View source for Medicine:Epilepsy-intellectual disability in females

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'''Epilepsy-intellectual disability in females''' also known as '''PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9''' ('''EIEE9'''), is a rare type of epilepsy that affects predominately females and is characterized by clusters of brief seizures, which start in infancy or early childhood, and is occasionally accompanied by varying degrees of cognitive impairment.<ref name=":0">{{Cite journal|last1=Depienne|first1=C|last2=LeGeurn|first2=E|date=2012|title=PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder|url=http://www.hal.inserm.fr/inserm-00669941/document|journal=Hum Mutat|volume=33|issue=4|pages=627–634|doi=10.1002/humu.22029|pmid=22267240|s2cid=40463330}}</ref><ref name=":1">{{cite journal|title=PCDH19-related female-limited epilepsy: Further details regarding early clinical features and therapeutic efficacy|url=http://resolver.scholarsportal.info/resolve/09201211/v106i1-2/191_pfefdrecfate|journal=Epilepsy Research|volume=106|issue=1–2|pages=191–199|doi=10.1016/j.eplepsyres.2013.04.005|pmid=23712037|author1=Higurashi, N.|author2=Nakamura, M.|author3=Sugai, M.|author4=Ohfu, M.|author5=Sakauchi, M.|author6=Sugawara, Y.|author7=Nakamura, K.|author8=Kato, M.|author9=Usui, D.|author10=Mogami, Y.|author11=Fujiwara, Y.|author12=Ito, T.|author13=Ikeda, H.|author14=Imai, K.|author15=Takahashi, Y.|author16=Nukui, M.|author17=Inoue, T.|author18=Okazaki, S.|author19=Kirino, T.|author20=Tomonoh, Y.|author21=Inoue, T.|author22=Takano, K.|author23=Shimakawa, S.|author24=Hirose, S.|year=2013|s2cid=20561773}}</ref><ref name=":2">{{Cite web|url=http://pcdh19info.org/|title=PCDH19 Alliance|access-date=August 22, 2016}}</ref><ref name=":3">{{Cite journal|last1=Specchio|first1=N|last2=Marini|first2=C|last3=Terracciano|first3=A|date=2011|title=Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations|journal=Epilepsia|volume=52|issue=7|pages=1251–1257|doi=10.1111/j.1528-1167.2011.03063.x|pmid=21480887|doi-access=free}}</ref> The striking pattern of onset seizures at a young age, genetic testing and laboratory results, potential developmental delays or developmental regression and associated disorders, eases diagnosis.

The National Institutes of Health Office and Rare Disease Research characterizes PCDH19 gene-related epilepsy as a rare disorder.<ref name=":4">{{Cite web|url=https://rarediseases.info.nih.gov/diseases/10806/pcdh19-related-female-limited-epilepsy|title=PCDH19-related female-limited epilepsy {{!}} Genetic and Rare Diseases Information Center(GARD) – an NCATS Program|website=rarediseases.info.nih.gov|access-date=2016-08-22}}</ref> Although formal epidemiologic data is not available, results from diagnostic screenings indicate that approximately 1 out of 10 girls who have seizure onset before five years of age may have PCDH19 mutations.<ref name=":5">{{Cite journal|last1=Depienne|first1=Christel|last2=Bouteiller|first2=Delphine|last3=Keren|first3=Boris|last4=Cheuret|first4=Emmanuel|last5=Poirier|first5=Karine|last6=Trouillard|first6=Oriane|last7=Benyahia|first7=Baya|last8=Quelin|first8=Chloé|last9=Carpentier|first9=Wassila|date=2009-02-13|title=Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females|journal=PLOS Genet|volume=5|issue=2|pages=e1000381|doi=10.1371/journal.pgen.1000381|issn=1553-7404|pmc=2633044|pmid=19214208 |doi-access=free }}</ref><ref name=":6">{{cite journal | vauthors = Depienne C, Trouillard O, Bouteiller D, Gourfinkel-An I, Poirier K, Rivier F, Berquin P, Nabbout R, Chaigne D, Steschenko D, Gautier A, Hoffman-Zacharska D, Lannuzel A, Lackmy-Port-Lis M, Maurey H, Dusser A, Bru M, Gilbert-Dussardier B, Roubertie A, Kaminska A, Whalen S, Mignot C, Baulac S, Lesca G, Arzimanoglou A, LeGuern E |display-authors = 6| title = Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females | journal = Hum. Mutat. | volume = 32 | issue = 1 | pages = E1959–75 | date = January 2011 | pmid = 21053371 | pmc = 3033517 | doi = 10.1002/humu.21373 }}</ref><ref name=":17">{{Cite book|title=Neurobiology of Disease|last=Johnston|first=Michael|publisher=Oxford University Press|year=2016|isbn=978-0199937844|pages=307–309}}</ref>

