Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders

Abstract

Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.

Role of long purine stretches in controlling the expression of genes associated with neurological disorders

“…The present finding of downregulation of RBFOX1 (Table 2) supports its critical role in controlling the expression of number of genes in epilepsy. It is also interesting to note that mutations observed in PCDH19 PR-gene (van Harssel et al, 2013), calcium dependent cell adhesion protein which is primarily expressed in brain, could have been induced by PRs.…”

“…play a possible role in causing intellectual disability and seizure(van Harssel et al, 2013) (van Harssel et al, 2013 and duplication in GRIA3 showed to affect intellectual disability(Wu et al, …”

PCDH19-related epilepsy: a rare but recognisable clinical syndrome in females

“…The key clinical characteristics of this rare epilepsy syndrome are the early onset (mean age 9–10 months6) of fever-associated seizures and prominent seizure clusters 7. Patients develop several different seizure types, most commonly tonic–clonic or tonic, but occasionally atonic and absence seizures.…”

Etiologies for Seizures Around the Time of Vaccination

“…Eight children (cases 4-11) were diagnosed with Dravet syndrome (previously described 17 ) and had a pathogenic SCN1A mutation. One girl (case 12) had epilepsy and mental retardation restricted to female subjects and a de novo protocadherin 19 (PCDH19) mutation (described as case 7 in van Harssel et al 28 Five of the 8 children had fever-sensitive epilepsy classified as febrile seizures plus (cases 16 and 19-22). In 3 children, a (grand)parent had had febrile seizures as well, consistent with a diagnosis of genetic epilepsy with febrile seizure plus (GEFS+) syndrome.…”