Major advances have recently been made
in our under-standing
of the genetic basis of monogenic inheritedepilepsies.
Progress has been particularly spectacularwith
respect to idiopathic epilepsies, with the discoverythat
mutations in ion channel subunits are implicated.However,
important advances have also been made inmany
inherited symptomatic epilepsies, for which directmolecular
diagnosis is now possible, simplifying previ-ously
complex investigations. It is expected that identi-fication
of the genes implicated in familial forms
ofepilepsies
will lead to a better understanding of theunderlying
pathophysiological mechanisms of these dis-orders
and to the development of experimental modelsand
new therapeutic strategies. In this article, we reviewthe
clinical and genetic data concerning most of theinherited
human epilepsies.Epilepsies
are frequent heterogeneous disor-ders1 and
are caused by many factors.2 The contributionof genetic and environmental
factors varies amongepileptic
disorders. Genetic factors are generally thoughtto
contribute to the etiology of 40% to 60% of humanepilepsies.2,3 Inherited
epilepsies are usually classifiedaccording
to whether the mode of inheritance is com-plex
or monogenic. In epilepsies with a complex mode ofinheritance, epilepsy
results from the interactionbetween environmental factors and genetic
susceptibil-ity, whereas
in monogenic epilepsies, the genetic com-ponent
is prevalent, although environmental factors maycontribute
to phenotypic expression and could explainincomplete
penetrance or variable clinical expression.Finally, in
epilepsies caused by exogenous factors (theleast
genetically determined of the epilepsies), geneticsusceptibility
could explain why only some of the indi-viduals
exposed to the same factors later developepilepsy.Genetic
studies in epilepsies are difficult to perform forseveral
reasons. First, most epilepsies have a complexmode of inheritance and it is difficult
to identify thegenes
involved. Nonparametric analyses in a large num-ber
of affected individuals (ie, hundreds) are necessary.However, difficulties are also
encountered in geneticstudies
of monogenic epilepsies, particularly in the iden-tification
of large informative families with enoughaffected members to be useful for linkage
analysis. Sec-ond, phenotype
analysis can be problematic.The clinicalstatus
(ie, affected or not) of each member of the familymust
be determined. This involves a choice of more orless
stringent electroclinical criteria to confirm the pres-ence
of the disease. The collection of reliable medicalinformation
may be difficult, especially in the first gen-eration
of affected families. Moreover, the presence ofphenocopies (which are frequent for
epilepsy and febrileconvulsions)
and possible intrafamilial phenotypic het-erogeneity
must be taken into account.Despite
these difficulties, major advances have beenmade
in the genetics of epilepsy in the past 10 years.Nearly
all concern epilepsies with a monogenic modeof
inheritance, the least frequent of the inherited epilep-Genetics
of inherited human epilepsiesIsabelle
Gourfinkel-An, MD; Stéphanie Baulac, BS; Alexis Brice, MD;Eric
Leguern, MD, PhD; Michel Baulac, MDKeywords: channelopathies; complex mode of
inheritance; familial epilepsy; idiopathic epilepsy; monogenic inheritance; neuronal
migration; symptomatic epilepsy
Author affiliations: Unité d’Epileptologie,
Hôpital Pitié-Salpêtrière, Paris, France
(Isabelle Gourfinkel-An, Michel Baulac); Service d’Electrophysiologie,
Hôpital Pitié-Salpêtrière, Paris, France
(Isabelle Gourfinkel-An); INSERM U 289, Hôpital Pitié-Salpêtrière,
Paris, France (Stéphanie Baulac, Alexis Brice, Eric Leguern)
Address for correspondence: Prof Michel
Baulac, Unité d’Epileptologie, Hôpi-tal de
la Pitié-Salpêtrière, 47, Bd de l’Hôpital,
75651 Paris Cedex 13, France
(e-mail: michel.baulac@psl.ap-hop-paris.fr) 4
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a s p e c t s
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