JE, et al. Schizophrenia is a later -onset feature
of PCDH 19 girls clustering epilepsy. Epilepsia 2019;60(3):429–40. https://doi.
org/10.1111/epi.14678.
S. Kowkabi et al.
[52] Bassani S, Cwetsch AW, Gerosa L, et al. The female epilepsy protein PCDH19 is a
new GABAAR-binding partner that regulates GABAergic transmission as well as
migration and morphological maturation of hippocampal neurons. Hum Mol Genet
2018;27(6):1027–38. https://doi.org/10.1093/hmg/ddy019.
[53] Serratto GM, Pizzi E, Murru L, et al. The Epilepsy-Related Protein PCDH19
Regulates Tonic Inhibition, GABA AR Kinetics, and the Intrinsic Excitability of
Hippocampal Neurons. Molecular neurobiology .2020;57:5336-51. https://doi.
org/10.1007/s12035-020-02099-7.
[54] Mazzoleni S. SOLVING the puzzle of PROTOCADHERIN-19 mosaicism to
understand the pathophysiology of developmental and epileptic encephalopathy 9
(DEE9). Dipartimento di Biotecnologie Mediche e Medicina Traslazionale 2022.
https://hdl.handle.net/2434/918930.
[55] Mazzoleni S, Bassani S. PCDH19 interplay with GABA(A) receptors: a window to
DEE9 pathogenetic mechanisms. Neural Regen Res 2022;17(4):803–5. https://doi.
org/10.4103/1673-5374.322455.
[56] Lotte J, Bast T, Borusiak P, et al. Effectiveness of antiepileptic therapy in patients
with PCDH19 mutations. Seizure 2016;35:106–10. https://doi.org/10.1016/j.
seizure.2016.01.006.
[57] Tan C, Shard C, Ranieri E, et al. Mutations of protocadherin 19 in female epilepsy
(PCDH19-FE) lead to allopregnanolone deficiency. Hum Mol Genet 2015;24(18):
5250–9. https://doi.org/10.1093/hmg/ddv245.
[58] Neurosteroid MJ, Epilepsy DAW. Epilepsy Curr 2016;16(2):108–9. https://doi.org/
10.5698/1535-7511-16.2.108.
[59] Trivisano M, Lucchi C, Rustichelli C, et al. Reduced steroidogenesis in patients with
PCDH 19 -female limited epilepsy. Epilepsia 2017;58(6):e91–5. https://doi.org/
10.1111/epi.13772.
[60] Sullivan J, Gunning B, Zafar M, et al. Phase 2, placebo-controlled clinical study of
oral ganaxolone in PCDH19-clustering epilepsy. Epilepsy Res 2023;191:107112.
https://doi.org/10.1016/j.eplepsyres.2023.107112.
[61] Pham DH, Tan CC, Homan CC, et al. Protocadherin 19 (PCDH19) interacts with
paraspeckle protein NONO to co-regulate gene expression with estrogen receptor
alpha (ERalpha). Hum Mol Genet 2017;26(11):2042–52. https://doi.org/10.1093/
hmg/ddx094.
[62] LoParo D, Waldman IJMp. The oxytocin receptor gene (OXTR) is associated with
autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015;20(5):640–6.
https://doi.org/10.1038/mp.2014.77.
[63] Leonzino M, Busnelli M, Antonucci F, et al. The timing of the excitatory-to-
inhibitory GABA switch is regulated by the oxytocin receptor via KCC2. Cell Rep
2016;15(1):96–103. https://doi.org/10.1016/j.celrep.2016.03.013.
[64] Gerosa L, Mazzoleni S, Rusconi F, et al. The epilepsy-associated protein PCDH19
undergoes NMDA receptor-dependent proteolytic cleavage and regulates the
expression of immediate-early genes. 2022;39(8):110857. https://doi.org/
10.1016/j.celrep.2022.110857.
[65] Pancho A, Mitsogiannis MD, Aerts T, et al. Modifying PCDH19 levels affects
cortical interneuron migration. Front Neurosci 2022;16:887478. https://doi.org/
10.3389/fnins.2022.887478.
[66] Newbold SA. The proteolytic processing and nuclear function of Protocadherin-19:
Cardiff University; 2021. https://orca.cardiff.ac.uk/id/eprint/144599.
[67] Varughese RT, Karkare S, Poduri A, et al. Child neurology: initial presentation of
PCDH19-related epilepsy with new-onset refractory status epilepticus and
treatment with anakinra. Neurology 2022;99(5):208–11. https://doi.org/10.1212/
WNL.0000000000200855.
[68] Bertani G, Spagnoli C, Iodice A, et al. Steroids efficacy in the acute management of
seizure clusters in one case of PCDH19 female epilepsy. Seizure 2015;32:45–6.
https://doi.org/10.1016/j.seizure.2015.09.002.
[69] Chen G, Zhou H, Lu Y, et al. Case report: a novel mosaic nonsense mutation of
PCDH19 in a chinese male with febrile epilepsy. Front Neurol 2022;13:992781.
https://doi.org/10.3389/fneur.2022.992781.
