Patients with PCDH19 mutations

Published: February 03 2016
Last updated: September 27 2022

Effectiveness of antiepileptic therapy in patients with PCDH19 mutations

Introduction from Dr Markus Reuber, editor-in-chief of Seizure

Seizure 35 has published Effectiveness of antiepileptic therapy in patients with PCDH19 mutations

There has been much talk of “personalised medicine“ for people with epilepsy. This term refers to the choice of medication for a particular epileptogenic mechanism and the avoidance of side effects determined by genetic tests. In the ideal world of “personalised medicine“ drugs would not be used on a trial and error basis informed by trials in mixed populations of people with epilepsy but would target the precise mechanism causing and individual’s seizures identified by genetic tests.

Unfortunately, the time when we can expect to inhabit this ideal world seems to be slipping back constantly, as we learn ever more about the shifting sands of gene expression and the complexities of gene-gene and gene-environment interactions. Having said that, the genetic differentiation of the epilepsies is making impressive progress. This progress has allowed us to categorise epilepsies better and put us in a position to chose the most appropriate treatments not only on the basis of clinically defined syndromes but also on the basis of genetic categories. Whilst only a minority of all people with epilepsy have benefited from genetic insights into the cause(s) of their seizure disorders so far, this process has yielded some very important insights of great clinical importance – for instance the avoidance of sodium channel blockers in Dravet’s syndrome or the early use of the ketogenic diet in patients with GLUT1 deficiency syndrome.

My editor’s choice from the present issue of Seizure is a paper about the best antiepileptic drug choices in “Epilepsy, Female-restricted, with Mental Retardation“ (EFMR). Whilst EFMR is a rare condition caused by mutations of the PCDH19 gene, this paper is important because it is demonstrates to what extend “personalised medicine“ is possible right now. The clinical features of EFMR are highly variable but resemble those of Dravet’s syndrome, which is typically associated with SCN1A mutations. In both syndromes, psychomotor development is usually normal before the onset of seizures, but mental and motor delay and language regression are observed after seizure manifestation. In both syndromes, focal or generalised tonic clonic seizures may be triggered by fever. There are some clinical features which can differentiate between these conditions, but genetic testing for pathogenic PCDH19 mutations is diagnostic.

My editor’s choice by Lotte et al. describes clinical features and – most importantly antiepileptic drug (AED) response – in a cohort of 58 patients with this rare disorder 2. We learn that EFMR may present still present in girls older than six and that nearly half the patients become seizure free (most commonly with bromide and clobazam). A minority of affected children recover fully and develop normally. In view of the rarity of EFMR our first choice of AED will never be determined by a randomised controlled study. The manuscript by Lotte represents an alternative way of informing us about the spectrum of a rare genetic disorder and of guiding treatment choices on the basis of genetic characterisation and international collaboration.

Whilst we may still have to wait a long time for the “personalised medicine“ of our dreams, it is entirely realistic to expect much clinically useful information to be generated about many other genetically characterisable epilepsy syndromes in the near future.

(1) Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 2008 June; 40: 776–781.

(2) Lotte J, Bast T, Borusiak P et al. Effectiveness of antiepileptic therapy in patients with PCDH19 mutations. Seizure 2016;35:106-110.