Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat (LRR) and C-terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype-phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed.
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"Severe epilepsy hemizygous deletion of KCNAB2 Loss-of-function mutations/ haploinsufficiency Heilstedt et al., 2001 LGI1 ADLTE > 30 mutations (missense, splice-site mutations, short indels, single microdeletion) Failure in preventing channel inactivation resulting in more rapidly closing channels Kalachikov et al., 2002; Morante-Redolat et al., 2002; Nobile et al., 2009; Fanciulli et al., 2012 SQT3s and autismepilepsy phenotype p.Lys346Thr Gain-of-function mutation leading to enhance the channel's surface expression and stability at the plasma membrane, reduce protein degradation and alter protein compartmentalization Ambrosini et al., 2014 KCNJ10/Kir4.1 Seizure susceptibility p.Arg271Cys "
"Replacement of this charged amino acid with the hydrophobic tryptophan likely hampers the function of the mutated protein, ultimately resulting in the epilepsy phenotype. The function of the LGI1/Epitempin gene is still unclear, but its mutations were found in about half of the families with autosomal dominant lateral temporal epilepsy (ADLTE) (Nobile et al., 2009). "
"A more attractive hypothesis has been evoked by D'Orsi and Tinuper , claiming than Joan of Arc had suffered from temporal lobe epilepsy with auditory symptoms, as observed in autosomal dominant lateral temporal epilepsy (ADLTE), also called autosomal dominant partial epilepsy with auditory features (ADPEAF) or, in the sporadic form, idiopathic partial epilepsy with auditory features (IPEAF) . In this (familial or sporadic) form of epilepsy, which can be associated with LGI1 mutations  , auditory features are prominent, but other symptoms include complex visual hallucinations . Joan of Arc's attacks began at the age of 13 years, and occurred twice or three times a week. "
[Show abstract][Hide abstract]ABSTRACT: Objective:
The objective of this article is to describe whether Joan of Arc had epilepsy and how that may have influenced her sense of mission and ability to encourage thousands of people to help her to chase the English out of France.
Documentation of her Trial of Condemnation in 1431 provides a description of her episodes of experienced voices and visions.
From the age of thirteen, Joan of Arc experienced frequent episodes of auditory hallucinations associated with elementary or complex visual hallucinations (e.g., a great light or human faces). These had sudden onset, lasting seconds or minutes at most, and occurred when awake or during sleep, arousing her. Some could be triggered by an auditory stimulus. She had no disorganized thought between the episodes.
The semiology of the episodes is very suggestive of epileptic seizures, which have been considered as ecstatic by some authors or as partial epilepsy with auditory features by others, which seems more concordant with the ictal symptoms. The auditory and visual hallucinations could have had a religious content because during her childhood and adolescence, she was brought up in a religious environment, insomuch as this content first undefined only appeared after a few seizures. We can suppose that such hallucinations, without the knowledge of their medical origin, gave her a sense of divine mission, hence, a real strength to try to accomplish the orders she heard during the episodes. Her role during the Hundred Years' War and her narration of her strange episodes led her to be burned for heresy at the age of nineteen, yet rehabilitated 25years later and to be canonized for her achievements in 1920. This article is part of a Special Issue entitled "Epilepsy, Art, and Creativity".
Full-text · Article · Feb 2016 · Epilepsy & Behavior