== Signs and symptoms ==
PCDH19 gene-related epilepsy is a highly variable and rare epileptic syndrome, characterized by the early-onset of seizure clusters, with a range of 4 – 60 months, and an average onset at 12.9 months.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /> Other aspects, such as varying degrees of cognitive impairment and behavioral and psychiatric problems, are also common, but are not essential for diagnosis of PCDH19 gene-related epilepsy.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":7">{{Cite journal|last1=Dibbens|first1=LM|last2=Tarpey|first2=PS|date=June 2008|title=X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment|journal=Nat Genet|volume=40|issue=6|pages=776–781|doi=10.1038/ng.149|pmid=18469813|pmc=2756413}}</ref><ref name=":8">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK98182/|title=Genes in infantile epileptic encephalopathies|last1=Depienne|first1=Christel|last2=Gourfinkel-An|first2=Isabelle|last3=Baulac|first3=Stéphanie|last4=LeGuern|first4=Eric|date=2012-01-01|publisher=National Center for Biotechnology Information (US)|editor-last=Noebels|editor-first=Jeffrey L.|edition=4th|location=Bethesda (MD)|pmid=22787626|editor-last2=Avoli|editor-first2=Massimo|editor-last3=Rogawski|editor-first3=Michael A.|editor-last4=Olsen|editor-first4=Richard W.|editor-last5=Delgado-Escueta|editor-first5=Antonio V.}}</ref><ref name="scheffer">{{cite journal|year=2008|title=Epilepsy and mental retardation limited to females: an under-recognized disorder|journal=Brain|volume=131|issue=4|pages=918–927|doi=10.1093/brain/awm338|author=Scheffer, Ingrid|display-authors=0|pmid=18234694|doi-access=free}}</ref><ref name=":9">{{Cite journal|last1=Cappelletti|first1=Simona|last2=Specchio|first2=Nicola|last3=Moavero|first3=Romina|last4=Terracciano|first4=Alessandra|last5=Trivisano|first5=Marina|last6=Pontrelli|first6=Giuseppe|last7=Gentile|first7=Simonetta|last8=Vigevano|first8=Federico|last9=Cusmai|first9=Raffaella|title=Cognitive development in females with PCDH19 gene-related epilepsy|journal=Epilepsy & Behavior|volume=42|pages=36–40|doi=10.1016/j.yebeh.2014.10.019|pmid=25499160|year=2015|s2cid=13227576}}</ref><ref name=":22">{{Cite book|title=Pellock's Pediatric Epilepsy: Diagnosis and Therapy|last=Nordli Jr.|first=Douglas|publisher=Springer Publishing Company|year=2016|isbn=978-1617052439|pages=386}}</ref>{{excessive citations inline|date=December 2020}}

PCDH19 gene-related epilepsy shares several clinical features with other early-onset epileptic encephalopathies, such as Dravet Syndrome, [[Medicine:Generalized epilepsy with febrile seizures plus|Generalized epilepsy with febrile seizures plus]]&nbsp;(GEFS+), [[Medicine:Febrile infection-related epilepsy syndrome|FIRES]] (febrile infection–related epilepsy syndrome)&nbsp;Lennox-Gastaut syndrome&nbsp;or epilepsy of unknown origin.<ref name=":17" /> However, the disorder has a distinct evolution of symptoms, and is associated with specific genetic mutations of the PCDH19 gene.<ref name=":17" />

=== Seizures&nbsp; &nbsp;&nbsp; ===
The hallmark characteristic of PCDH19 gene-related epilepsy is early-onset cluster seizures that often cause cyanotic spells, which start in infancy or early childhood.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /> The onset of the first cluster of seizures usually coincides with a fever ([[Medicine:Febrile seizure|febrile seizure]]s), however subsequent seizures may be febrile or afebrile.<ref name=":0" /><ref name=":1" /><ref name=":10">{{cite journal | vauthors = Marini C, Mei D, Parmeggiani L, Norci V, Calado E, Ferrari A, Moreira A, Pisano T, Specchio N, Vigevano F, Battaglia D, Guerrini R | title = Protocadherin 19 mutations in girls with infantile-onset epilepsy | journal = Neurology | volume = 75 | issue = 7 | pages = 646–53 | date = August 2010 | pmid = 20713952 | doi = 10.1212/WNL.0b013e3181ed9e67 | s2cid = 40368257 }}</ref> The seizure clusters are generally brief seizures, lasting 1–5 minutes, often accompanied by fearful screaming observed in 63% of girls.<ref name=":0" /><ref name=":1" /><ref name=":17" /><ref name=":9" /><ref name=":10" /><ref name=":11">{{cite journal | vauthors = Marini C, Darra F, Specchio N, Mei D, Terracciano A, Parmeggiani L, Ferrari A, Sicca F, Mastrangelo M, Spaccini L, Canopoli ML, Cesaroni E, Zamponi N, Caffi L, Ricciardelli P, Grosso S, Pisano T, Canevini MP, Granata T, Accorsi P, Battaglia D, Cusmai R, Vigevano F, Dalla Bernardina B, Guerrini R |display-authors = 6| title = Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy | journal = Epilepsia | volume = 53 | issue = 12 | pages = 2111–9 | date = December 2012 | pmid = 22946748 | issn = 1528-1167| doi = 10.1111/j.1528-1167.2012.03649.x | hdl = 11365/1000813 |s2cid = 8071244| hdl-access = free }}</ref>{{excessive citations inline|date=December 2020}} These cluster seizures can occur more than 10 times a day over several days, with varying amounts of time between seizure clusters.<ref name=":0" /><ref name=":17" />

