Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome (LGS) is a rare, severe form of childhood epilepsy that is classified as a type of epileptic encephalopathy. The disease is characterized by three classic criteria: multiple seizure types, a specific brain wave pattern on electroencephalography, and cognitive impairment.¹

Multiple factors, which may be structural, metabolic, genetic, immunological, or infectious, can contribute to the development of LGS.² Approximately 75% of children have secondary LGS, with known etiology, whereas the remaining 25% have idiopathic or cryptogenic LGS, with unknown causation.¹ Genetic factors may be the cause of many cases of cryptogenic LGS.³

The most common known causes of LGS are structural abnormalities of the brain. These may be congenital, arising during prenatal development, or acquired as a consequence of injury to the brain during or after birth.² Some congenital brain abnormalities are the result of genetic mutations that affect brain development in utero.² 

Genetic Disorders Related to LGS

Specific genetic conditions, such as tuberous sclerosis complex (TSC) and hereditary metabolic disorders, have been associated with LGS. Other genetic conditions, such as Down syndrome and Miller-Dieker syndrome, have poorly understood connections to LGS.⁴ 

TSC is caused by mutations in either the TSC1 or TSC2 gene, which are inherited in an autosomal-dominant pattern.⁵ Inherited metabolic disorders are a diverse group of more than 700 conditions in which genetic defects interfere with the metabolism of certain nutrients. As a result, an accumulation of toxins and a decrease in nutritional support to the brain can lead to the development of LGS.^2,6

Read more about LGS etiology

Known Genetic Mutations Associated With LGS

More than 50 individual genetic mutations have been identified that contribute directly to the development of LGS. In most cases, the genetic mutations are not inherited but rather arise de novo.³

Some of the genes in which de novo mutations that may cause LGS have been identified include SCN1A, GABRB3, ALG13, CHD2, SLC25A39, TBC1D8, NRG2, DNAJC5, SCN8A, STXBP1, CDKL5, DNM1, KCNQ2, SCN2A, MTOR, DCX, and FLNA.^1,7,8 

Six de novo mutations in Mendelian Inheritance in Man (MIM) epileptic encephalopathic (EE) genes contribute to LGS. These genes are SCN1A, SCN2A, SCN8A, STXBP1, CDKL5, and KCNQ2.⁸

In one study, whole-exome sequencing was used to identify ⁷:

• 1 likely pathogenic X-linked variation in the IQSEC2 gene;
• 5 de novo mutations (three of uncertain significance [SLC25A39, TBC1D8, NRG2], one likely pathogenic variant [DNAJC5], and one pathogenic variant [CHD2]);
• 3 autosomal-recessive genetic mutations (two variants of uncertain significance (SSPO, CACNA1A) and one pathogenic variant (FRRS1L); and
• 5 unknown genetic variations in the SYN1 (likely pathogenic), SYN2, SHANK3, MAGI1, (unknown significance) and SCN10A (pathogenic) genes. 

These genes were either neuron-related, epilepsy-related, or specifically LGS-related. Of the 14 mutations discovered in the study, 2 were in the splicing site and the other 12 were in the coding region, including 1 frameshift deletion, 1 nonframeshift insertion, and 10 single-nucleotide variations.⁷

Read more about LGS pathophysiology

Genetic Testing

Although genetic testing does not identify structural or cryptogenic causes of LGS that are unrelated to genetic mutations, genetic screening may benefit a majority of the 25% of patients with idiopathic or cryptogenic LGS.⁹ As genetic testing and technology advance, the identification of the causes of cryptogenic LGS will become faster and more accurate.⁹ 

For patients with cryptogenic LGS, genetic testing can alter their course of treatment. According to the LGS Foundation, 12% to 50% of patients choose a change in treatment after genetic testing discovers a genetic cause.¹⁰

Current genetic testing for LGS can be done with blood or saliva samples and may include¹⁰:

• Single-gene testing, which looks for alterations in 1 gene;
• An epilepsy gene panel, which assesses for variations across 100 to 1000 genes with known epileptic associations;
• Whole-exome sequencing, which looks at all the genes coding for specific proteins that may cause LGS if they are dysfunctional as a consequence of genetic mutations;
• Whole-genome sequencing, which looks at the entirety of the human genome, including non-coding regions;
• Chromosomal microarray analysis (CMA), which identifies deletions or duplications of chromosomes; and
• Karyotyping, which identifies abnormal numbers of structures within chromosomes.

Read more about LGS testing

Genetic Testing Resources 

Genetic testing resources for patients with LGS and their caregivers include the Rare Genomes Project, Invitae, iHope Genetic Health, AmbitCare, and Probably Genetic.¹⁰   

References 

1. Amrutkar C, Riel-Romero RM. Lennox Gastaut syndrome. StatPearls [Internet]. Updated August 1, 2022. Accessed February 28, 2023. 
2. What causes LGS? LGS Foundation. Updated August 27, 2022. Accessed February 28, 2023.
3. Lennox-Gastaut syndrome. Children’s Hospital of Philadelphia. Accessed February 28, 2023.
4. Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for Lennox-Gastaut syndrome: current and future strategies. CNS Drugs. 2021;35(1):61-83. doi:10.1007/s40263-020-00784-8
5. Tuberous sclerosis complex. NIH National Institute of Neurological Disorders and Stroke. Accessed February 28, 2023.
6. Pampols T. Inherited metabolic rare disease. In: Posada de la Paz M, Groft S, eds. Rare Diseases Epidemiology. Adv Exp Med Biol. 2010;686:397-431. doi:10.1007/978-90-481-9485-8_23
7. Yang JO, Choi MH, Yoon JY, et al. Characteristics of genetic variations associated with Lennox-Gastaut syndrome in Korean families. Front Genet. 2021;11:590924. doi:10.3389/fgene.2020.590924
8. Epi4K and EPGP Investigators. De novo mutations in the classic epileptic encephalopathies. Nature. 2013;501(7466):217-221. doi:10.1038/nature12439
9. Montouris G, Aboumatar S, Burdette D, Kuzniecky R, Rosenfeld W, Chung S. Expert opinion: proposed diagnostic and treatment algorithms for Lennox–Gastaut syndrome in adult patients. Epilepsy Behav. 2020;110:107146. doi:10.1016/j.yebeh.2020.107146
10. Genetic testing in LGS. LGS Foundation. Accessed February 28, 2023.

Reviewed by Kyle Habet, MD, on 2/27/2023.

---

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.