Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Early Infantile Epileptic Encephalopathy (EIEE) [G40.3]

OMIM numbers: 300088300460 (PCDH19)

Dr. rer. nat. Karin Mayer

Scientific Background

Early infantile epileptic encephalopathy (EIEE) is a heterogenous group of 12, genetically different, forms of severe epilepsy (EIEE1-EEIE12). It has its onset within the first year of life, usually between the 2nd and 10th month. Frequent tonic seizures following what is known as burst suppression pattern in the EEG are typical. About 75% of all patients with EIEE develop West syndrome, which is characterized by BNS seizures with hypsarrhythmia in the EEG and a developmental arrest. Early infantile epileptic encephalopathy type 9, also known as epilepsy and mental retardation limited to females (EFMR), was already described in 1971 in a family with 15 affected female patients. In 2008, the gene location on chromosome Xq22 was identified in a study of further families. The first seizures occurred prior to 14 months of life and were frequently associated with fever. The types of seizures include tonic-clonic, tonic, partial, atonic, myoclonic and absences. The developmental delay and the intellectual development may vary significantly.

Early infantile epileptic encephalopathy is caused by mutations in the gene for protocadherin 9 (PCDH19). Protocadherin 9 is expressed during the brain development. It represents the first member of the cadherin family which is changed in epilepsy and intellectual disability. So far, 50 different PCDH19 mutations have been described; in EFMR, the frequency is estimated to be 10%. Genomic deletions containing the entire PCDH19 gene or several exons within the region of Xq22.1 were identified in 3% of all female patients. Only heterozygous female carriers are affected, while hemizygous male carriers are asymptomatic. This unusual inheritance pattern of an X-bound disease is called cellular interference. Male carriers displaying no signs or symptoms only exhibit cells with PCDH19 mutations; in the female organism, however, mosaics form due to the presence of cells with and without PCDH19 because of the random X inactivation. These mosaics then become pathogenetic. The so far only male symptomatic patient with a PCDH19 mutation also carries a mosaic, which confirms the mechanism according to which cells with and without mutation have to be present for the disease to develop.