UPDATES IN PROGRESS: We’re currently working on updating this section. Please check back soon!
Also called
- EIEE9
- Early infantile epileptic encephalopathy type 9
- EFMR
- Juberg-Hellmann syndrome
Scientific background
Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of 75 genetically distinct severe epilepsies (EIEE1-EEIE75) (as of mid-2019) that begin in the first year of life, predominantly between the 2nd and 10th month of life. Frequent tonic seizures with a specific suppression-burst pattern in the EEG are characteristic. 75% of patients with EIEE develop West syndrome, which is characterized by BNS seizures with hypsarrhythmia in the EEG and developmental arrest. X-linked epilepsy with intellectual disability (EIEE9), also known as epilepsy and mental retardation limited to females (EFMR), was first described in 1971 in a family with 15 affected female patients. In 2008, the gene locus was localized to chromosome Xq22 based on further families. The first seizures occurred before the age of 14 months and were often associated with fever.
Symptoms
The types of seizures include tonic-clonic, tonic, partial, atonic, myoclonic, and absence seizures. Developmental delay and intellectual development can be highly variable.
Causes
X-linked epilepsy with intellectual disability is caused by pathogenic variants in the protocadherin 9 (PCDH19) gene. Protocadherin 9 is expressed during brain development and is the first member of the cadherin family to be altered in epilepsy and mental retardation. To date, more than 200 different pathogenic PCDH19 variants have been described. Genomic deletions within the Xq22.1 region, involving the entire PCDH19 gene or multiple exons, have been identified in 3% of female patients. Only heterozygous carriers of pathogenic variants are affected, while hemizygous male carriers are asymptomatic. This unusual mode of inheritance of an X-linked disorder is referred to as cellular interference. While clinically unremarkable male carriers only have cells with pathogenic PCDH19 variants, the presence of cells with and without pathogenic PCDH19 variants in the female organism due to random X inactivation results in mosaics that only then have a pathogenic effect.
The literature describes isolated cases of symptomatic male patients with a pathogenic PCDH19 variant, in whom this was also present as a mosaic. This confirms the mechanism according to which cells with and without the pathogenic variant must be present for the disease to develop.
References
Liu et al. 2019, J Med Genet 56): 81 / Gerosa et al. 2019. , Dev Neurobiol 79: 75 / de Lange et al. 2017, Neurogenetics 18: 147 / Duszyc et al. 2015, J Appl Genet 56: 49 / Depienne et al. 2012, Hum Mutat 33:627 / Depienne et al. 2011, Hum Mutat. 32:E1959 / Hynes et al. 2010, Med Genet 47,:211 / Depienne et al. 2009, PLoS Genet 5:e1000381 / Marini 2010, Neurology 75, 646 / Dibbens 2008, Nat Genet 40, 776 / Juberg et Hellman 1971, J Pediat 79:726
