Homozygous LGI1 Variant Linked to Severe Developmental and Epileptic Encephalopathy

Expanding the Genetic Landscape of Childhood Epilepsies

Developmental and epileptic encephalopathies (DEEs) present a formidable clinical challenge, characterized by severe, often drug-resistant seizures and profound developmental impairments that begin in childhood [1, 2]. While genetic testing increasingly identifies underlying etiologies, the same gene can produce a wide spectrum of disease, complicating prognosis and treatment planning [3, 4]. For clinicians managing these complex cases, understanding how a specific genetic variant translates into a mild, treatable epilepsy or a devastating encephalopathy is a critical knowledge gap [5, 6, 7, 8]. A recent case report illuminates this issue by detailing how the number of altered gene copies can dramatically shift the clinical course of an LGI1-related epilepsy from a benign, manageable condition to a fatal neonatal encephalopathy [9, 10, 11].

LGI1: From Benign Epilepsy to Severe Encephalopathy

The leucine-rich glioma inactivated-1 (LGI1) gene is primarily known for its association with autosomal-dominant lateral temporal lobe epilepsy (ADLTE). This syndrome is linked to heterozygous LGI1 variants, where an individual has one altered gene copy, and typically manifests as a relatively benign condition with focal seizures that are well-controlled with standard antiseizure medications. Importantly, ADLTE is not typically considered part of the developmental and epileptic encephalopathy (DEE) spectrum. In stark contrast, DEEs are defined by their severity, involving intractable seizures that are believed to contribute directly to progressive cognitive and motor decline. While many DEEs have a genetic basis, the report of a severe DEE phenotype arising from an LGI1 variant challenges the established clinical profile of this gene, suggesting that gene dosage is a critical determinant of disease severity.

A Case of Profound LGI1-Related Encephalopathy

The severe consequences of a complete loss of LGI1 function were illustrated in the case of a 7-month-old girl born to consanguineous parents. Her clinical course was aggressive from the outset, with drug-resistant epilepsy developing in the neonatal period. The seizure burden was immense, featuring recurrent multifocal seizures that progressed to refractory status epilepticus. This intractable epilepsy failed to respond to intensive treatment, including multiple antiseizure medications and a ketogenic diet. In parallel with the seizure activity, the infant displayed profound global developmental delay, a clinical hallmark that strongly suggested a DEE diagnosis. The patient's condition ultimately led to her death from aspiration pneumonitis and septic shock at 7 months of age, highlighting the lethality of this specific genetic presentation.

Genetic Findings: Homozygosity and Phenotypic Severity

To identify the underlying cause of this severe presentation, clinicians performed whole-exome sequencing, a genomic analysis that examines the protein-coding regions of a patient's DNA. The test revealed a homozygous pathogenic variant (c.1438C>T p.Gln480Ter) in the LGI1 gene. The term homozygous indicates the patient inherited two copies of the altered gene, one from each parent. This specific variant creates a premature stop signal in the gene's instructions, which is predicted to result in a complete loss of functional LGI1 protein. Familial testing provided crucial context, confirming that both unaffected parents were heterozygous carriers, possessing one normal and one altered copy of the gene. This clear gene-dosage effect, where one altered copy is tolerated but two are catastrophic, explains the dramatic difference between the parents' health and their child's severe encephalopathy. This finding, supported by animal model data, reinforces the critical role of LGI1 protein in neurodevelopment and seizure control.

Clinical Implications for Genetic Counseling

This case significantly expands the known clinical spectrum of LGI1-related disorders, providing an essential lesson for diagnosis and counseling. While heterozygous LGI1 variants are associated with the manageable ADLTE syndrome, this report demonstrates that homozygosity for a pathogenic LGI1 variant can cause a severe DEE characterized by neonatal-onset refractory seizures, profound developmental failure, and early death. This distinction between the heterozygous and homozygous states underscores the severe consequences of a complete LGI1 loss of function. For practicing physicians, these findings highlight the critical importance of genetic counseling. Especially among consanguineous families, where the risk of inheriting two copies of a rare pathogenic variant is elevated, the potential for a dramatically worsened phenotype with homozygosity should be a key point of discussion. This information is vital for preconception counseling, prenatal diagnosis, and for providing families with an accurate prognosis and anticipatory guidance when a severe, early-onset epilepsy is diagnosed.

References

1. Samanta D. A comprehensive review of evolving treatment strategies for Dravet syndrome: Insights from randomized trials, meta-analyses, real-world evidence, and emerging therapeutic approaches.. Epilepsy & behavior : E&B. 2025. doi:10.1016/j.yebeh.2024.110171

2. Altıntaş M, Yıldırım M, Bektaş Ö, Teber S. Progressive Myoclonus Epilepsy and Beyond: A Systematic Review of SEMA6B-related Disorders.. Neuropediatrics. 2025. doi:10.1055/a-2442-5741

3. Stevelink R, Campbell C, Chen S, et al. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics. 2023. doi:10.1038/s41588-023-01485-w

4. Kessi M, Peng J, Duan H, et al. The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review. Frontiers in Molecular Neuroscience. 2022. doi:10.3389/fnmol.2022.807202

5. Mastrangelo M, Gasparri V, Bernardi K, Foglietta S, Ramantani G, Pisani F. Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review. Children. 2023. doi:10.3390/children10030553

6. Samanta D, Naik S. Efficacy and safety of cenobamate in developmental and epileptic encephalopathies: A systematic review and meta-analysis.. Seizure. 2025. doi:10.1016/j.seizure.2025.11.016

7. Specchio N, Auvin S, Strzelczyk A, Brigo F, Villanueva V, Trinka E. Efficacy and safety of stiripentol in the prevention and cessation of status epilepticus: A systematic review. Epilepsia Open. 2024. doi:10.1002/epi4.13036

8. Sharawat I, Panda P, Kasinathan A, Panda P, Dawman L, Joshi K. Efficacy and tolerability of fenfluramine in patients with Dravet syndrome: A systematic review and meta-analysis.. Seizure. 2021. doi:10.1016/j.seizure.2020.12.016

9. Samanta D, Jain P, Cunningham J, Arya R. Comparative efficacy of neuromodulation therapies in Lennox-Gastaut syndrome: A systematic review and meta-analysis of vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation.. Epilepsia. 2025. doi:10.1111/epi.18544

10. Samanta D, Bhalla S, Bhatia S, et al. Antiseizure medications for Lennox-Gastaut Syndrome: Comprehensive review and proposed consensus treatment algorithm.. Epilepsy & behavior : E&B. 2025. doi:10.1016/j.yebeh.2024.110261

11. Doman A, Strzelczyk A, Paprocka J. Antiseizure medications in CDKL5 encephalopathy- systematic review.. Seizure. 2025. doi:10.1016/j.seizure.2025.08.002