Epilepsy-intellectual disability in females

Epilepsy-intellectual disability in females
Classification and external resources
Specialty
OMIM	300088
Patient UK	Epilepsy-intellectual disability in females

Epilepsy-intellectual disability in females also known as epileptic encephalopathy, early infantile, 9 (EIEE9), and previously called epilepsy-intellectual disability in females, 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.

Signs and symptoms

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 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 autism 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.

Developmental problems

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.

Causes

Genetics

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.

It has been suggested that the greater occurrence of PCDH19-epilepsy in females may relate to X-chromosome inactivation, through a mechanism termed ‘‘cellular interference’’.

A 2010 study, found a relationship between the PCDH19 gene and early onset female seizures, as did a 2011 study.

A 2011 study 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 found that 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 reported with similar findings.

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.

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.

Classification

Due to its recent discovery, EFMR does not have a specific classification according to the International League Against Epilepsy.

EFMR is thought to develop based upon a deficiency of the calcium-dependent cell-adhesion PCDH19 (protocadherin 19) gene. Its cause 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.

Diagnosis

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).

Diagnostic test

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)

Treatment

Drug therapy

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.

Urgent care

At the hospital, physicians follow standard protocol for managing seizures. Cluster seizures are generally controlled by benzodiazepines such as diazepam, midazolam, 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.

Epidemiology

Although classified as a rare disease, eleven early studies indicate that between 5% and 10% of children with febrile seizures could have the PCDH19 mutation.

History

EFMR was first described in a family in North America in 1971 in the Journal of Pediatrics and twice in the 1990s. 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.

Research

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 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.

It was assumed that all encephalopathies or cognitive impairments were irreversible, but an experiment with mice showed that is not always the case. 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. This research revolutionized understanding regarding genetic syndromes that present with neurological impairment or intellectual disabilities.

External links

• International Epilepsy Congress.
• Insieme per la Ricerca PCDH19 – ONLUS (Italian)
• Audio-Guide of EFMR by Ingrid Scheffer
• Video Dra. Helle Hjalgrim in Congress
• Research for PCDH19
• EFMR/PCDH19 Facebook group
• PCDH19 Alliance