Epilepsy in females with mental retardation
|Epilepsy Female restricted with/without Mental Retardation|
|Classification and external resources|
Epilepsy-intellectual disability in females, also called Juberg-Hellman Syndrome and Epilepsy Limited to Females with Intellectual Disability (EFID), has been identified through the incidence of female seizure sufferers in a family over several generations. The first family was reported in 1971 in the Journal of Pediatrics. The striking pattern of onset at a young age, seizure patterns, test and laboratory results, potential developmental delays or developmental regression and associated disorders, eases diagnosis. Genetic markers have not yet been developed to an extent that they can be used for diagnosis in individual cases or small families.
A study conducted at the Epilepsy Research Centre at the University of Melbourne's Department of Medicine estimated in 2007 that two thirds of EFMR patients have borderline intellectual functioning or intellectual disability. There appears to be a connection to depression, autism, obsessive and aggressive behaviors and other psychiatric disorders.
- 1 Studies
- 2 Causes
- 3 Classification
- 4 Treatment
- 5 Research
- 6 Notes
- 7 References
- 8 External links
EFMR was first described in a family in North America in 1971 in the Journal of Pediatrics and twice in the 1990s.[nb 1] The syndrome 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 X-linked dominant with male carriers. Women and men with the affected gene can transmit the disease. The men expressed a normal phenotype. The disorder was shown to be linked to mutations via Xq22 microsatellite markers.[nb 2]
University of Melbourne study
Published in 2007, a study was completed of four families with 58 individuals by the Epilepsy Resource Centre at the University of Melbourne. The study included CT Scan and MRI imaging, electroencephalogram (EEG) testing, neurological exams, intellectual assessment and questionnaires to identify seizure history. It was found that the EFMR seizures generally began in females when they were infants, with mean onset at 14 months. They were likely to include an accompanying fever and may include convulsions. Seizures were of various types[nb 3] and appeared in clusters. Many seizures of short duration occur over a period of several days. The EEG test results showed "generalized and focal epileptiform abnormalities." Obsessive and aggressive behavioral characteristics and autistim were common associated disorders.
Over the course of female patients' childhoods, intellectual development was delayed in some cases, normal and then regressive in others and in some cases there was normal intellectual development. 67% of the females had mild to profound intellectual disability (ID) or borderline intellectual functioning. Some of the patients in the study were also with Angelman syndrome, sodium channelopathies or forms of Rett syndrome. The EFMR seizures generally ended later in the girl's childhood (mean age of 12 years), yet some continued into adulthood. Men and women are carriers of the disorder, although men do not generally exhibit EFMR history such as seizures and intellectual development issues, although 5 fathers in the 4 families had obsessive and controlling tendencies. The linkage of chromosome Xq22.1 to EFMR was confirmed in all of the families.
Other recent studies, such as L.M. Dibbens's work as reported in Neurology in 2011 that found instances where patients had PCDH19 mutation, but their parents did not. They found that "gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of EFMR.
A study in Denmark of 18 unrelated females was reported in 2011 in Epilepsia by Dr. Hellen Hjalrim and others. One-third of subjects who exhibited early-onset EFMR-like symptoms had the PCDH19 mutations. Four men and women had the mutation but no symptoms. Most (15/18) had tested negative for SCN1A previously. They discovered a correlation between some females with early onset seizures and EFMR, based upon the presence of PCDH19 mutations. A study in Japan of 116 individuals was reported with similar findings.
Although classified as a rare disease, eleven early studies indicate that between 5% and 10% of children with febrile seizures could have the PCDH19 gene.
Men and women can transmit the PCDH19 mutation, although women but not men usually exhibit symptoms. Women with a mutation have a 50% chance of having children who are carriers. Males have a 100% chance of transmitting the mutation to a daughter and 0% chance to a son. The striking pattern of onset at a young age, seizure patterns, test and laboratory results, potential developmental delays or developmental regression and associated disorders makes diagnosis more certain. Through the identification of the genetic markers in studied families, diagnosis of an individual can be made through genetic testing.
Possible association with immunizations
There appears to be an association in some cases between vaccinations and seizures with patients with Dravet syndrome (DS), Generalized epilepsy with febrile seizures plus (GEFS+) and seizures in females with mental retardation (EFMR). An Italian multicentric study of the relationship between vaccinations and seizure occurrence found that vaccines were a trigger for seizures in 25% of the studied cases, but do not appear to affect the progression of seizures over time.
