In this update, the author provides an overview on the prevalence of familial mesial temporal lobe epilepsy and its clinical presentation in kindreds investigated through the Epi4K Consortium and Epilepsy Phenome/Genome Project.
• Some families have a benign outcome, whereas others have a more heterogeneous presentation, including refractory patients.
• Hippocampal atrophy is a common feature in some families, not always associated with poor seizure control.
• No specific genes have been identified thus far, although linkage to different loci have been found in individual families.
• Prevalence of familial mesial temporal lobe epilepsy is estimated at 20% to 24% of families with nonacquired focal epilepsy.
Historical note and terminology
Genetic factors in the causation of epilepsy have been recognized since the time of Hippocrates. However, until the second half of the 20th century, generalized epilepsies were thought to be genetic in origin, whereas focal or partial epilepsies were largely attributed to environmental factors, such as birth injuries, infections, postnatal head trauma, and brain lesions such as tumors and vascular insults.
In a series of publications (Andermann and Metrakos 1969; Andermann 1980; Andermann 1982; Andermann 1985) based on family studies of patients operated for focal epilepsy at the Montreal Neurological Hospital, Eva Andermann was able to demonstrate that genetic factors were important in patients with focal epilepsy, particularly temporal lobe epilepsy, and that both generalized and focal epilepsies fit a model of multifactorial inheritance (now termed complex inheritance), with interaction of 1 or more genes and environmental factors.
It was only in the 1990s that several autosomal dominant forms of focal epilepsy were described by the group of Berkovic and Steinlein (Berkovic and Steinlein 1999). These included: autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, familial focal epilepsy with variable foci, and autosomal dominant rolandic epilepsy with speech dyspraxia.
The first description of familial occurrence of temporal lobe epilepsy was in 1994 by Berkovic and colleagues who described familial temporal lobe epilepsy as a benign syndrome with late seizure onset, no history of prolonged febrile seizures, and no MRI evidence for mesial temporal sclerosis (Berkovic et al 1994). However, subsequent familial temporal lobe epilepsy series identified patients who were not as benign, with a high proportion of hippocampal atrophy, some of whom required surgical treatment for their epilepsy (Cendes et al 1998; Kobayashi et al 2001). These families showed phenotypic heterogeneity in different family members, as well as between families, with respect to history of prolonged febrile seizures, severity of the epilepsy and presence of hippocampal atrophy. The original series of Berkovic and colleagues (Berkovic et al 1994; Berkovic et al 1996) was population-based, arising from a twin study, whereas the later publications were hospital-based.
Familial temporal lobe epilepsy was included in the proposal for classification of epileptic syndromes by the International League Against Epilepsy (ILAE), supporting it as a well-defined syndrome (Engel 2001; Engel 2006). It has been further maintained in the 2010 ILAE commission report as an adolescence-adulthood electroclinical syndrome (Berg et al 2010).
With the description of the lateral form of familial temporal lobe epilepsy, also known as autosomal dominant partial epilepsy with auditory features (Ottman et al 1995) and associated with mutations in the LGI-1 gene on chromosome 10q (Kalachikov et al 2002; Morante-Redolat et al 2002), the distinction between mesial and lateral families became more obvious (Berkovic and Steinlein 1999; Kobayashi et al 2001; Kobayashi et al 2003c; Kobayashi et al 2009a; Santos et al 2002; Vadlamudi et al 2003; Berkovic et al 2004a; Andermann et al 2005).
It is important to recognize that it is impossible to distinguish familial and nonfamilial temporal lobe epilepsy patients based solely on the clinical presentation, for both mesial and lateral forms. As the family history is not always accurately documented, and because some family members are asymptomatic or very mildly affected, many so-called “sporadic” or “isolated” patients may actually have a familial epilepsy syndrome.
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