Downloaded for Anonymous User (n/a) at Pontifical Catholic University of Chile from ClinicalKey.com by Elsevier on March
28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
Epilepsy & Behavior 154 (2024) 109730
[70] Lee DM, Chung HJJJotKCNS. A Case of Effective Treatment of a Patient with PCDH
19-Related Epilepsy using Corticosteroid. Ann Child Neurol. 2018;26(1):32-7.
https://doi.org/10.26815/jkcns.2018.26.1.32.
[71] Rakotomamonjy J, Sabetfakhri NP, McDermott SL, et al. Characterization of
seizure susceptibility in Pcdh19 mice. Epilepsia 2020;61(10):2313–20. https://doi.
org/10.1111/epi.16675.
[72] Hayashi S, Inoue Y, Hattori S, et al. Loss of X-linked Protocadherin-19 differentially
affects the behavior of heterozygous female and hemizygous male mice. Sci Rep
2017;7(1):5801. https://doi.org/10.1038/s41598-017-06374-x.
[73] Robens BK, Yang X, McGraw CM, et al. Mosaic and non-mosaic protocadherin 19
mutation leads to neuronal hyperexcitability in zebrafish. Neurobiol Dis 2022;169:
105738. https://doi.org/10.1016/j.nbd.2022.105738.
[74] Light SEW, Jontes JD. Multiplane calcium imaging reveals disrupted development
of network topology in zebrafish pcdh19 mutants. eNeuro 2019;6(3). https://doi.
org/10.1523/ENEURO.0420-18.2019.
[75] van Harssel JJ, Weckhuysen S, van Kempen MJ, et al. Clinical and genetic aspects
of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations
in males with autism spectrum disorders. Neurogenetics 2013;14(1):23–34.
https://doi.org/10.1007/s10048-013-0353-1.
[76] Dimova PS, Kirov A, Todorova A, et al. A novel PCDH19 mutation inherited from
an unaffected mother. Pediatr Neurol 2012;46(6):397–400. https://doi.org/
10.1016/j.pediatrneurol.2012.03.004.
[77] Lim J, Ryu J, Kang S, et al. Autism-like behaviors in male mice with a Pcdh19
deletion. Mol Brain 2019;12(1):95. https://doi.org/10.1186/s13041-019-0519-3.
[78] de Lange IM, Rump P, Neuteboom RF, et al. Male patients affected by mosaic
PCDH19 mutations: five new cases. Neurogenetics 2017;18(3):147–53. https://doi.
org/10.1007/s10048-017-0517-5.
[79] Hudson JD, Tamilselvan E, Sotomayor M, et al. A complete Protocadherin-19
ectodomain model for evaluating epilepsy-causing mutations and potential protein
interaction sites. Structure 2021;29(10):1128–43 e4. https://doi.org/10.1016/j.
str.2021.07.006.
[80] Hung LY, Subramaniam SR, Tong TT, et al. X-chromosome inactivation and
PCDH19-associated epileptic encephalopathy: a novel PCDH19 variant in a chinese
family. Clin Chim Acta 2021;521:285–8. https://doi.org/10.1016/j.
cca.2021.07.023.
[81] Leonardi E, Sartori S, Vecchi M, et al. Identification of four novel PCDH19
mutations and prediction of their functional impact. Ann Hum Genet 2014;78(6):
389–98. https://doi.org/10.1111/ahg.12082.
[82] Dadali E, Mishina I, Borovikov A, et al. Clinical genetic characteristics of epilepsy
due to mutations in the PCDH19 gene (OMIM: 300088). Neurosci Behav Physiol
2020;50:1099–104. https://doi.org/10.1007/s11055-020-01011-z.
[83] de Nys R, Kumar R, Gecz J. Protocadherin 19 clustering epilepsy and neurosteroids:
opportunities for intervention. Int J Mol Sci 2021;22(18):9769. https://doi.org/
10.3390/ijms22189769.
[84] Depienne C, LeGuern E. PCDH19-related infantile epileptic encephalopathy: an
unusual X-linked inheritance disorder. Hum Mutat 2012;33(4):627–34. https://
doi.org/10.1002/humu.22029.
[85] Gecz J, Thomas PQJCOiG. Disentangling the paradox of the PCDH19 clustering
epilepsy, a disorder of cellular mosaics. Curr Opin Genet Dev. 2020; 65:169-75.
https://doi.org/10.1016/j.gde.2020.06.012.
[86] Shibata M, Ishii A, Goto A, et al. Comparative characterization of PCDH19
missense and truncating variants in PCDH19-related epilepsy. J Hum Genet 2021;
66(6):569–78. https://doi.org/10.1038/s10038-020-00880-z.
[87] Cooper SR, Jontes JD, Sotomayor M. Structural determinants of adhesion by
Protocadherin-19 and implications for its role in epilepsy. Elife 2016;5:e18529.