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SZT2 disease, also known as Early Infantile Epileptic Encephalopathy-18 (, is a very rare genetic condition that occurs when a child carries two bad copies of the SZT2 gene, typically inherited by chance from unrelated parents. The gene was first discovered in 2009 (1), the 2nd in a series of laboratory mice bred to have a low seizure threshold (more susceptible; hence the gene name i.e. Seizure Threshold 2). From 2013 to 2020, multiple reports of children with this genetic condition began to appear in the literature, most with independent SZT2 mutations (2, 3, 6-15). The physiological role of the SZT2 protein only began to emerge in 2017 with two studies (4, 5) showing that SZT2 forms a novel complex (called “KICSTOR”) that regulates (keeps in check) a molecular signaling pathway called mTOR (, known to be important for cell growth and survival and implicated in several medical conditions, including cancer and other neurological diseases such as tuberous sclerosis. While literature on SZT2 itself is still limited, the common clinical features (intractable seizures and distinct neuroradiological anomalies) and emerging ideas about its normal function provides hope that effective therapies will be developed.


SZT2 Symptoms:

The following are some (not all) common symptoms noted in patients with SZT2:

  • One of the most common features of this disease is seizures that do not respond well to available medications.

  • The first seizures usually occur between 3 months and 3 years of age. 

  • Infantile spasms at first year of age is possible (WEST SYNDROME)

  • Seizures are often drug resistant and difficult to control.

  • Hypotonia (low muscle tone)

  • Macrocephaly (large head)

  • Strong forehead

  • Abnormal EEG

  • Loss of  milestones or regression with increased seizures 

  • Mild to severe cognitive/intellectual delay

  • Mild to severe delayed development 


1: Frankel WN, Yang Y, Mahaffey CL, Beyer BJ, O'Brien TP. Szt2, a novel gene for

seizure threshold in mice. Genes Brain Behav. 2009 Jul;8(5):568-76. doi:

10.1111/j.1601-183X.2009.00509.x. PMID: 19624305; PMCID: PMC2728062.


2: Basel-Vanagaite L, Hershkovitz T, Heyman E, Raspall-Chaure M, Kakar N,

Smirin-Yosef P, Vila-Pueyo M, Kornreich L, Thiele H, Bode H, Lagovsky I, Dahary

D, Haviv A, Hubshman MW, Pasmanik-Chor M, Nürnberg P, Gothelf D, Kubisch C,

Shohat M, Macaya A, Borck G. Biallelic SZT2 mutations cause infantile

encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet.

2013 Sep 5;93(3):524-9. doi: 10.1016/j.ajhg.2013.07.005. Epub 2013 Aug 8. PMID:

23932106; PMCID: PMC3769928.


3: Venkatesan C, Angle B, Millichap JJ. Early-life epileptic encephalopathy

secondary to SZT2 pathogenic recessive variants. Epileptic Disord. 2016 Jun

1;18(2):195-200. doi: 10.1684/epd.2016.0828. PMID: 27248490.


4: Wolfson RL, Chantranupong L, Wyant GA, Gu X, Orozco JM, Shen K, Condon KJ,

Petri S, Kedir J, Scaria SM, Abu-Remaileh M, Frankel WN, Sabatini DM. KICSTOR

recruits GATOR1 to the lysosome and is necessary for nutrients to regulate

mTORC1. Nature. 2017 Mar 16;543(7645):438-442. doi: 10.1038/nature21423. Epub

2017 Feb 15. PMID: 28199306; PMCID: PMC5360989.


5: Peng M, Yin N, Li MO. SZT2 dictates GATOR control of mTORC1 signalling.

Nature. 2017 Mar 16;543(7645):433-437. doi: 10.1038/nature21378. Epub 2017 Feb

15. Erratum in: Nature. 2018 May 16;: PMID: 28199315; PMCID: PMC5570594.


6: Tsuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, Teik

KW, Ch'ng GS, Kato M, Mizuguchi T, Takata A, Miyatake S, Miyake N, Osaka H,

Yamagata T, Nakajima H, Saitsu H, Matsumoto N. Novel biallelic SZT2 mutations in

3 cases of early-onset epileptic encephalopathy. Clin Genet. 2018

Feb;93(2):266-274. doi: 10.1111/cge.13061. Epub 2017 Sep 18. PMID: 28556953.


7: Nakamura Y, Togawa Y, Okuno Y, Muramatsu H, Nakabayashi K, Kuroki Y, Ieda D,

Hori I, Negishi Y, Togawa T, Hattori A, Kojima S, Saitoh S. Biallelic mutations

in SZT2 cause a discernible clinical entity with epilepsy, developmental delay,

macrocephaly and a dysmorphic corpus callosum. Brain Dev. 2018

Feb;40(2):134-139. doi: 10.1016/j.braindev.2017.08.003. Epub 2017 Oct 12. PMID:



8: Naseer MI, Alwasiyah MK, Abdulkareem AA, Bajammal RA, Trujillo C, Abu-Elmagd

M, Jafri MA, Chaudhary AG, Al-Qahtani MH. A novel homozygous mutation in SZT2

gene in Saudi family with developmental delay, macrocephaly and epilepsy. Genes

Genomics. 2018 Nov;40(11):1149-1155. doi: 10.1007/s13258-018-0673-5. Epub 2018

Feb 28. PMID: 30315519.


9: Pizzino A, Whitehead M, Sabet Rasekh P, Murphy J, Helman G, Bloom M, Evans

SH, Murnick JG, Conry J, Taft RJ, Simons C, Vanderver A, Adang LA. Mutations in

SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy. Am

J Med Genet A. 2018 Jun;176(6):1443-1448. doi: 10.1002/ajmg.a.38717. Epub 2018

Apr 25. PMID: 29696782.


10: Imaizumi T, Kumakura A, Yamamoto-Shimojima K, Ondo Y, Yamamoto T.

Identification of a rare homozygous <i>SZT2</i> variant due to uniparental

disomy in a patient with a neurodevelopmental disorder. Intractable Rare Dis

Res. 2018 Nov;7(4):245-250. doi: 10.5582/irdr.2018.01117. PMID: 30560016; PMCID:



11: Domingues FS, König E, Schwienbacher C, Volpato CB, Picard A, Cantaloni C,

Mascalzoni D, Lackner P, Heimbach A, Hoffmann P, Stanzial F, Hicks AA,

Parmeggiani L, Benedicenti F, Pellegrin S, Casara G, Pramstaller PP. Compound

heterozygous SZT2 mutations in two siblings with early-onset epilepsy,

intellectual disability and macrocephaly. Seizure. 2019 Mar;66:81-85. doi:

10.1016/j.seizure.2018.12.021. Epub 2018 Dec 23. PMID: 30818181.


12: Iodice A, Spagnoli C, Frattini D, Salerno GG, Rizzi S, Fusco C. Biallelic

SZT2 mutation with early onset of focal status epilepticus: Useful diagnostic

clues other than epilepsy, intellectual disability and macrocephaly. Seizure.

2019 Jul;69:296-297. doi: 10.1016/j.seizure.2019.05.015. Epub 2019 May 19. PMID:



13: Sun X, Zhong X, Li T. Novel SZT2 mutations in three patients with

developmental and epileptic encephalopathies. Mol Genet Genomic Med. 2019

Sep;7(9):e926. doi: 10.1002/mgg3.926. Epub 2019 Aug 8. PMID: 31397114; PMCID:


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