LGI1 – this is what you need to know

LGI1This is the Epilepsiome page on LGI1, a gene for a familial focal epilepsy syndrome referred to a as autosomal dominant partial epilepsy with auditory features. LGI1 is one of the few genes for focal epilepsies and patients mainly have focal seizures from the auditory or visual cortex. LGI1 is a common finding in these familial epilepsies, but rare in other types of epilepsies.


Here are the most recent blog posts on LGI1


In a nutshell. LGI1 is a gene for familial lateral temporal lobe epilepsy, an inherited focal epilepsy that mainly presents with the rare epilepsy syndrome of lateral temporal lobe epilepsy. Sporadic, i.e. non-familial cases with lateral temporal lobe epilepsy rarely carry mutations in this gene, even though some cases have been described. In families LGI1 mutations, other focal epilepsies can seen, even though the variability is not a prominent as in families with other focal epilepsy genes such as DEPDC5.

Phenotype | Genetics | Mechanism 


Figure 1. LGI1 connects postsynapse and presynapse through a transsynaptic network interacting with ADAM22 and ADAM23. (Modified from Kegel et al., 2013 under a CC license http://asn.sagepub.com/content/5/3/AN20120095)

Figure 1. LGI1 connects postsynapse and presynapse through a transsynaptic network interacting with ADAM22 and ADAM23. (Modified from Kegel et al., 2013 under a CC license http://asn.sagepub.com/content/5/3/AN20120095)


Phenotype

Can’t you hear the radio?  “S.W. was spending an afternoon at his girlfriend’s house when he suddenly heard a radio sound in his right ear.  He asked his girlfriend whether she was aware of this sound as well, but he could not understand her answer. S.W. then lost consciousness and convulsed. He presented with a second seizure several months later. S.W. was started on carbamazepine and remained seizure-free. Interestingly, his mother had seizures starting at the same age. Furthermore, his sister had her first seizure at the age of 8 years and frequently reported auras where she would see colorful pictures and hear noises like a familiar song. These episodes sometimes occurred seconds before she had a generalized tonic-clonic seizure.” 

LGI1. This case report taken from our book chapter in Steven Waxman’s Molecular Neurology illustrates a family with lateral temporal lobe epilepsy (LTLE), a rare form of seizure disorder in which auditory features often precede a generalized tonic-clonic seizure. Auditory or acoustic features including elementary sounds (buzzing, ringing, radio sounds, machine noises) or more complex acoustic phenomena (voices, specific songs, music) arise from the lateral temporal lobe, a part of the brain important for auditory processing.  LTLE is the premier example that genetic epilepsies are not necessarily due to ion channels.

Phenotype. The classical phenotype of LGI1-related epilepsy is lateral temporal lobe epilepsy with auditory features, also called autosomal dominant epilepsy with auditory features (ADEAF). The cortical region for auditory processing is located in the lateral temporal cortex and individuals with LGI1 mutations can have either focal seizures presenting as auditory auras, focal dyscognitive seizures (complex partial seizures) and evolution to bilateral convulsive seizures (secondarily generalized seizures). There are several reports of patients with LGI1 mutations with other partial seizures including receptive aphasia (loss of speech comprehension) and visual auras. In most cases, seizures can be controlled with antiepileptic drugs such as carbamazepine or valproic acid. The clinical course of ADEAF is mostly benign and brain imaging is usually unremarkable. It is important to note that even though the LGI1-related epilepsy is technically a temporal lobe epilepsy, it is conceptually different from the much more common mesial temporal lobe epilepsy. Lateral temporal lobe epilepsy (LTLE) is a cortical epilepsy, while seizures in mesial temporal lobe epilepsy (MTLE) are generated in the hippocampus. There is some evidence that families with truncating mutations late in the protein may be less likely to have auditory features.


Genetics

Genetics. In 2002, two groups, Kalachikov and collaborators as well as Morante-Redolat and collaborators, identified mutations in LGI1 as the cause of familial lateral temporal lobe epilepsy. The LGI1 protein was initially identified as a candidate gene for glial tumor progression and subsequently named leucine-rich gene, glioma inactivated 1 (LGI1). Ever since the initial discovery, probably more than 200 individuals from 50 families have been identified. The pathogenic mechanism is mainly haploinsufficiency, where one copy of the gene either is disrupted, through truncating mutations, or encodes a nonfunctional protein carrying missense mutations. Missense mutations in LGI1 may cluster in one of the functional domains that is relatively early in the protein. There are also some deletions reported. While LGI1 mutations are relatively common in familial lateral temporal lobe epilepsy (33-50% of families with at least two affected individuals with auditory auras or aphasic seizures), they are very rare in sporadic patients.

How do I interpret an LGI1 variant in a patient? LGI1 is included on any major epilepsy panel and depending on the reporting practice of the lab, novel variants in this gene are sometimes reported independent of the phenotype. While there is a broad phenotypic spectrum with many epilepsy genes, this is not true for LGI1, where the phenotype is restricted to mild focal epilepsies. Therefore, if a variant in LGI1 is returned in a patient with a different phenotype such as an epileptic encephalopathy or generalized epilepsy, the relevance of this variant may be questioned, particularly with novel missense variants. Variants in the LGI1 gene are distributed throughout the gene and there are no recurrent variants that may facilitate interpretation. LGI1 variants are usually inherited in an autosomal dominant fashion, with reduced penetrance (67%; Rosanoff and Ottman Neurology 71, 567-571, 2008). If one parent carries a pathogenic LGI1 mutation, the likelihood that each child will inherit the mutant allele is 50%. The chance that the child will manifest the syndrome is 33% (50% x 67%). In general, the risk of developing ADEAF is 33% for any first-degree relative of a family member who has an LTLE-causing mutation in LGI1.

Is there are a mutation database? No, as of 2015, there is no mutation database and the entry into ClinVar and OMIM is not complete.  One of the most comprehensive reviews is the 2012 publication by Ho and collaborators that lists 33 variants from 36 families.


Mechanism

Secreted. The LGI1 protein is secreted from the presynapse, historically providing the first example of a non-ion channel epilepsy. The LGI1 protein binds postsynaptically to ADAM22 and presynaptically to ADAM23. Both proteins are involved in cell-cell adhesion and play an important role in synaptic maturation by establishing a physical contact between the pre- and the postsynapse. LGI1 forms a dimer and is the linking element between both membrane proteins. LGI1 also exerts other functions. It regulates AMPA receptor-mediated synaptic currents in the hippocampus through interaction with ADAM22; inhibits inactivation of the presynaptic voltage-gated potassium channel Kv1.1; has a role in postnatal developmental maturation of synapses and dendrites of hippocampal neurons. It remains unclear which of these functions underlies LTLE.

Autoimmune disorder. Autoimmune limbic encephalitis (LE) is an acquired neurological disorder of adulthood. Patients suffer from psychiatric symptoms, including memory loss and confusion, and from epilepsy. A subset of patients with LE have autoantibodies directed against the LGI1 protein. The autoimmune epilepsy related to LGI1 is more and more understood and there is some suggestion that the so-called faciobrachial dystonic seizures may be a common first finding. Interestingly, auditory auras are not a typical seizure type in autoimmune epilepsy due to LGI1 antibodies. In later stages, this autoimmune epilepsy leads to limbic encephalitis, and immunotherapy may be an effective treatment. LGI1 antibodies associated with LE neutralize the specific protein-protein interaction between LGI1 and ADAM22/ADAM23, further supporting the functional importance of the interaction between LGI1 and ADAM22/23 receptors.

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