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PubMed This is a summary of 20 peer-reviewed journal articles Updated
Neurology

Understanding the Causes: Genetics, Brain Structure, and Evolution

At a Glance

Lennox-Gastaut Syndrome (LGS) has many possible causes, including genetic mutations, structural brain abnormalities, and early brain injuries. Many cases evolve from West Syndrome. Identifying the exact cause through advanced MRI or genetic testing can sometimes guide targeted treatments.

Understanding why Lennox-Gastaut Syndrome (LGS) developed can be one of the most important steps in navigating care. LGS is polyetiological, which means it has many different possible causes [1][2]. Finding the “root cause” is not always possible, but when it is, it can sometimes open the door to more targeted treatments [3][4].

Structural Causes

In many cases, LGS is caused by a physical difference in how the brain was formed or by an early brain injury [5][6].

  • Cortical Dysplasia: This occurs when some brain cells do not travel to the right place during development, creating a “mismatch” in the brain’s wiring [7].
  • Tuberous Sclerosis Complex (TSC): A genetic condition that causes non-cancerous tumors to grow in the brain and other organs, which can trigger the seizures seen in LGS [8].
  • Brain Injury: Issues like lack of oxygen at birth or a severe infection (like meningitis) can damage brain networks and lead to LGS later in childhood [7].

Genetic Causes

Advances in science have shown that many cases of LGS that were once “unexplained” actually have a genetic cause [9]. These are often de novo mutations, meaning they happened by chance in the child and were not inherited from the parents [9].

  • Key Genes: Researchers have identified several genes linked to LGS, including SCN2A, KCNT1, GABRB3, and HDAC4 [9][10][11].
  • Precision Medicine: For some genes, like KCNT1, doctors may attempt treatments with medications like quinidine. However, these are often experimental, require intense cardiac monitoring (EKGs) due to severe heart risks, and are not universally effective [12].

The Evolution from West Syndrome

LGS does not always start on its own. For many children, it is the next stage of a journey that began with West Syndrome (also known as infantile spasms) [13][14].

  • The Transition Statistics: While about 20% to 30% of all LGS cases start as West Syndrome, looking at it from the other direction, 25% to 60% of children with West Syndrome eventually transition into LGS [15][14].
  • Risk Factors: Children are more likely to transition from West Syndrome to LGS if their initial spasms were difficult to treat or if they had developmental delays before the spasms started [14][16].

Recommended Testing

To find the cause, your neurology team may recommend a “deep dive” using advanced tools:

  1. 3T High-Resolution MRI: A more powerful scan than a standard MRI, used to find tiny structural issues like cortical dysplasia [17][18].
  2. Whole Exome Sequencing (WES): A genetic test that looks at all the “coding” parts of DNA to find rare mutations [9][3].
  3. Metabolic Testing: Blood and urine tests to see if the brain is struggling to process certain nutrients or chemicals [19].

Identifying the cause can be a relief, but it is also okay if the cause remains “unknown.” In both cases, the focus remains on managing the seizures and supporting development [20][4].

Common questions in this guide

Is Lennox-Gastaut Syndrome inherited from parents?
Often, it is not inherited. Many genetic cases of LGS are caused by de novo mutations, meaning the genetic change happened by chance in the child and was not passed down from either parent.
Does West Syndrome always turn into Lennox-Gastaut Syndrome?
No, but it is a common progression. About 25% to 60% of children with West Syndrome eventually transition into LGS, particularly if their initial infantile spasms were difficult to treat or if they had early developmental delays.
What tests are used to find the cause of LGS?
Neurologists usually recommend advanced tools like a high-resolution 3T MRI to check for subtle brain structure issues, and Whole Exome Sequencing to look for rare genetic mutations. Metabolic tests may also be ordered.
Why did my doctor order a 3T MRI for LGS?
A high-resolution 3-Tesla MRI is a more powerful scan than a standard MRI. It is used to find tiny structural issues in the brain, such as cortical dysplasia, that could be the root cause of the seizures.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Has a 3-Tesla (3T) MRI been completed to check for subtle structural issues like cortical dysplasia?
  2. 2.Should we perform Whole Exome Sequencing (WES) to look for genetic causes like SCN2A or KCNT1?
  3. 3.If a genetic mutation is found, does it suggest a 'precision medicine' treatment that we aren't currently using?
  4. 4.Since there is a history of West Syndrome, does that evolution change our long-term expectations for development?
  5. 5.Are there any metabolic tests we should run before we commit to long-term medication plans?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (20)
  1. 1

    [Why the diagnosis of Lennox-Gastaut syndrome is a rare one?]

    Belousova ED, Gorchanova ZK, Dorofeeva MY

    Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova 2019; (119(11. Vyp. 2)):41-47 doi:10.17116/jnevro201911911241.

    PMID: 32207730
  2. 2

    Evolution and course of early life developmental encephalopathic epilepsies: Focus on Lennox-Gastaut syndrome.

    Berg AT, Levy SR, Testa FM

    Epilepsia 2018; (59(11)):2096-2105 doi:10.1111/epi.14569.

