Child Neurology: Expanding the LGI1 Spectrum: Homozygous Loss-of-Function Variant in an Infant With Epileptic...

Area of Science:

• Neurogenetics
• Epileptology
• Developmental Neuroscience

Background:

• Epilepsy syndromes are classified by seizure types, onset age, EEG patterns, and prognosis.
• Autosomal-dominant lateral temporal lobe epilepsy (ADLTE) is linked to LGI1 gene variants.
• Developmental and epileptic encephalopathies (DEEs) are severe childhood epilepsies often with genetic causes.

Purpose of the Study:

• To investigate the genetic basis of a severe, early-onset epilepsy syndrome in an infant.
• To explore the phenotypic spectrum of LGI1 gene variants, particularly homozygous loss-of-function.
• To emphasize the importance of genetic counseling in consanguineous families.

Main Methods:

• Clinical case study of a 7-month-old girl with drug-resistant epilepsy and global developmental delay.
• Whole-exome sequencing to identify the genetic variant.
• Analysis of family members' genotypes to understand inheritance patterns.

Main Results:

• A homozygous pathogenic variant (c.1438C>T p.Gln480Ter) in the LGI1 gene was identified in the patient.
• The patient presented with severe, refractory epilepsy and profound developmental delay, leading to death at 7 months.
• Heterozygous carriers in the family exhibited milder, pharmacoresponsive seizures, contrasting with the patient's severe phenotype.

Conclusions:

• Homozygous LGI1 loss-of-function can cause a severe, DEE-like phenotype, distinct from typical ADLTE.
• LGI1 plays a crucial role in neurodevelopment and seizure control.
• Genetic counseling is vital for consanguineous families to discuss the risks of homozygous pathogenic variants and potential phenotype worsening.