Epilepsy syndromes are clinically defined by their specific set of features, including seizure types, age at onset, electroencephalographic patterns, and prognosis. For example, autosomal-dominant lateral temporal lobe epilepsy (ADLTE) is a well-recognized epilepsy syndrome associated with heterozygous leucine-rich glioma inactivated-1 (LGI1) gene variants. Relatedly, developmental and epileptic encephalopathies (DEEs) are a diverse group of severe, childhood-onset epilepsy syndromes associated with developmental impairments. While DEEs are often associated with a genetic etiology, ADLTE does not usually present as a DEE spectrum. A 7-month-old girl, born to consanguineous parents, developed drug-resistant epilepsy from the neonatal period. She had recurrent multifocal seizures, progressing to refractory status epilepticus despite multiple antiseizure medications and ketogenic diet. She also had profound global developmental delay, suggestive of a DEE. Whole-exome sequencing revealed a homozygous pathogenic variant (c.1438C>T p.Gln480Ter) in the LGI1 gene. Both unaffected parents and 2 other affected family members were found to carry the variant in the heterozygous state. This homozygous variant was predicted to cause our patient's aggressive epilepsy phenotype because heterozygous carriers typically exhibit only benign, pharmacoresponsive seizures. The patient succumbed to aspiration pneumonitis and septic shock at 7 months of age. This case, along with supporting data from animal models, suggests a critical role for LGI1 in neurodevelopment and seizure control. In addition to highlighting the severe consequences of homozygous LGI1 loss of function, it underscores the importance of genetic counseling. Especially among consanguineous families, the potential for worsening phenotype with homozygosity should be discussed.
M et al. (Mon,) studied this question.