This article includes discussion of familial lateral temporal lobe epilepsy, autosomal dominant lateral temporal lobe epilepsy, autosomal dominant partial epilepsy with auditory features, familial neocortical temporal lobe epilepsy, familial partial epilepsy with aphasic seizures, and FLTLE. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Recognition of a genetic basis of temporal lobe epilepsy in some families represents a major advance. In some forms, such as familial lateral temporal lobe epilepsy, it allows recognition of improved prognosis contrasting with the often intractable sporadic forms of the disorder. The LGI1 or the RELN genes are mutated in approximately 50% of kindreds. In addition, DEPDC5 and SCNA1 gene mutations have been found in families and sporadic patients. In this article, the author reports on new clinical studies comparing families with LGI1 or RELN mutations, as well as experimental studies of excitability in hippocampal CA3 neurons demonstrating a role of LGI1 in regulating Kv1 channels and glutamate levels.
• Familial lateral temporal lobe epilepsy is typically characterized by auditory auras, but other types of manifestations can be present in affected individuals.
• Mutations in LGI1, RELN, DEPDC5, and SCNA1 genes have been reported.
• Approximately 50% of families will present a mutation in the LGI1 gene on chromosome 10q.
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 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 colleagues (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.
Familial temporal lobe epilepsy was included in the new proposals for classification of epileptic syndromes by the International League Against Epilepsy, supporting it as a well-defined syndrome (Engel 2001; Engel 2006; Berg et al 2010).
The first description of familial lateral temporal lobe epilepsy was in 1995 by Ottman and colleagues, who reported an autosomal dominant focal epilepsy syndrome with auditory features (Ottman et al 1995). Autosomal dominant partial epilepsy syndrome with auditory features corresponds to a neocortical or lateral temporal lobe epilepsy.
After detailed descriptions of many families with temporal lobe epilepsy, it has been possible to define 2 groups of familial temporal lobe epilepsy based on clinical and molecular characteristics (Vadlamudi et al 2003; Andermann et al 2005): familial mesial temporal lobe epilepsy, with clinical features of mesial temporal onset and no clear-cut molecular definition to date (Kobayashi et al 2001; Kobayashi et al 2009a); and familial lateral temporal lobe epilepsy, most often associated with LGI1 gene mutations in chromosome 10q (Ottman et al 1995; Kalachikov et al 2002; Morante-Redolat et al 2002).
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 only mildly affected, many so-called “sporadic” or “isolated” patients may actually have a familial epilepsy syndrome.
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