Over time, children with PCDH19 gene-related epilepsy tend to exhibit multiple seizure types, including focal, generalized tonic-clonic, tonic, [[Medicine:Atonic seizure|atonic]], myoclonus, and absence seizures.<ref name=":9" /><ref name=":22" /> In a small study of 35 female patients with PCDH19 gene-related epilepsy, rare episodes of status epilepticus occurred in about 30% of patients in the early course of the disorder.<ref name=":11" />&nbsp;

In PCDH19 gene-related epilepsy, the seizures are often refractory to treatment, especially in infancy and childhood.<ref name=":17" /><ref name=":7" /><ref name=":11" /> Additionally, seizures are usually characterized by persistence of cluster seizures, with variable frequency.<ref name=":17" /><ref name=":11" /> In a study of 35 female patients with PCDH19 gene-related epilepsy, approximately 30% had become seizure free in the girl's childhood (mean age of 12 years), yet some continued into adulthood.<ref name=":11" /> In the same study, a few patients still had recurrent cluster seizures that evolved into [[Medicine:Status epilepticus|status epilepticus]] in childhood or early adolescence.<ref name=":11" />

===Developmental problems===
Beyond early-onset and treatment-resistant cluster seizures, PCDH19 gene-related epilepsy is usually, but not always, associated with cognitive and sensory impairment of varying degrees, and psychiatric and behavioral problems.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":17" /><ref name=":7" /><ref name=":8" /><ref name="scheffer" /><ref name=":9" />{{excessive citations inline|date=December 2020}} It is estimated that up to 60 to 75% of the females have cognitive deficits, ranging from mild to severe intellectual disability, which do not appear to be related to frequency or severity of seizures.<ref name=":2" /><ref name=":3" /><ref name=":17" /><ref name=":7" /><ref name=":8" /><ref name="scheffer" /> Development over the course of a female patients' childhood can follow one of three courses: delays from birth that persist into adulthood, normal development and then regression, or normal intellectual development.<ref name=":2" /><ref name=":17" /> It is not yet clear why some people experience delayed intellectual growth and others regress with epilepsy.<ref name="scheffer" /><ref name="Marini">{{cite conference|date=June 29, 2010|title=Infantile onset focal epilepsy and epilepetic encephalopathies associated with PCDH19 gene mutations: New de novo and familial mutations.|conference=9th European Congress on Epileptology|volume=51|pages=1–189|doi=10.1111/j.1528-1167.2010.02658.x|pmid=20590792|author=Marini C.|display-authors=0|hdl=11446/404|hdl-access=free}}</ref>

From the University of Melbourne study, two-thirds of PCDH19 gene-related epilepsy patients have&nbsp;[[Medicine:Borderline intellectual functioning|borderline intellectual functioning]]&nbsp;or&nbsp;[[Medicine:Intellectual disability|intellectual disability]], while one third have normal intelligence.<ref name="scheffer" /> A connection to&nbsp;[[Medicine:Depression (mood)|depression]],&nbsp;[[Medicine:Autism|autism]], obsessive&nbsp;and&nbsp;aggressive behaviors&nbsp;and other disorders has been observed in PCDH19 gene-related epilepsy.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":17" /><ref name=":7" /><ref name=":8" /><ref name="scheffer" />{{excessive citations inline|date=December 2020}} Approximately 40-60% of girls diagnosed with a PCDH19 mutation are on the autism spectrum.<ref name=":2" /><ref name=":8" /><ref name="scheffer" /><ref name=":10" />

Many of those with PCDH19 gene mutations also exhibit behavioral and psychological problems – including [[Medicine:Attention deficit hyperactivity disorder|ADHD]], aggression, [[Medicine:Obsessive–compulsive disorder|obsessive-compulsive disorder]], and anxiety.<ref name=":2" /><ref name=":8" /><ref name="scheffer" /><ref name=":10" /> Other neurological abnormalities may present, including sleep disturbances, ictal apnea, motor deficits, [[Medicine:Hypotonia|hypotonia]], language delay, [[Medicine:Sensory Integration Dysfunction|sensory integration problems]] and [[Medicine:Dysautonomia|dysautonomia]].<ref name=":2" />

==Causes==
A 2008 study found a relationship between the PCDH19 gene and early onset female seizures, with subsequent studies confirming the relationship.<ref name="scheffer" /><ref name=":9" /><ref name="Marini" /><ref>{{Cite journal|last=Specchio|first=N|date=2011-08-01|title=Stormy Onset Epilepsy in Girls with De Novo Protocadherin 19 Mutations|journal=Epilepsia|language=en|volume=52|pages=4–22|doi=10.1111/j.1528-1167.2011.03206.x|issn=1528-1167|doi-access=free}}</ref>

PCDH19 gene-related epilepsy can arise as a single case in a family, due to a de novo error in cell replication, or it can be inherited.<ref name=":17" /><ref name=":7" /><ref name=":8" /> In a large series of cases in which inheritance was determined, half of the PCDH19 mutations occurred de novo, and half were inherited from fathers in good health, and who had no evidence of seizures or cognitive disorders.<ref name=":17" /><ref name=":7" /><ref name=":8" />