Due to its recent discovery, EFMR does not have a specific classification according to the International League Against Epilepsy. Scheffer proposed at the XXIX International Congress of Epilepsy in Rome in August 2011 that this form of epilepsy be grouped with genetic epilepsies.
EFMR is thought to develop based upon a deficiency of the calcium-dependent cell-adhesion PCDH19 (protocadherin 19) gene.[nb 4] Its etiology and 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 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.
It occurs almost exclusively in girls, has been associated with febrile seizures or following immunization in the first stage of life, normally before three years old. Vaccines can trigger (not cause) seizures, especially the vaccine for pertussis-diphtheria-tetanus, as happens with Generalized epilepsy with febrile seizures plus (Dravet Syndrome).
Seizures often occur with fever and/or convulsions and manifest in episodes of cluster seizures (many seizures in a day), and onset is usually before three years of age. Reversal of acquired intellectual capability over the course of childhood is possible, generally within three years of EFMR onset. Individuals with EFMR as GEFS+ present with a range of seizure types (partial, tonic, tonic-clonic, myoclonus, absences and atonic seizures).
The test is particularly indicated in girls 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 ordered by 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 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. (See Genetic Counseling)
From the University of Melbourne study, two thirds of EFMR patients have borderline intellectual functioning or intellectual disability, while one third have normal intelligence. A connection to depression, autism, obsessive and aggressive behaviors and other disorders has been observed.
It is not yet clear why some people experience delayed intellectual growth and others regress with epilepsy. Currently researchers disagree, some believing that the genetic load is responsible for developmental disorders and that seizures in themselves are not capable of causing brain damage if they are not prolonged.
Antiepileptic drugs (AEDs) are used in most cases to control seizures, but severe cases express high drug resistance. Patients may respond well to treatment with levetiracetam and in cases of drug resistance, an alternative treatment is stiripentol. ganaxolone is a neurosteroid that is currently in Phase III clinical trials and may offer an alternative therapy. No specific protocol or published research specifically supports the use of these drugs. All information about drug therapy here are from the experience of experts in the last International Epilepsy Congress.
At the hospital, physicians follow standard protocol for managing seizures. Cluster seizures are generally controlled by benzodiazepines such as diazepam, midolazam, lorazepam or clonazepam. The use of oxygen is recommended in the United States, but in Europe it is only recommended in cases of prolonged epileptic status.
The Epilepsies Research Centre and Department of Medicine, University of Melbourne, are working on a molecule to cure the disease. On May 26, 2011 it patented a method of diagnosis and EFMR treatment.
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.[clarification needed]
Until Dr. Adrian Bird´s experiment with mice, it was assumed that all encephalopathies or cognitive impairments was irreversible, but Dr. Bird showed that is not always the case. During the experiment Bird blocked MECP2 protein and males died and females developed Rett syndrome (seizures, cognitive and psychomotor problems, respiratory problems, etc.) When the researcher reversed the situation and let the MECP2 protein work properly, the mice recovered. This research revolutionized understanding regarding genetic syndromes that present with neurological impairment or intellectual disabilities. Ethical considerations affect human experimentation that do not affect mice experiments.
- EFMR was first described in three consecutive reports: 1) Juberg, R.C.; Hellman, C.D. "A new familial form of convulsive disorder and mental retardation limited to females." Journal of Pediatrics 1971;79:726-32.; 2) Fabisiak, K.; Erickson, R.P. "A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms.Clinical Genetics. 1990;38:353-8.; 3) Ryan SG, et. al. "Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing." Nature Genetics 1997;17:92-5.
- The disorder that affected the families was shown to be linked to genetic mutations via Xq22 markers. The discovery was reported in two publications: 1) Ryan, S.G.; et al. "Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing." Nature Genetics 1997;17:92-5. 2) Dibbens, L.M (2010). "Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations". neurology.org.
- including partial, tonic, tonic-clonic, myoclonus, absences and atonic seizures.
- Cell adhesion is mediated by cell surface proteins.
- Stevenson RE, Holden KR, Rogers RC, Schwartz CE (May 2012). "Seizures and X-linked intellectual disability". Eur J Med Genet 55 (5): 307–12. doi:10.1016/j.ejmg.2012.01.017. PMC 3531238. PMID 22377486.
- Carol Perez-Iratxeta, Peer Bork, and Miguel A. Andrade. "Genes2Diseases database".
- "Online Mendelian Inheritance in Man® An Online Catalog of Human Genes and Genetic Disorders".
- Scheffer, Ingrid, et al. (2007). "Epilepsy and mental retardation limited to females: an under-recognized disorder". Brain: A Journal of Neurology (Oxford Journals) 131 (4): 918–927. doi:10.1093/brain/awm338.
