Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations

Abstract

SUMMARYPurpose: To describe clinical and neuropsychological features of six consecutive sporadic girls with protocadherin 19 (PCDH19) mutations. Methods: Following recent descriptions of PCDH19 mutation in girls with epilepsy, we sequenced this gene in patients with infantile or early childhood seizures onset, either focal or generalized, without an obvious etiology. Key Findings: Mean age at the time of the study was 13.5 ± 11 years. Mean age at seizure onset was 15.5 ± 11 months (range 9-38). All patients experienced clusters of either focal or generalized seizures, precipitated during febrile illness in five patients. Attacks were very frequent at onset, but they became less numerous during follow-up. Ictal electroencephalography (EEG) showed temporal lobe involvement in five patients. Periictal EEG showed focal or multifocal epileptiform and slow abnormalities. Cognitive impairment became obvious after seizure onset in three patients and was associated with autistic features in two. Genetic analysis revealed five new and one known de novo PCDH19 mutation that were missense in four and frameshift in two. Variants are clustered in the large exon 1, corresponding to the extracellular domain of the PCDH19 protein. Significance: Our findings emphasize that de novo PCDH19 mutations are associated with infantile or early childhood onset of febrile or afebrile seizures often occurring in clusters. Cognitive impairment is not constantly present and autistic features are observed in some patients. Most patients have a ''stormy'' seizure onset, often related to fever; however, seizure severity does not clearly correlate with the degree of cognitive deficit. PCDH19 is likely a major epilepsy gene; phenotypes associated with mutations of this gene range from epileptic encephalopathies to mild epilepsy, yet large series of patients will be necessary to fully delineate phenotypic spectrum.

Epilepsy in ring 14 chromosome syndrome

“…In both of our cases, fever determined a worsening of seizures, as was also previously reported [8,21,27,29,30]. Seizure recurrence might be in clusters, as reported for other genetic epileptic conditions such as epilepsy due to PCDH19 mutation [33], and a differential diagnosis should be considered in those cases.…”

Male patients affected by mosaic PCDH19 mutations: five new cases

“…In female patients, seizure frequency often diminishes around puberty [3, 5, 11, 28–30], possibly due to hormonal changes [30]. Our 13-year old patient has been seizure free since the age of 10 years old; our 10-year-old patient only has one cluster of seizures per year.…”

Genetic Testing in Epilepsy: What Should you be Doing?

“…Further studies have shown that over 10% of cohorts of girls with onset of seizures under 5 years of age have PCDH19 mutations; many are de novo mutations and therefore do not have the characteristic family history seen in EFMR (21)(22)(23). Girls with normal intellect or intellectual disability who present with clusters of brief febrile seizures in infancy should be considered for PCDH19 testing.…”