Men and women can transmit the PCDH19 mutation, although females, but not males, usually, but not always, exhibit symptoms, which can be very mild. Females with a mutation have a 50% chance of having children who are carriers. Men have a 100% chance of transmitting the mutation to a daughter and 0% chance to a son.<ref name=":17" /><ref name=":7" /><ref name=":8" /><ref name="scheffer" />

Although males do not generally exhibit PCDH19 gene-related history such as cluster seizures, in a study involving four families with PCDH19 gene mutations, 5 of the fathers had obsessive and controlling tendencies.<ref name="scheffer" /> The linkage of chromosome Xq22.1 to PCDH19 gene-related epilepsy in females was confirmed in all of the families.<ref name="scheffer" />

The inheritance pattern is very unusual, in that men that carry the PCDH19 gene mutation on their only X-chromosome are typically unaffected, except in rare instances of somatic mosaicism.<sup>[11]</sup><ref name=":17" /> Alternatively, approximately 90% of women, who have the mutation on one of their two X-chromosomes, exhibit symptoms.<ref name=":17" /><ref name=":7" /><ref name=":8" /> It has been suggested that the greater occurrence of PCDH19-epilepsy in females may relate to&nbsp;[[Biology:X-inactivation|X-chromosome inactivation]], through a hypothesized mechanism termed ''cellular interference''.<ref name=":1" /><ref name=":17" />

A 2011 study found instances where patients had PCDH19 mutation, but their parents did not. They found that "gonadal mosaicism"&nbsp;of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of a mutated PCDH19 gene.<ref name=":1" /><ref name=":17" /><ref>{{Cite journal|last1=Dibbens|first1=L. M.|last2=Kneen|first2=R.|last3=Bayly|first3=M. A.|last4=Heron|first4=S. E.|last5=Arsov|first5=T.|last6=Damiano|first6=J. A.|last7=Desai|first7=T.|last8=Gibbs|first8=J.|last9=McKenzie|first9=F.|date=2011-04-26|title=Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations|journal=Neurology|language=en|volume=76|issue=17|pages=1514–1519|doi=10.1212/WNL.0b013e318217e7b6|issn=0028-3878|pmid=21519002|s2cid=25105085}}</ref>

===Genetics===
The PCDH19 gene is located on the long (q) arm of the X chromosome at position 22.1.<ref name=":0" /><ref name=":5" /><ref name=":7" /><ref name=":9" /> The gene encodes for protocadherin 19, a transmembrane protein of calcium-dependent cell-cell adhesion molecules that is strongly expressed in neural tissue, such as the hippocampus, cerebral cortex, thalamus, and amygdala.<ref name=":17" /><ref name=":7" /><ref name=":9" /> Protocadherin 19 appears to be related to synaptic transmission and formation of synaptic connections during brain development.<ref name=":7" /><ref name=":9" />

A mutation in the PCDH19 gene can cause the protocadherin 19 protein to be malformed, reduced in function or not produced at all.<ref name=":7" /> This abnormal expression of protocadherin 19 causes deficits in [[Biology:GABAergic|GABAergic]] signaling, causing the occurrence of seizures beginning in the early years of life.<ref name=":7" />

The expression of the PCDH19 mutation is highly variable, with some individuals appearing unaffected, and others showing severe disease.<ref name=":1" /> Even monozygotic twins with the mutation may have variations in seizure frequency and degree of cognitive impairment.<ref name=":1" />

Currently, the PCDH19 gene is the second most clinically relevant gene in the epilepsy field; the second largest number of epilepsy related mutations characterized thus far occur in the PCDH19 gene.<ref name=":0" /><ref name=":1" /><ref name=":9" /><ref name=":10" /> The SCN1A gene, associated with Dravet Syndrome, is the most clinically relevant.<ref name=":12">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK1318/|title=SCN1A-Related Seizure Disorders|last1=Miller|first1=Ian O.|last2=Sotero de Menezes|first2=Marcio A.|chapter=SCN1A Seizure Disorders|date=1993-01-01|publisher=University of Washington, Seattle|editor-last=Pagon|editor-first=Roberta A.|location=Seattle (WA)|pmid=20301494|editor-last2=Adam|editor-first2=Margaret P.|editor-last3=Ardinger|editor-first3=Holly H.|editor-last4=Wallace|editor-first4=Stephanie E.|editor-last5=Amemiya|editor-first5=Anne|editor-last6=Bean|editor-first6=Lora J.H.|editor-last7=Bird|editor-first7=Thomas D.|editor-last8=Fong|editor-first8=Chin-To|editor-last9=Mefford|editor-first9=Heather C.}}</ref><ref>{{Cite journal|last1=Sugawara|first1=Takashi|last2=Tsurubuchi|first2=Yuji|last3=Agarwala|first3=Kishan Lal|last4=Ito|first4=Masatoshi|last5=Fukuma|first5=Goryu|last6=Mazaki-Miyazaki|first6=Emi|last7=Nagafuji|first7=Hiroshi|last8=Noda|first8=Masaharu|last9=Imoto|first9=Keiji|date=2001-05-22|title=A missense mutation of the Na+ channel αII subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction|journal=Proceedings of the National Academy of Sciences|language=en|volume=98|issue=11|pages=6384–6389|doi=10.1073/pnas.111065098|issn=0027-8424|pmc=33477|pmid=11371648|bibcode=2001PNAS...98.6384S|doi-access=free}}</ref>

