The definition of phenotypes for genetic epilepsy analysis

Giuliano Avanzini, Simona Binelli

Research output: Contribution to journalArticlepeer-review


An important requirement for genetic analysis of human inherited disease to be successful is the selection of homogeneous phenotypes. Epileptologists have long been engaged in identify pure forms of epilepsy based on natural history and electro-clinical picture both interjetai and ictal. The results of this kind of analysis are reflected by the International Classification of Epilepsies and Epileptic Syndromes (Epilepsia 30, 389-399. 1989) which is now under revision. Relevant to genetic analysis are the epilepsies included in the category of idiopathic epilepsies, presenting with an ictal symptomatology which is not associated with any other neurological signs or symptoms. They are considered to depend on alterations in neural excitability that cannot be attributed to "any underlying cause other than a possible hereditary predisposition". The following form are recognized : Partial idiopathic epilepsies - Benign childhood epilepsy with centro-temporal spikes (BECT) - Childhood epilepsy with occipital paroxysms - Other (benign partial epilepsy with affective symptoms, benign partial epilepsy with extreme somato- sensory evoked potentials) - Primary reading epilepsy Generalized idiopathic epilepsies - Benign neonatal (familial) convulsions (BNFC) - Benign myoclonic epilepsy in infancy - Childhood absence epilepsy (CAE) - Juvenile absence epilepsy (JAE) - Juvenile myoclonic epilepsy (JME) - Epilepsy with grand male seizures on awakening - Others (e.g. grand mal at random) - Epilepsies with seizures precipitation (e.g. photogenic) In addition febrile convulsions are often clustered in the same family suggesting an hereditary predisposition. The value of the ILAE classification for genetic investigations is challenged by twin studies showing a casewise concordance of only 0.76 for idiopathic generalized epilepsies (Berkovic et al, Ann. Neurol 43, 435-445, 1998). Moreover an analysis carried out by the Italian League against Epilepsy (Epilepsia 34, 819-826, 1993) on 74 families with 296 affected members have shown a variable degree of phenotypic heterogeneity in the family of probands with idiopathic epilepsies. Relatives with non concordant forms have been found in families of probands presenting with: CAE (75.6 %), BECT (72.2 %), JME (55.5 %) and febrile convulsions (29.2 %). Thus the clinically defined boundaries between different forms of epilepsy may not be suitable to identify genetically homogeneous epileptic phenotypes, which may explain why linkage analysis failed so far to localize chromosomal loci consistently linked to the commonest idiopathic epilepsies. On the other hand the "epilepsy genes" mapped so far correspond to clinical forms not included in the International Classification such as Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE, Steinlein et al. Nature Genetics 11, 201-203,1995), Generalized Epilepsy with Febrile Seizure plus (GEFS+, Wallace el al, Nature Genetics 19, 366-370, 1998) and Rolandic Epilepsy with Speech Dyspraxia (Scheffer et al, Ann Neurol 38, 633-642,1995), the only exception being Benign Neonatal Familial Convulsions (BNFC) which is due to a mutation of either KCNQ2 or KCNQ3 genes both coding for potassium channels (Bievert et al. Science 279, 403-405, 1998; Charlier et al, Nature Genetics 18, 53-55, 1998; Singh et al. Nature Genetics 18, 25-29, 1998) and is therefore genetically heterogeneous. The above data suggest that classic epileptic syndrome should be reaggregated according to different criteria, e.g. identification of epileptic genetic traits (photosensitivity, special EEC patterns such as Doose's theta rhythm, bilateral synchronous delta bursts recently reported by Zara et al. Neurology 51, 493-498, 1998) whose different combinations result in the spectrum of known idiopathic epilepsy types.

Original languageEnglish
Pages (from-to)198-199
Number of pages2
JournalItalian Journal of Neurological Sciences
Issue number3
Publication statusPublished - 1999

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)


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