By: Imogen Ronde
By: Imogen Ronde
What is Lennox-Gastaut Syndrome?
Lennox-Gastaut Syndrome is a rare and severe form of epilepsy which occurs in an estimated 1-10% of all childhood epilepsies (Camfield, 2011). Age of onset ranges from 1-7 years (Crumrine, 2002), however there is also a peak age of onset between three and five years of age (Camfield, 2011).
History:
Lennox-Gastaut Syndrome was first described in 1966 by Gastaut et al., who proposed the term Lennox Syndrome (who first reported the syndrome)for “childhood-onset epilepsy characterized by frequent tonic and absence seizures.” This definition was clarified in 1989 by the International League Against Epilepsy (Camfield, 2011).
What causes Lennox-Gastaut Syndrome?
Lennox-Gastaut Syndrome can occur as the result of a brain injury, at any time from the prenatal to neonatal periods, but can also occur in a previously healthy child (Arzimanoglou et al., 2009). It can also be caused by central nervous system infections, brain malformation, and tuberous sclerosis, as well as inherited genetic and metabolic conditions (Lennox-Gastaut Syndrome Information Page, 2019). There is evidence that it may be caused by a nonsense mutation in the TANC2 gene, which was found during whole-genome sequencing of a Chinese boy (Tian et al., 2021). A nonsense mutation causes the translation of mRNA to protein to stop prematurely, resulting in nonfunctional proteins (Kasper & Buzin, 2022).
Whole-genome sequencing has also provided evidence for two tandem repeat expansions in patients with Lennox-Gastaut Syndrome, a CGG repeat expansion in the 5’ untranslated region of the DIP2B gene, and a CTG expansion in the ATXN8OS gene. Tandem repeat expansions are repeated DNA sequences that can cause unstable changes in proteins, and may be the cause of epilepsies in other patients as well (Fan & Chu, 2007). These biological markers could be an important tool in the future for treatment and prevention of Lennox-Gastaut Syndrome.
Signs and Symptoms:
Lennox-Gastaut Syndrome is characterized by multiple types of seizures, as well as periods of frequent seizures and seizure-free periods. There is also a particular patten of brain electrical activity, a slow spike-wave pattern of about 1.5-2.5 Hz, that can be seen using electroencephalograms (Lennox-Gastaut Syndrome Information Page, 2019). While it may not occur at the time of first seizures, most patients display cognitive impairments as well (Crumrine, 2002)
Complications associated with Lennox-Gastaut Syndrome:
Due to cognitive impairment, most patients with Lennox-Gastaut Syndrome have reduced quality of life circumstances. Patients often require continuous care, and are depressed or anxious because of their condition. Many need to use wheelchairs and wear a helmet in case of drop seizures, which some reported occurred anywhere between 45 and 110 times a month, in order to prevent injuries, which cause additional pain and discomfort. These complications can lead to distress in caregivers, especially parents, who have an extremely high caregiver burden (Lo et al, 2021).
How is it diagnosed?
Lennox-Gastaut Syndrome is diagnosed by multiple seizures and types of seizure, which are often resistant to treatment options, an unusual EEG spike pattern, and some amount of cognitive impairment. Patients usually have normal MRIs, and so are also screened with a metabolic evaluation and a neuropsychologic evaluation for cognitive and language assessments (Crumrine, 2002).
Management and treatment:
Lennox-Gastaut Syndrome is very difficult to treat, as it is resistant to most anti-seizure medications. A combination of anticonvulsant medications may be necessary, which can cause side-effects, but other options include the ketogenic diet, vagus nerve stimulation, and epilepsy surgery (Lennox-Gastaut Syndrome Information Page, 2019). There are ongoing studies with multiple different dugs, but two promising ones are Fenfluramine, an appetite-suppressant that seems to have anti-seizure qualities, and cannabidiol, which has been approved as adjunctive therapy with clobazam in patients with Lennox-Gastaut Syndrome (Verrotti & Striano, 2021).
Prognosis:
Sadly, long-term outcomes regarding both seizure control and intellectual development are disappointing (Camfield, 2011). There is no cure for Lennox-Gastaut Syndrome, and complete recovery from seizures and normal development are extremely rare (Lennox-Gastaut Syndrome Information Page, 2019).
Resources:
Arzimanoglou, A. et al. (2009). Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. The Lancet, 8, 82–93.
Camfield, P. R. (2011). Definition and natural history of Lennox-Gastaut syndrome. Epilepsia, 52, 3–9. https://doi.org/10.1111/j.1528-1167.2011.03177.x
Kasper, Carol & Buzin, Carolyn. (2022). GENETICS OF HEMOPHILIA A AND B An introduction for clinicians, 2007.
Fan H, Chu JY. A brief review of short tandem repeat mutation. Genomics Proteomics Bioinformatics. 2007 Feb;5(1):7-14. doi: 10.1016/S1672-0229(07)60009-6. PMID: 17572359; PMCID: PMC5054066.
Lennox-Gastaut Syndrome Information Page. (2019, March 27). Retrieved March 29, 2022, from https://www.ninds.nih.gov/Disorders/All-Disorders/Lennox-Gastaut-Syndrome-Information-Page
Crumrine, P. K. (2002). Lennox-Gastaut Syndrome. Journal of Child Neurology, 17(Supplement 1), S70–S75. https://doi.org/10.20966/chn
Tian, Y., Shi, Z., Hou, C., Li, W., Wang, X., Zhu, H., Li, X., & Chen, W.-X. (2021). Truncating mutation in TANC2 in a Chinese boy associated with Lennox-Gastaut syndrome: a case report. BMC Pediatrics, 21(1), 546. https://doi-org.proxy.westernu.edu/10.1186/s12887-021-03021-3
Lo, S. H., Lloyd, A., Marshall, J., & Vyas, K. (2021). Patient and Caregiver Health State Utilities in Lennox-Gastaut Syndrome and Dravet Syndrome. Clinical Therapeutics, 43(11), 1861. https://doi-org.proxy.westernu.edu/10.1016/j.clinthera.2021.09.017
Verrotti, A., & Striano, P. (2021). Novel therapeutic options for Dravet and Lennox-Gastaut syndrome. Expert Review of Neurotherapeutics, 21(11), 1191–1194. https://doi-org.proxy.westernu.edu/10.1080/14737175.2020.1862651
Qaiser, F., Sadoway, T., Yin, Y., Ali, Q. Z., Nguyen, C. M., Shum, N., Backstrom, I., Marques, P. T., Tabarestani, S., Munhoz, R. P., Krings, T., Pearson, C. E., Yuen, R. K. C., & Andrade, D. M. (2021). Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox–Gastaut syndrome. Brain Communications, 3(3). https://doi-org.proxy.westernu.edu/10.1093/braincomms/fcab207