==Diagnosis==
PCDH19 gene-related epilepsy is clinically based on patient and family seizure history, cognitive and behavioral neuropsychological evaluation, neurological examination, [[Biology:Electroencephalography|electroencephalogram (EEG)]] studies, and long term observation. Diagnosis is confirmed using molecular testing for PCDH19 mutations.<ref name=":10" /><ref name=":12" />

===Diagnostic test===
The test is particularly indicated in children who have had cluster seizures in series. It is also recommended for patients who are diagnosed GEFS+ and when the seizures are associated with fever, infection, experienced regression, delayed cognitive growth or behavioral problems. The test is typically ordered by&nbsp;neurologists. The diagnostic test can be done by drawing blood or saliva of the patient and their immediate family. It is analyzed in laboratories that specialize in&nbsp;[[Medicine:Genetic testing|genetic testing]]. Genetic testing can aid in a firmer diagnosis and understanding of the disorder, may aid in identifying the optimal treatment plan and if positive, testing of the parents can determine if they are carriers. {{citation needed|date=December 2020}}

===Classification===
Due to its recent discovery, PCDH19 gene-related epilepsy does not have a specific classification according to the International League Against Epilepsy.

PCDH19 gene-related epilepsy is thought to develop based upon a deficiency of the calcium-dependent cell-adhesion PCDH19 (protocadherin 19) gene.<ref name="PCHD19">{{cite journal |title= PCDH19 Gene |journal= Genetic Home Reference |url= http://ghr.nlm.nih.gov/gene/PCDH19 |access-date= December 30, 2011 |archive-date= July 5, 2013 |archive-url= https://web.archive.org/web/20130705012406/http://ghr.nlm.nih.gov/gene/PCDH19 |url-status= dead }}</ref>{{#tag:ref|Cell adhesion is mediated by cell surface proteins.|group="nb"}} Its cause and [[Medicine:Pathophysiology|pathophysiology]] (cause and mechanisms by which damage occurs) are different from other epilepsies, although the symptoms are very similar to other epileptic syndromes, such as [[Medicine:Generalized epilepsy with febrile seizures plus|Generalized epilepsy with febrile seizures plus]] (GEFS+), Dravet syndrome with SCN1A negative, FIRES (febrile infection–related epilepsy syndrome) Lennox-Gastaut syndrome or epilepsy of unknown origin.<ref name="firessyndrome">{{cite journal|date=November 2011|title=Acute-onset epilepsy triggered by fever mimicking FIRES febrile infection–related epilepsy syndrome: The role of protocadherin 19 (PCDH19) gene mutation|journal=Epilepsia|volume=52|issue=11|pages=e172–e175|doi=10.1111/j.1528-1167.2011.03193.x|author1=Nicola Specchio|author2=Lucia Fusco|author3=Federico Vigevano|pmid=21777234|s2cid=35858941|doi-access=free}}</ref>

==Treatment==

===Medication===
Antiepileptic drugs&nbsp;(AEDs) are used in most cases to control seizures, however, PCDH19 gene-related epilepsy is generally associated with early-onset development of drug resistant seizures.<ref name=":5" /><ref name=":17" /><ref name=":22" /> Existing data supports the use of "rational polypharmacy," which consists of a step-wise addition of AEDs until a patient responds favorably or experiences intolerable adverse events.<ref name=":5" /> In general, as in other types of uncontrolled epilepsy, the use of drugs with different mechanisms of action appears to be more effective than combining drugs with similar mechanisms of action.<ref name=":5" />

No currently marketed AEDs have been extensively studied in PCDH19 gene-related epilepsy and there is no established treatment strategy for girls diagnosed with PCDH19 gene-related epilepsy.<ref name=":22" /><ref name=":12" /> Patients may respond well to treatment with [[Chemistry:Levetiracetam|levetiracetam]] and in cases of drug resistance, [[Chemistry:Stiripentol|stiripentol]], which is not approved in the U.S. but is available through the FDA Expanded Access IND process.<ref name=":1" /><ref name=":12" /> Seizures might be easier to control with age, especially after the second decade of life. However, some publications have shown that medication withdrawal is highly associated with seizure recurrence.<ref>{{Cite journal|last1=Aledo-Serrano|first1=Ángel|last2=Ser|first2=Teodoro del|last3=Gil-Nagel|first3=Antonio|date=2020-06-05|title=Antiseizure medication withdrawal in seizure-free patients with PCDH19-related epilepsy: a multinational cohort survey|url=https://www.seizure-journal.com/article/S1059-1311(20)30169-2/abstract|journal=Seizure: European Journal of Epilepsy|volume=80|pages=259–261|language=en|doi=10.1016/j.seizure.2020.06.007|pmid=32682289|s2cid=219559784|issn=1059-1311|doi-access=free}}</ref>

