Epilepsy-intellectual disability in females
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 predominantly 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.
[8] 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.
[4][5][6][7] 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.
[11] 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.
[11][18] 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.
[18] 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.
[6][13][14][17] Other neurological abnormalities may present, including sleep disturbances, ictal apnea, motor deficits, hypotonia, language delay, sensory integration problems and dysautonomia.
[11][12][13][14] 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.
[14] 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.
[11][12][13] It has been suggested that the greater occurrence of PCDH19-epilepsy in females may relate to X-chromosome inactivation, through a hypothesized mechanism termed cellular interference.
[23] 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.
[24][25] PCDH19 gene-related epilepsy is clinically based on patient and family seizure history, cognitive and behavioral neuropsychological evaluation, neurological examination, electroencephalogram (EEG) studies, and long term observation.
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.
[16][24] Patients may respond well to treatment with levetiracetam and in cases of drug resistance, stiripentol, which is not approved in the U.S. but is available through the FDA Expanded Access IND process.
[12] 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.
[9][10][11] 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.
[4][8][16] 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.
[32] 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.
[32][33][34] 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] 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.
[37][38] 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.
[37][38] The Cute Syndrome Foundation and Insieme per la Ricerca PCDH19 - ONLUS recently awarded a two-year research grant to Drs.
[clarification needed] This research revolutionized understanding regarding genetic syndromes that present with neurological impairment or intellectual disabilities.
[42][43] The Epilepsies Research Centre and Department of Medicine, University of Melbourne, are working on a compound to treat this disease.
