Mendelian Inheritance in Man

10·5 million children worldwide are estimated to have active epilepsy. Over the past 15 years, syndrome-oriented clinical and EEG diagnosis, and better aetiological diagnosis, especially supported by neuroimaging, has helped to clarify the diversity of epilepsy in children, and has improved management. Perinatal and postinfective encephalopathy, cortical dysplasia, and hippocampal sclerosis account for the most severe symptomatic epilepsies. Ion channel defects can underlie both benign age-related disorders and severe epileptic encephalopathies with a progressive disturbance in cerebral function. However, the reasons for age-related expression in children are not understood. Neither are the mechanisms whereby an epileptic encephalopathy originates. Several new drugs have been recently introduced but have provided limited therapeutic benefits. However, treatment and quality of life have improved because the syndrome-specific efficacy profile of drugs is better known, and there is heightened awareness that compounds with severe cognitive side-effects and heavy polytherapies should be avoided. Epilepsy surgery is an important option for a few well-selected individuals, but should be considered with great caution when there is no apparent underlying brain lesion.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68182-8.pdf

Epilepsy in Children

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants. We have found a mutation in a gene encoding a GABA(A) receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Mutant GABA A receptor γ2-subunit in childhood absence epilepsy and febrile seizures

We examined the phenotypic variation and clinical genetics in nine families with generalized epilepsy with febrile seizures plus (GEFS+). This genetic epilepsy syndrome with heterogeneous phenotypes was hitherto described in only one family. We obtained genealogical information on 799 individuals and conducted detailed evaluation of 272 individuals. Ninety-one individuals had a history of seizures and 63 had epilepsy consistent with the GEFS+ syndrome. Epilepsy phenotypes were febrile seizures (FS) in 31, febrile seizures plus (FS+) in 15, FS+ with other seizure types (atonic, myoclonic, absence, or complex partial) in 8, and myoclonic-astatic epilepsy in 9 individuals. Inheritance was autosomal dominant with approximately 60% penetrance. This study confirms and expands the spectrum of GEFS+ and provides new insights into the phenotypic relationships and genetics of FS and the generalized epilepsies of childhood. Moreover, the ability to identify large families with this newly recognized common, childhood-onset, generalized genetic epilepsy syndrome suggests that it should be a prime target for attempts to identify genes relevant to FS and generalized epilepsy.

Generalized epilepsy with febrile seizures plus: A common childhood‐onset genetic epilepsy syndrome

Understanding the aetiology of epilepsy is essential both for clinical management of patients and for conducting neurobiological research that will direct future therapies. The aetiology of epilepsy was formerly regarded as unknown in about three-quarters of patients; however, massively parallel gene-sequencing studies, conducted in a framework of international collaboration, have yielded a bounty of discoveries that highlight the importance of gene mutations in the aetiology of epilepsy. These data, coupled with clinical genetic studies, suggest a new paradigm for use in the clinic: many forms of epilepsy are likely to have a genetic basis. Enquiry about a genetic cause of epilepsy is readily overlooked in the clinic for a number of understandable but remediable reasons, not least an incomplete understanding of its genetic architecture. In addition, the importance of de novo mutagenesis is often underappreciated, particularly in the epileptic encephalopathies. Other genomic surprises are worth emphasizing, such as the emerging evidence of a genetic contribution to focal epilepsies-long regarded as acquired conditions-and the complex role of copy number variation. The importance of improved understanding of the genetics of the epilepsies is confirmed by the positive outcomes, in terms of treatment selection and counselling, of receiving a genetic diagnosis.

The hidden genetics of epilepsy—a clinically important new paradigm

Evidence for genetic heterogeneity in epilepsy is strong. We evaluated the concordance of clinical forms in the same family in a series of families with several cases of idiopathic epilepsy, collected as part of the Study on the Genetics of Epilepsy of the Italian League against Epilepsy (LICE). The studied families had at least three members affected by an idiopathic form of epilepsy in one or more generations. Seventy‐four families (with a total of 296 affected members) have been analyzed; two families had cases with benign neonatal familial convulsions (BNFC); in 25% of the remaining families all members were affected by the same clinical form, 13.9% had a prevalent clinical form with only one affected member with a different seizure type, 36.1% had two clinical forms, and 25% had three forms of epilepsy in the same family. There are no clinical differences in the form of epilepsy between the families concordant for one clinical form and families with two or three clinical forms of idiopathic epilepsies. The distribution of the clinical form in the affected relatives in our families showed the higher concordance with the proband in febrile convulsions (FC, 70.8%) and in epilepsy with generalized tonic‐clonic seizures (EGTC, 63.0%). FC and EGTC were highly diffused in the affected relatives in the families with other forms of idiopathic epilepsy, above all in the more distantly related affected family members. In our families we observed a rare association between childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy (JME). In every idiopathic form of epilepsy, there was a high concordance for the seizure phenotype in first‐degree affected relatives, whereas in more distantly related family members concordance was less evident and there was a tendency toward a different phenotypic expression.

Concordance of clinical forms of epilepsy in families with several affected members

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Concordance of clinical forms of epilepsy in families with several affected members