===Urgent care===
At the hospital, physicians follow standard protocol for managing seizures. Cluster seizures are generally controlled by&nbsp;benzodiazepines&nbsp;such as&nbsp;[[Chemistry:Diazepam|diazepam]],&nbsp;[[Chemistry:Midazolam|midazolam]],&nbsp;[[Chemistry:Lorazepam|lorazepam]]&nbsp;or&nbsp;[[Chemistry:Clonazepam|clonazepam]]. The use of&nbsp;[[Chemistry:Oxygen therapy|oxygen]] is recommended in the United States, but in Europe it is only recommended in cases of prolonged epileptic status.<ref>{{Cite web|url=http://www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm|title=The Epilepsies and Seizures: Hope Through Research|website=www.ninds.nih.gov|access-date=2016-08-22}}</ref>

==Epidemiology==
[[File:Prevalence of different gene mutations in genetic epilepsies according to literature data by year 2020.jpg|450px|thumb|right|According to data collected by 2020, [[Biology:Protocadherin 19|PCDH19]] (orange) was among the six genes most involved in genetic epilepsies. From a review by Giovanni Battista Dell'Isola et al., 2021.<ref name="pmid35111125">{{cite journal | vauthors = Dell'Isola GB, Vinti V, Fattorusso A, Tascini G, Mencaroni E, Di Cara G, Striano P, Verrotti A | title = The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation | journal = Frontiers in Neurology | volume = 12 | issue = | pages = 780053 | date = 2021 | pmid = 35111125 | pmc = 8801579 | doi = 10.3389/fneur.2021.780053 | url = | doi-access = free }}</ref> ]]

The National Institute of Health Office and Rare Disease Research characterizes PCDH19 gene-related epilepsy as a rare disorder.<ref name=":4" /> Rare diseases, by definition, are diseases that affect fewer than 200,000 people in the United States. Since the mutation associated with PCDH19 gene-related epilepsy was only recently identified in 2008, the true incidence of the disease is generally unknown.<ref name=":7" />

Although formal epidemiologic data is not available, results from diagnostic screening indicates that approximately 1 out of 10 girls who have seizure onset before five years of age may have PCDH19 gene mutations.<ref name=":5" /><ref name=":6" /><ref name=":17" /> Additionally, PCDH19 screening of several large cohorts of females with early onset febrile-related epilepsy has resulted in a rate of approximately 10% of mutation-positive individuals.<ref name=":17" /><ref name=":10" /><ref name=":12" />

==History==

Juberg and Hellman originally described the disorder in 1971 in the&nbsp;''Journal of Pediatrics'', where they reported a family in which 15 female relatives, who were related either as sisters or first cousins through their fathers, had early onset seizures with cognitive impairments.<ref name=":0" /><ref name=":4" /><ref name=":22" /> In subsequent peer-reviewed literature, the disorder was referred to as "epilepsy and mental retardation limited to female" (EFMR), and later called EIEE9 or Juberg-Hellman Syndrome.<ref name=":0" /><ref name=":4" /><ref name=":7" /> The&nbsp;[[Medicine:Syndrome|syndrome]]&nbsp;in this family was characterized by the occurrence of childhood seizures. Some of the girls showed developmental regression with intellectual disabilities that ranged from mild to profound. The disorder has an unusual inheritance pattern. It is considered&nbsp;X-linked&nbsp;dominant with male carriers. Women and men with the affected gene can transmit the disease. The men expressed a normal&nbsp;[[Biology:Phenotype|phenotype]]. The disorder was shown to be linked to&nbsp;[[Biology:Mutation|mutation]]s&nbsp;via Xq22&nbsp;[[Biology:Microsatellite|microsatellite]]&nbsp;markers.[[Medicine:Epilepsy-intellectual disability in females#cite note-23|<sup>[nb 4]</sup>]] [[Medicine:Epilepsy-intellectual disability in females#cite note-scheffer-4|<sup>[4]</sup>]]

Due to the apparent female-limited expression of the condition, it eluded genetic mapping until 1997, which is when Ryan et al. mapped the responsible gene to the X-chromosome.<ref name=":13">{{Cite journal|last1=Tan|first1=Chuan|last2=Shard|first2=Chloe|last3=Ranieri|first3=Enzo|last4=Hynes|first4=Kim|last5=Pham|first5=Duyen H.|last6=Leach|first6=Damian|last7=Buchanan|first7=Grant|last8=Corbett|first8=Mark|last9=Shoubridge|first9=Cheryl|date=2015-09-15|title=Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency|journal=Human Molecular Genetics|language=en|volume=24|issue=18|pages=5250–5259|doi=10.1093/hmg/ddv245|issn=0964-6906|pmid=26123493|doi-access=free}}</ref>

Eleven years after the success of Ryan et al., in 2008, systematic sequencing of X-chromosome exons in seven large families diagnosed with EFMR revealed PCDH19 gene mutations as the cause. This led to a shift in describing EMFR as PCDH19 gene-related epilepsy.<ref name=":5" /><ref name=":8" /><ref name="scheffer" /><ref name=":10" /><ref name=":13" /> The discovery of the PCDH19 gene mutation led to the development of a genetic test for PCDH19 gene-related epilepsy.{{citation needed|date=December 2020}}