    PMID: 30255934
  3. 3

    Current and emerging pharmacotherapies in Lennox-Gastaut syndrome.

    Samanta D, Nath M

    Expert opinion on pharmacotherapy 2025; (26(10)):1133-1147 doi:10.1080/14656566.2025.2516630.

    PMID: 40468679
  4. 4

    Antiseizure medications for Lennox-Gastaut Syndrome: Comprehensive review and proposed consensus treatment algorithm.

    Samanta D, Bhalla S, Bhatia S, et al.

    Epilepsy & behavior : E&B 2025; (164()):110261 doi:10.1016/j.yebeh.2024.110261.

    PMID: 39854828
  5. 5

    Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials.

    Pong AW, Ross J, Tyrlikova I, et al.

    Expert opinion on emerging drugs 2022; (27(1)):75-90 doi:10.1080/14728214.2022.2059464.

    PMID: 35341431
  6. 6

    Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy.

    Aronica E, Specchio N, Luinenburg MJ, Curatolo P

    Brain : a journal of neurology 2023; (146(7)):2694-2710 doi:10.1093/brain/awad048.

    PMID: 36806388
  7. 7

    Epilepsy Surgery is a Viable Treatment for Lennox Gastaut Syndrome.

    Keator CG

    Seminars in pediatric neurology 2021; (38()):100894 doi:10.1016/j.spen.2021.100894.

    PMID: 34183143
  8. 8

    Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy.

    Montebello G, Di Giovanni G

    International journal of molecular sciences 2025; (26(13)) doi:10.3390/ijms26136234.

    PMID: 40650012
  9. 9

    Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

    Yang JO, Choi MH, Yoon JY, et al.

    Frontiers in genetics 2020; (11()):590924 doi:10.3389/fgene.2020.590924.

    PMID: 33584793
  10. 10

    Neuropathologic Findings in Lennox-Gastaut Syndrome (SCN2A-Related): A Case Report and Review of Literature.

    Thompson C, Khatskevich K, Welsh CT, et al.

    Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2025; (28(5)):420-424 doi:10.1177/10935266251345684.

    PMID: 40536032
  11. 11

    Phenotypic Manifestations of a New Variant in HDAC4 Gene.

    Ianniello M, De Angelis V, Ottaiano A, et al.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2025; (198(6)):32-37 doi:10.1002/ajmg.b.33029.

    PMID: 40167013
  12. 12

    Quinidine Therapy for Lennox-Gastaut Syndrome With KCNT1 Mutation. A Case Report and Literature Review.

    Jia Y, Lin Y, Li J, et al.

    Frontiers in neurology 2019; (10()):64 doi:10.3389/fneur.2019.00064.

    PMID: 30804880
  13. 13

    Pediatric Epileptic Encephalopathies: Pathophysiology and Animal Models.

    Shao LR, Stafstrom CE

    Seminars in pediatric neurology 2016; (23(2)):98-107.

    PMID: 27544466
  14. 14

    Evolution of Infantile Spasms to Lennox-Gastaut Syndrome: What Is There to Know?

    Nelson JA, Demarest S, Thomas J, et al.

    Journal of child neurology 2021; (36(9)):752-759 doi:10.1177/08830738211000514.

    PMID: 33764203
  15. 15

    [Transional syndrome: from West to Lennox-Gastaut syndromes].

    Malagon Valdez J

    Medicina 2018; (78 Suppl 2()):2-5.

    PMID: 30199357
  16. 16

    A Multicenter Retrospective Observational Cohort Study of Seizure Freedom before Lennox-Gastaut Syndrome (the "Gap"). Opportunities for Prevention.

    Deering L, Nelson A, Yozawitz E, et al.

    medRxiv : the preprint server for health sciences 2024; doi:10.1101/2024.12.03.24318373.

    PMID: 39677451
  17. 17

    Late onset Lennox-Gastaut syndrome.

    Hisamoto Y

    Seminars in pediatric neurology 2025; (56()):101240 doi:10.1016/j.spen.2025.101240.

    PMID: 41371874
  18. 18

    Neurostimulation for Generalized Epilepsy: Should Therapy be Syndrome-specific?

    Warren AEL, Tobochnik S, Chua MMJ, et al.

    Neurosurgery clinics of North America 2024; (35(1)):27-48 doi:10.1016/j.nec.2023.08.001.

    PMID: 38000840
  19. 19

    Current and emerging pharmacotherapy for the treatment of Lennox-Gastaut syndrome.

    Besag FMC, Vasey MJ, Chin RFM

    Expert opinion on pharmacotherapy 2023; (24(11)):1249-1268 doi:10.1080/14656566.2023.2215924.

    PMID: 37212330
  20. 20

    Early Diagnosis and Treatment of Lennox-Gastaut Syndrome.

    Resnick T, Sheth RD

    Journal of child neurology 2017; (32(11)):947-955 doi:10.1177/0883073817714394.

    PMID: 28689466

This page explains the potential causes of Lennox-Gastaut Syndrome for educational purposes only. Your child's neurology team is the best source for interpreting genetic and metabolic test results.

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