Abstracts

Rationale: Epilepsy and Mental Retardation Limited to Females (EFMR) is a rare condition in which otherwise normal female infants develop sudden onset of seizures. The clinical spectrum is broad, including a Dravet-like syndrome with multiple seizure types. The disease-causing gene was recently identified as PCDH19, which resides on the X chromosome and encodes protocadherin 19. Ictal apnea (IA) has not been reported in this syndrome, and the genetic mechanism by which alteration of PCDH19 results an atypical X-linked inheritance pattern is uncertain. Methods: Case 1: Whole genome array CGH was performed using the SignatureChip 105K oligonucleotide array (10-35 Kb spatial resolution). Case 2: Standard targeted sequence analysis of exons 1-6 of the PCDH19 gene was performed. Results: Case 1: An otherwise healthy 19 mo old girl presented with new onset seizures at age 11 mos. Initial seizure semiology was bilateral upper extremity clonic movements and unresponsiveness. Seizures were refractory to multiple AED trials but finally stopped with topiramate. At age 18 mos she had another seizure cluster with eye opening, upper extremity flexion, and profound apnea with desaturation to SaO2 of 10%. Ictal EEG revealed biposterior onset of rhythmic sharp theta activity with rapid secondary generalization. Inter-ictal EEG was normal. Brain MRI was normal. Family history was negative. CGH microarray detected a deletion in Xq21.33-Xq22.1 (estimated size 2.89-3.01 Mb), which contains the PCDH19 gene. Case 2: An otherwise healthy 22 mo girl presented with new onset seizures at age 8 mos. Initial seizure semiology was eye opening, variable extremity movements, unresponsiveness, and apnea with desaturation to a SaO2 of 50%. Seizures were refractory to multiple AED trials but ultimately controlled on phenobarbital. At age 20 months, she had another seizure cluster with similar semiology and profound ictal apnea with desaturation to SaO2 of 6%. Ictal EEG showed biposterior onset of rhythmic sharp theta activity with rapid secondary generalization. Interictal EEG was normal. Brain MRI was normal. Family history was negative. PCDH19 sequence analysis revealed heterozygosity for c.434_435insG alteration in exon 1 of the PCDH19 gene, which has not been previously reported. Conclusions: Our findings have two fundamental implications. First, profound IA is unusual and has not been described in the setting of a specific epilepsy syndrome outside of the neonatal period. These two cases suggest IA may be a unique seizure type in children with PCDH19 related epilepsy. Additional cases are necessary to determine the strength of this association. Second, previous authors have proposed a dominant negative model to explain the atypical X-linked inheritance pattern. Case #1 is the first affected female with a deletion of the PCDH19 gene, which represents the most compelling evidence to date that the dominant negative model is incorrect.