In 2009, Depienne et al. identified a male with a [[Biology:Mosaic (genetics)|somatic mosaicism]] for PCDH19 gene deletion and a Dravet-like seizure disorder.<ref name=":5" /><ref name=":17" /><ref name=":13" /><ref name=":23">{{Cite journal|last1=Terracciano|first1=Alessandra|last2=Trivisano|first2=Marina|last3=Cusmai|first3=Raffaella|last4=De Palma|first4=Luca|last5=Fusco|first5=Lucia|last6=Compagnucci|first6=Claudia|last7=Bertini|first7=Enrico|last8=Vigevano|first8=Federico|last9=Specchio|first9=Nicola|date=2016-03-01|title=PCDH19-related epilepsy in two mosaic male patients|journal=Epilepsia|language=en|volume=57|issue=3|pages=e51–e55|doi=10.1111/epi.13295|issn=1528-1167|pmid=26765483|doi-access=free}}</ref><ref name=":24">{{Cite journal|last1=Thiffault|first1=Isabelle|last2=Farrow|first2=Emily|last3=Smith|first3=Laurie|last4=Lowry|first4=Jennifer|last5=Zellmer|first5=Lee|last6=Black|first6=Benjamin|last7=Abdelmoity|first7=Ahmed|last8=Miller|first8=Neil|last9=Soden|first9=Sarah|date=2016-06-01|title=PCDH19-related epileptic encephalopathy in a male mosaic for a truncating variant|journal=American Journal of Medical Genetics Part A|language=en|volume=170|issue=6|pages=1585–1589|doi=10.1002/ajmg.a.37617|issn=1552-4833|pmid=27016041|s2cid=36753614}}</ref> The findings resulted in Depienne et al. to identify PCDH19 mutations in patients with SCN1A negative Dravet syndrome.<ref name=":5" /><ref name=":17" /><ref name=":13" /> This led to additional reports of PCDH19 positive patients, which broadened the clinical spectrum of the disorder.<ref name=":13" /><ref name=":23" /><ref name=":24" />

== Society and culture ==
Caregivers of individuals living with PCDH19 gene-related epilepsy may seek support and information from a variety of resources, including the PCDH19 Alliance, The Cute Syndrome Foundation, and Insieme per la Ricerca PCDH19 - ONLUS (Italy).{{citation needed|date=December 2020}}

The PCDH19 World Conference, which is organized by Insieme per la Ricerca PCDH19 - ONLUS, occurs every other year, in odd years, in Rome, Italy. In alternating years, the PCDH19 Epilepsy Professional and Family Symposium is hosted in San Francisco, California.{{citation needed|date=December 2020}}

In 2014, the PCDH19 Registry was established, which is organized and funded by the PCHD19 Alliance, Boston Children's Hospital and the University of California, San Francisco.<ref name=":2" /> International PCDH19 Awareness Day is held annually on November 9.{{citation needed|date=December 2020}}

==Research==

=== Registry ===
A PCDH19 Registry was established by the PCDH19 Alliance, Boston Children's Hospital and the [[Organization:University of California, San Francisco|University of California, San Francisco]], to provide a meaningful resource of patients with PCDH19 gene-related epilepsy and to better understand the epilepsy and behavioral aspects associated with the mutation.<ref name=":2" /><ref name=":14">{{Cite web|url=http://www.childrenshospital.org/centers-and-services/epilepsy-genetics-program/research-and-innovation|title=Epilepsy Genetics Program {{!}} Research and Innovation|website=www.childrenshospital.org|access-date=2016-08-22}}</ref>

Parallel associations European families are sponsoring basic and applied research in an Australian team and researching in other projects with the aim of finding a drug target for epilepsy PCDH19.<sup>[28]</sup>

=== Basic research ===
Ann Poduri and Alex Rotenberg at Boston Children's Hospital are currently conducting PCDH19-related epilepsy in zebrafish.<ref name=":14" /><ref name=":15">{{Cite web|url=http://www.thecutesyndrome.com/research.html|title=PCDH19 and SCN8A Research Funded By The Cute Syndrome|website=The Cute Syndrome Foundation: Funding PCDH19 Epilepsy&nbsp;&<br />SCN8A&nbsp;Epilepsy&nbsp;Research|access-date=2016-08-22}}</ref> The research, which is funded by grants from The Cute Syndrome Foundation and The Richard A. and Susan F. Smith President's Innovation Fund of Boston Children's Hospital, hopes to establish an animal model of PCDH19 gene-related epilepsy, which can then be used to screen potential therapeutics and treatments.<ref name=":14" /><ref name=":15" />

Dr. Jack Parent and his research team at the [[Organization:University of Michigan|University of Michigan]] are currently conducting research to understand how PCHD19 gene mutations leads to disruptions in brain development.<ref name=":16">{{Cite web|url=http://pcdh19info.org/research/|title=RESEARCH - PCDH19 Alliance|website=PCDH19 Alliance|language=en-US|access-date=2016-08-22}}</ref><ref name=":18">{{Cite web|url=http://www.thecutesyndrome.com/news.html|title=News about PCDH19 Epilepsy and SCN8A Epilepsy and The Cute Syndrome Foundation|website=The Cute Syndrome Foundation: Funding PCDH19 Epilepsy&nbsp;&<br />SCN8A&nbsp;Epilepsy&nbsp;Research|access-date=2016-08-22}}</ref> The research, funded by a grant from The Cute Syndrome Foundation, is seeking to reprogram fibroblasts from subjects with the PCHD19 mutation into [[Biology:Induced pluripotent stem cell|induced pluripotent stem cell]]s (iPSC), which will then be used to make patient-specific neurons in a cell culture environment.<ref name=":16" /><ref name=":18"/> The researchers are looking to see if these patient-specific neurons produce epileptic-like activity, as well as to discover the mechanism underlying the seizures and cognitive dysfunction associated with PCDH19 mutations.<ref name=":16" /><ref name=":18"/>

