| Epilepsy Female restricted with/without Mental Retardation | |
|---|---|
| Classification and external resources | |
| OMIM | 300088 |
Epilepsy in Females with Mental Retardation (EFMR) is suggested to be an under-recognized disorder epileptic seizure that 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. Because of the striking pattern of onset at a young age, seizure patterns, test and laboratory results, potential developmental delays or developmental regression and associated disorders, it is very easy to diagnose the disorder in a family. Through the identification of the genetic markers in studied families, diagnosis of an individual can be made through genetic testing.[1]
Based upon a study conducted by the Epilepsy Research Centre, Department of Medicine, at the University of Melbourne which was reported in the Brain: A Journal of Neurology in 2007, it is estimated that two thirds of the EFMR patients have borderline intellectual functioning or intellectual disability. There seems to be a connection to depression, autism, obsessive and aggressive behaviors, and other psychiatric disorders.[1]
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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 seizures in childhood, some of the girls showed developmental regression with intellectual disabilities that ranged from mild to profound. The disorder has an unusual inheritance pattern, is considered X-linked dominant with carriers men, where women and men with the affected gene can transmit the disease. The men were found always to have a normal phenotype. The disorder was shown to be linked to genetic mutations via the Xq22 microsatellite markers.[nb 2][1]
As published in 2007, a study was completed of four families with 58 individuals by the Epilepsy Resource Centre at the University of Melbourne which included CT Scan and MRI imaging, electroencephalogram (EEG) testing, neurological exams, intellectual assessment and use of a questionnaire to identify seizure history. It was found that the EFMR seizures generally began in females when they were young children (mean onset at 14 months), 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 that may occur over a period of several days. The EEG test results showed "generalized and focal epileptiform abnormalities." Obsessive and aggressive behavioral characteristics and autistim and were common associated disorders.[1][2]
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 childhoold (mean age of 12 years), yet some continued into adulthood.[1] Men and women are carriers of the disorder, and 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.[1]
A study in Florence, Italy by Dr. Carla Marini and others of 116 individuals, published in 2010, found a causal relationship between the PCDH19 gene and early onset female seizures,[3] as did Dr. N. Specchio and others in a study in Italy that was reported in 2011.[4]
Other recent studies, such as the study that was published by L.M. Dibbens 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."[5]
A study in Denmark of 18 unrelated females was reported in 2011 in Epilepsia by Dr. Hellen Hjalrim and others. Of the study subjects who exhibited early-onset EFMR like symptoms, one third of them had the PCDH19 mutations. 4 men and women had the mutation but no EFMR symptoms. It was found that most (15/18) had tested negative for SCN1A previously. They concluded that there seems to be a correlation between some females with early onset seizures and EFMR, based upon the presence of PCDH19 mutations.[6] A study in Japan of 116 individuals was reported with similar findings to previous studies.[7]
Although it is classified as a rare disease, 11 early studies indicate that between 5% and 10% of children with febrile seizures plus could have the PCDH19 gene. Epidemiological studies will identify the incidence of this syndrome and genetic studies in the epileptic population are required to know more about the incidence of EFMR.[8]
Men and women can transmit the PCDH19 mutation, the difference is that men do not suffer the disease and women usually suffer it. Women with a mutation have a 50% chance of having children who are carriers of PCDH19. Males however have a 100% chance of transmitting the mutation to a daughter and 0% chance to a son.[9][10] Because of the striking pattern of onset at a young age, seizure patterns, test and laboratory results, potential developmental delays or developmental regression and associated disorders, it is very easy to diagnose the disorder in a family. Through the identification of the genetic markers in studied families, diagnosis of an individual can be made through genetic testing.[1]
The European Bioinformatics Institute reports that there are 107 experiments conducted related to 73 parts of the body to better understand the PCDH19 gene.[11][12]
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+),[13] and seizures in females with mental retardation (EFMR).[14] From an Italian multicentric study of the relationship between vaccinations and seizure occurrence, vaccines were believed to be a trigger for seizures in 25% of the studied cases, but it does not appear to affect the progression of seizures over time.[13]
New vaccines that have emerged in the past 10 years have reduced the incidence of seizures following vaccination. Acellular pertussis vaccine is an example of one such vaccine.[15]
Due to it's recent discovery, it does not have a specific classification according to the International League Against Epilepsy. Dr. Ingrid 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.[16][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.[14]
It is known to occur almost exclusively in girls, has been associated with febrile seizures or following immunization in the first stage of life, normally before three years old.[1] It is known that vaccines can be the trigger (not cause) of seizures especially the vaccine for pertussis-diphtheria-tetanus, as happens with Generalized epilepsy with febrile seizures plus (Dravet Syndrome).[17]
Seizures often occur with fever and/or convulsions, manifests itself in episodes of cluster seizures (many seizures in a day), and onset is usually before three years of age. There is the possibility of reversal of acquired intellectual capability over the course of childhood, generally within three years of the onset of EFMR. Individuals with EFMR as GEFS+ present with a range of seizure types (partial, tonic, tonic-clonic, myoclonus, absences, and atonic seizures).[1][6]
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 person concerned and their immediate families. 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)
Be discarded completely (if no other cause) of epilepsy surgery and avoid an operation that can worsen the patient's condition.
From the University of Melbourne study, two thirds of the EFMR sufferers have borderline intellectual functioning or intellectual disability, and one third have normal intelligence. There seems to be a connection to depression, autism, obsessive and aggressive behaviors, and other disorders.[1]
It is not yet clear why some people experience delayed intellectual growth and others regress with epilepsy. Currently there is no consensus among researchers because some believe that the genetic load is actually responsible for developmental disorders and seizures in themselves are not capable of causing brain damage if they are not prolonged.[1][18]
Antiepileptic drugs (AEDs) are used in most of the cases to control seizures, but in severe cases there is high drug resistance. There is evidence that patients respond well to treatment with levetiracetam and in cases of drug resistance experts indicated that some patients were treated with stiripentol. Studies are being conducted for future use of galaxolona, a neurosteroid drug that is not yet marketed, which is currently in Phase III of clinical trials. It is important to note that there is still no specific protocol or published research that specifically support 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 will follow standard protocol for managing seizures. Cluster seizures will generally be controlled by benzodiazepines drugs administered by physicians, 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 team epilepsies Research Center and Department of Medicine, University of Melbourne, are working on a molecule to get a cure for the disease. On May 26, 2011 was published patent a method of diagnosis and EFMR treatment could in future be used for the treatment of disease in the future.[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.[20]
To meet the ultimate goal of stopping seizures and other developmental problems, advances are being made in clinical evaluation and diagnosis, pharmacology, pharmacogenomics, and stem cell research. Until Dr. Adrian Bird´s experiment with mice, it was assumed that all encephalopathies or cognitives impairments was irreversible, but Dr. Bird showed that is not always the case. During the experiment the researcher blocked the protein MECP2 and males mice died and females mice developed Rett syndrome (seizures, cognitive and psychomotor problems, respiratory problems, etc.). When the researcher reversed the situation and they let the MECP2 protein work properly, the mice capabilities returned. This research revolutionized understanding and hope regarding some genetic syndromes that present with neurological impairment or intellectual disabilities, bearing in mind that the mouse brain is not like the human. There are also ethical limitations when experimenting with humans do not exist in the mice experiments.[21]
