LGI1 – autosomal dominant epilepsy with auditory features

Autosomal dominant epilepsy with auditory features (ADPEAF) is a focal epileptic syndrome marked by lateral temporal seizures presenting with auditory auras and ictal aphasia. Heterozygous variants in the LGI1 gene, encoding leucine-rich, glioma-inactivated protein 1, underlie approximately 50% of familial ADPEAF cases, establishing LGI1 as a key gene in this syndrome (PMID:12205652).

LGI1 variants segregate in an autosomal dominant manner with ~60% penetrance across more than 20 unrelated pedigrees (PMID:15079011). Case series report >60 affected individuals, including large Norwegian and Italian families with Cys46Arg (c.136T>C (p.Cys46Arg)) and F318C (c.953T>G (p.Phe318Cys)) as recurrent missense alleles (PMID:12205652; PMID:12771268). Segregation analyses confirm co-segregation of LGI1 variants with disease in multiple generations.

The LGI1 mutational spectrum comprises >25 distinct alleles, predominantly missense changes within the N-terminal leucine-rich repeat (LRR) and C-terminal epitempin (EPTP) domains, as well as truncating and splice variants leading to protein loss-of-function (PMID:19191227). A recurrent hotspot at cysteine residues (e.g., Cys46) underscores the structural vulnerability of the LRR domain.

Functional assays demonstrate that most ADPEAF-linked LGI1 missense and truncating variants abolish secretion of LGI1 from transfected cells, indicating a loss-of-function mechanism (PMID:15857855; PMID:17296837). Lgi1 knockout and knock-in mice exhibit early-onset seizures, increased excitatory synaptic transmission, white matter abnormalities, and impaired oligodendrocyte differentiation, recapitulating human ADPEAF phenotypes (PMID:26878798).

Mechanistically, LGI1 interacts with synaptic receptors ADAM22/23 to regulate presynaptic glutamate release. Disruption of LGI1-ADAM22 binding and ER quality control–mediated degradation of misfolded LGI1 converge to increase neuronal excitability. Chemical chaperone treatment (4-phenylbutyrate) rescues folding, restores LGI1-ADAM22 interaction, and reduces seizure susceptibility in mouse models (PMID:25485908).

No substantial conflicting reports dispute LGI1’s role in ADPEAF, and large cohorts with consistent segregation and concordant functional data support a Strong ClinGen classification.

Key Take-home: Genetic testing for LGI1 variants is clinically actionable for diagnosis of ADPEAF and may inform precision therapeutic strategies targeting protein folding and synaptic stabilization.

References

• Annals of Neurology • 2002 • LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. PMID:12205652
• Neurology • 2003 • Novel LGI1 mutation in a family with autosomal dominant partial epilepsy with auditory features. PMID:12771268
• Human Mutation • 2009 • LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. PMID:19191227
• Human Molecular Genetics • 2005 • ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. PMID:15857855
• Scientific Reports • 2016 • LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development. PMID:26878798
• Nature Medicine • 2015 • Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy. PMID:25485908

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