Original articleLevetiracetam efficacy in PCDH19 Girls Clustering Epilepsy
Introduction
PCDH19 causes a distinctive epilepsy syndrome known as PCDH19 Girls Clustering Epilepsy (PCDH19-GCE) [1,2]. This syndrome has a broad range of phenotypes ranging from a mild self-limited disorder to a highly refractory developmental and epileptic encephalopathy. A recent Scottish epidemiology study found an incidence of PCDH19 pathogenic variants of 1 in 20,500 live female births; it was the second most common cause of developmental and epileptic encephalopathy in girls [3].
PCDH19 is an X-chromosome gene. It encodes a member of the delta-2 non-clustered protocadherins (d2-PCDHs), which belong to the cadherin super-family of cell-cell adhesion molecules with diverse roles in neuronal migration, neuronal cell specification or synaptic function [4]. In addition to its canonical role in brain wiring [5], PCDH19 protein has also been proposed to co-regulate gene expression with estrogen receptor alpha (ERa) [6]. While the fine detail of the underlying mechanism(s) of PCDH19-CE is not yet fully understood, there is mounting evidence suggesting that cellular mosaicism, that is the presence of cells with and cells without functioning PCDH19 protein, is the fundamental disease driver [5].
Girls with PCDH19-GCE present at a mean age of 11.8 months (range 4–72) with clusters of focal impaired awareness and focal to bilateral tonic-clonic seizures [2,[7], [8], [9], [10], [11]]. Often triggered by fever, clusters can consist of up to 30 seizures and last 1–14 days [ [9], [10], [11], [12], [13], [14], [15]]. Inter-cluster intervals last weeks to months [2,[9], [10], [11], [12], [13], [14], [15]]. Typically, development is normal at onset of seizures and may regress with clusters [2,9,10,14]. Initially skills can be regained during the inter-cluster interval but eventually intellectual disability may be evident [9,10,14,16]. Seizures often cease in the second to third decade [2,[9], [10], [11], [12],14,16,17]. Two-thirds of women have intellectual disability, which ranges from mild to severe. A significant number have psychiatric co-morbidities such as autism spectrum disorder and psychosis [[9], [10], [11], [12],14,16,17]. Seizure onset before 12 months of age is associated with a poorer cognitive outcome 11,16].
Preventing and aborting clusters of seizures is difficult and, despite trials of multiple antiepileptic drugs (AEDs), girls often require recurrent hospital admissions [11]. Through clinical practice, we noted remarkable seizure control with levetiracetam for several girls with drug-resistant PCDH19-GCE. Here, we report the impact of levetiracetam on girls with PCDH19-GCE in two cohorts: a research cohort in which detailed historical clinical information was available and an international cohort of individuals with PCDH19 variants who were surveyed via an online questionnaire.
Section snippets
Materials and methods
We evaluated response to levetiracetam in two cohorts of patients with PCDH19-GCE.
Cohort A
We identified 40 females with epilepsy due to PCDH19 pathogenic variants from 19 Australian and New Zealand families. 17/40 (43%) females had trialled levetiracetam. Adequate efficacy data were available for 14 girls (Table 1), and for 3, behavioural exacerbation meant that levetiracetam was discontinued before seizure efficacy could be assessed.
The 14 girls who had an adequate trial of levetiracetam were previously drug-resistant; they had an average of 5 AEDs prior to the introduction of
Discussion
PCDH19-GCE has a characteristic clinical presentation where typically developing infant girls present with clusters of seizures, which often prove highly refractory [10,14]. Earlier age of seizure onset is associated with poorer cognitive outcome [11,16]. Although there are no studies to show that the seizure burden per se impacts negatively on their development, the regression of development associated with more severe clusters suggests that seizure load contributes independently to poor
Acknowledgements
We thank the children and their families for participating in our research. We thank Leanne Dibbens for genetic testing of some patients. We gratefully acknowledge support from the Health Research Council of New Zealand, Cure Kids New Zealand, the Ted and Mollie Car Endowment Trust and the National Health and Medical Research Council of Australia. We thank the Epi25 consortium for data generation for some of the patients. We thank the Epi25 principal investigators, local staff from individual
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