The Cute Syndrome Foundation and Insieme per la Ricerca PCDH19 - ONLUS recently awarded a two-year research grant to Drs. Maria Passafaro and Elena Battaglioli, from the CNR Neuroscience Institute and University of Milano, respectively.<ref name=":18"/><ref name=":19">{{Cite web|url=http://www.pcdh19research.org/ENG/news_iniziative_ENG.html|title=Insieme per la Ricerca PCDH19 – ONLUS|website=www.pcdh19research.org|access-date=2016-08-22|archive-url=https://web.archive.org/web/20160726105421/http://www.pcdh19research.org/ENG/news_iniziative_ENG.html|archive-date=2016-07-26|url-status=dead}}</ref> The researchers plan to unravel the molecular mechanism of PCDH19 gene mutations.<ref name=":18" /><ref name=":19" />  The proposal also includes using AON exon skipping, which would be the first use of this method in epilepsy.<ref name=":18" /><ref name=":19" />

Parallel associations European families are sponsoring basic and applied research in an Australian team and researching in other projects with the aim of finding a drug target for epilepsy PCDH19.<ref name="researchau">PCDH19 Association "Insieme per la Ricerca PCDH19"</ref>{{clarify|date=December 2011}}

=== Gene therapy ===
It was assumed that all encephalopathies or cognitive impairments were irreversible, but an experiment with mice showed that is not always the case.<ref>{{Cite journal|last1=Guy|first1=Jacky|last2=Gan|first2=Jian|last3=Selfridge|first3=Jim|last4=Cobb|first4=Stuart|last5=Bird|first5=Adrian|date=2007-02-23|title=Reversal of Neurological Defects in a Mouse Model of Rett Syndrome|journal=Science|language=en|volume=315|issue=5815|pages=1143–1147|doi=10.1126/science.1138389|issn=0036-8075|pmid=17289941|bibcode=2007Sci...315.1143G|pmc=7610836}}</ref>&nbsp;In that experiment, MECP2 protein was blocked; males died, and females developed Rett syndrome (seizures, cognitive and psychomotor problems, respiratory problems, etc.) When the researchers reversed the situation and let the MECP2 protein work properly, the mice recovered.<sup>[''clarification needed'']</sup>&nbsp;This research revolutionized understanding regarding genetic syndromes that present with neurological impairment or intellectual disabilities.{{cn|date=September 2023}}

=== Therapeutics ===
In February 2015, Marinus Pharmaceuticals commenced a Phase 2 proof-of-concept clinical trial to evaluate the safety and efficacy of [[Biology:Ganaxolone|ganaxolone]], a synthetic analog of the neurosteroid [[Biology:Allopregnanolone|allopregnanolone]], for the treatment of uncontrolled seizure in pediatric females with PCDH19 gene-related epilepsy.<ref name=":20">{{Cite web|url=http://ir.marinuspharma.com/releasedetail.cfm?ReleaseID=894284|title=Marinus Pharmaceuticals Initiates Clinical Trial With Ganaxolone in PCDH19 Female Pediatric Epilepsy (NASDAQ:MRNS)|website=ir.marinuspharma.com|access-date=2016-08-22}}</ref><ref name=":21">{{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT02358538?term=NCT02358538&rank=1|title=A Multicenter, Open-Label Proof-of-Concept Trial of Ganaxolone in Children With PCDH19 Female Pediatric Epilepsy - Full Text View - ClinicalTrials.gov|website=clinicaltrials.gov|access-date=2016-08-22}}</ref> The study will enroll up to 10 female pediatric patients, between the ages of 2 and 10 years old, with a confirmed PCDH19 genetic mutation.<ref name=":16" /><ref name=":18"/><ref name=":21" /> The primary endpoint of the study is percent change in seizure frequency per 28 days relative to baseline.<ref name=":20" /><ref name=":21" />

The Epilepsies Research Centre and Department of Medicine, University of Melbourne, are working on a compound to treat this disease. On May 26, 2011, it patented a method of diagnosis and PCDH19 gene-related epilepsy treatment.<ref>{{cite patent|country=US|number=US 2011/0126302 A1|status=pending|title=[http://www.google.es/patents/about?id=foDmAQAAEBAJ Diagnostic and Therapeutic Methods for EFMR (Epilepsy and Mental Retardation]|pubdate=May 26, 2011|gdate=|fdate=January 5, 2009|pridate=|inventor=Dibbens, L.M.; Scheffer, I.; Berkovic, S.F.; Mulley, J.C.; Geez, J|invent1=|invent2=|assign1=|assign2=|class=}}</ref>

==Notes==
{{Reflist|group=nb}}

==References==
{{Reflist}}

== External links ==
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[[Category:Syndromes affecting the nervous system]]

{{Sourceattribution|Epilepsy-intellectual disability in females}}