Review articleGenetic abnormalities underlying familial epilepsy syndromes
Introduction
Familial epilepsy syndrome generally refers to epilepsies with identifiable inheritance but without neurodegenerative aspects such as mental retardation and cerebellar ataxia, which are often seen in progressive myoclonus epilepsy syndrome. Exploiting their inheritance with high penetrance, genetic defects have been recently identified in some familial epilepsies (Table 1). We provide in this review a detailed description of the genetic abnormalities identified in familial epilepsies. Only specific genes identified as causally related to familial epilepsies will be discussed, although loci for other familial epilepsies have been mapped to various chromosomal regions.
Section snippets
Autosomal dominant nocturnal frontal lobe epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was first reported in 1994 and has since been recognized as a new clinical entity of epilepsy. This partial epilepsy is characterized by clusters of a brief seizure during light sleep, and is often misdiagnosed as nightmare or parasomnia [1], [2]. The predominant seizure pattern has frontal lobe semiology with clusters of brief nocturnal motor attacks occurring during non-rapid eye movement (NREM) sleep. Onset usually occurs in
Benign familial neonatal convulsions
Benign familial neonatal convulsions (BFNC) is monogenic epilepsy inherited via an autosomal dominant trait with high penetrance and characterized by clusters of generalized and partial seizures afflicting exclusively, if any, neonates, and remits spontaneously. Thus, in most affected cases, seizures develop 2–3 days after birth. BFNC is classified as idiopathic generalized epilepsy according to International league against epilepsy (ILAE) classification [21]. Seizure types are
Generalized epilepsy with febrile seizures plus (GEFS+)
Febrile seizures (FS) are the most common provoked seizures afflicting infants and young children. No specific gene responsible for simple FS has yet been identified but four loci have been reported for FS; FEB1 at chromosome 8q13–q21; FEB2, 19p; FEB3, 2q23–24; FEB4, 5q14–q15 [48], [49], [50], [51]. A small proportion of patients with FS develop afebrile seizures later in life. This clinical subset of FS includes a clinical entity referred to as generalized epilepsy with febrile seizures plus
Others
Other genetic abnormalities have been identified in individuals with epilepsy, albeit such epilepsies are often associated with a known syndrome or found in small pedigrees. A missense mutation in KCNA1, a voltage gated K+-channel gene, causes periodic ataxia type 1, EA1 (MIM 160120) and can sometimes lead to partial seizures [79]. This provides supporting evidence that not only KCNQ K+-channels, which are involved in M-current formation, but also other K+-channels expressed in the brain may be
Conclusions
All identified causative genes of human familial epilepsy syndromes encode ion channels or their auxiliary subunits expressed in the brain. Although such familial epilepsies are distinguished from idiopathic epilepsy by dominant inheritance with high penetrance, the similarities in symptomatology between dominant disorders and certain types of idiopathic epilepsy syndromes suggest that at least some forms of idiopathic epilepsies as well as FS could be explained by defects in ion channels. Such
Electronic database information
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim/.
Acknowledgments
We are indebted to our patients with epilepsy and their families for their helpful cooperation and encouragement in our research. We thank Ms Minako Yonetani and Miyuki Yamashita for their technical assistance, Ms Mayumi Sakai for preparation of the figures and Ms Yumiko Oka for typing and formatting the manuscript. Our research was conducted as part of a comprehensive project organized by The Epilepsy Genetic Study Group, Japan (Chairperson, S.K.) and supported in part by Grants for Scientific
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