- Reutens, D.C; et al. (Nov–Dec 1992). "Validation of a questionnaire for clinical seizure diagnosis.". Epilepsia 33 (6): 1065–71. doi:10.1111/j.1528-1157.1992.tb01760.x. PMID 1464265.
- Marini C (June 29, 2010). "Infantile onset focal epilepsy and epilepetic encephalopathies associated with PCDH19 gene mutations: New de novo and familial mutations.". 9th European Congress on Epileptology: 1. doi:10.1111/j.1528-1167.2010.02658.x.
- Specchio, N. (August 24, 2011). "Stormy Onset Epilepsy in Girls with De Novo Protocadherin 19 Mutations". Epilepsia 52 (Supplement s6): 21. doi:10.1111/j.1528-1167.2011.03206.x.
- Dibbens, L.M.; et al. (April 26, 2011). "Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations". Neurology 76 (17): 1514–1519. doi:10.1212/WNL.0b013e318217e7b6.
- Hjalgrim, Hellen (August 24, 2011). "Expansion of the Phenotype associated with PCDH19 mutations". Epilepsia 52 (Supplement s6): 18. doi:10.1111/j.1528-1167.2011.03206.x.
- Higurashi, N. (November 1, 2011). "PCDH19 mutation in Japanese females with epilepsy". Epilepsy Research 99 (1-2): 28–37. doi:10.1016/j.eplepsyres.2011.10.014. PMID 22050978.
- Hardies K. (August 28, 2011). "Exploring the causative role of PCDH19 Xq22 in female patients with Epilepsy". Epilepsia 52 (Supplement 6): 23–263. doi:10.1111/j.1528-1167.2011.03207.x.
- "PCDH19". European Bioinformatics Institute of the European Molecular Biology Laboratory. 2011. Retrieved December 30, 2011.
- "PCDH19". The Human Protein Atlas, Uppsala University. 2011. Retrieved December 30, 2011.
- Scheffer, Ingrid.; et al. (2007). "Epilepsy and mental retardation limited to females: an under-recognized disorder: Genetic tree diagram". Brain: A Journal of Neurology (Oxford Journals) 131 (4): 918–927.
- Scheffer, Ingrid.; et al. (2007). "Epilepsy and mental retardation limited to females: an under-recognized disorder: Family tree of genealogical study". Brain: A Journal of Neurology (Oxford Journals) 131 (4): 918–927.
- Petrelli C; et. al (24 Aug 2011). "Relation between vaccination and occurrence of seizures in SCN1A mutation positive patients: the first Italian multicentric study". Epilepsia 52 (Supplement s6): 7. doi:10.1111/j.1528-1167.2011.03206.x.
- Specchio, Nichola (November 2011). "Acute-onset epilepsy triggered by fever mimicking FIRES febrile infection–related epilepsy syndrome: The role of protocadherin 19 (PCDH19) gene mutation". Epilepsia 52 (11): e172–e175. doi:10.1111/j.1528-1167.2011.03193.x.
- Brown, Natasha; Berkovic, Samuel F.; Scheffer, Ingrid E (April 2007). "Vaccination, seizures and 'vaccine damage'". Current Opinion in Neurology 20 (2): 181–187. doi:10.1097/WCO.0b013e3280555160.
- "PCDH19 Gene". Genetic Home Reference (Genetics Home Reference, U.S. National Library of Medicine). Retrieved December 30, 2011.
- Berg, Anne T. (January 2002). "Seizure Risk with Vaccination". Epilepsy Currents (American Epilepsy Society) 2 (1): 15–16. doi:10.1046/j.1535-7597.2002.00002.x. PMC 320893. PMID 15309176.
- "Seizures and Epilepsy: Hope Through Research". National Institute of Neurological Disorders and Stroke. Retrieved December 30, 2011.
- Seizures and Epilepsy
- 2011/0126302 A1 US pending US 2011/0126302 A1, Dibbens, L.M.; Scheffer, I.; Berkovic, S.F.; Mulley, J.C.; Geez, J, "Diagnostic and Therapeutic Methods for EFMR (Epilepsy and Mental Retardation", published May 26, 2011
- PCDH19 Association "Insieme per la Ricerca PCDH19"
- Bird Adrian (February 23, 2007). "Reversal of Neurological Defects in a Mouse Model of Rett Syndrome". Science 315 (5815): 1143–1147. doi:10.1126/science.1138389. PMID 17289941.