Midline Non-ictal Rhythmic Waveforms As Possible Electroencephalographic Biomarkers of Smith-Klingsmore Syndrome in Children

Overview

Journal Clin Neurophysiol Pract

Publisher Elsevier

Specialty Neurology

Date 2024 Mar 18

PMID 38495955

Authors

Valerio Simonelli

Anna Rita Ferrari

Roberta Battini

Paola Brovedani

Emanuele Bartolini

Affiliations

Soon will be listed here.

Abstract

Introduction: Pathogenic variants of the MTOR gene result in the Smith-Kingsmore syndrome, whose phenotypical spectrum includes facial dysmorphisms and neurological features. Expressivity is variable, patients exhibit a combination of intellectual disability, macrocephaly and epilepsy. The diagnosis can be missed, failing to detect the causative pathogenic mutation in patients with somatic mosaicism or even skipping to analyze when the phenotype is not completely expressed.

Case Study: Herein, we report two children harboring the same MTOR recurring mutation (c.5395G>A/p.Glu1799Lys) whose EEG displayed a peculiar combination of midline rhythmic waveforms and asynchronous spike-and-wave discharges with anterior fast activity in sleep and wake. : We suggest these features might be considered as possible hallmarks of the syndrome and could aid to expedite the diagnosis when the phenotype is incomplete.

References

Poole R, Curry P, Marcinkute R, Brewer C, Coman D, Hobson E . Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant. Am J Med Genet A. 2021; 185(8):2445-2454. DOI: 10.1002/ajmg.a.62350. View

Carli D, Ferrero G, Fusillo A, Coppo P, La Selva R, Zinali F . A new case of Smith-Kingsmore syndrome with somatic MTOR pathogenic variant expands the phenotypic spectrum to lateralized overgrowth. Clin Genet. 2021; 99(5):719-723. DOI: 10.1111/cge.13931. View

Moller R, Weckhuysen S, Chipaux M, Marsan E, Taly V, Bebin E . Germline and somatic mutations in the gene in focal cortical dysplasia and epilepsy. Neurol Genet. 2016; 2(6):e118. PMC: 5089441. DOI: 10.1212/NXG.0000000000000118. View

Moloney P, Cavalleri G, Delanty N . Epilepsy in the mTORopathies: opportunities for precision medicine. Brain Commun. 2021; 3(4):fcab222. PMC: 8495134. DOI: 10.1093/braincomms/fcab222. View

Tischkowitz M, Colas C, Pouwels S, Hoogerbrugge N . Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. Eur J Hum Genet. 2020; 28(10):1387-1393. PMC: 7608293. DOI: 10.1038/s41431-020-0651-7. View

Gordo G, Tenorio J, Arias P, Santos-Simarro F, Garcia-Minaur S, Moreno J . mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. Clin Genet. 2017; 93(4):762-775. DOI: 10.1111/cge.13135. View

Hughes J . Two forms of the 6/sec spike and wave complex. Electroencephalogr Clin Neurophysiol. 1980; 48(5):535-50. DOI: 10.1016/0013-4694(80)90289-8. View

Mirzaa G, Campbell C, Solovieff N, Goold C, Jansen L, Menon S . Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol. 2016; 73(7):836-845. PMC: 4979321. DOI: 10.1001/jamaneurol.2016.0363. View

Moosa S, Bohrer-Rabel H, Altmuller J, Beleggia F, Nurnberg P, Li Y . Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism. Am J Med Genet A. 2016; 173(1):264-267. DOI: 10.1002/ajmg.a.37999. View

10.

Besterman A, Althoff T, Elfferich P, Gutierrez-Mejia I, Sadik J, Bernstein J . Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity. PLoS Genet. 2021; 17(7):e1009651. PMC: 8279410. DOI: 10.1371/journal.pgen.1009651. View

11.

Northrup H, Aronow M, Bebin E, Bissler J, Darling T, de Vries P . Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021; 123:50-66. DOI: 10.1016/j.pediatrneurol.2021.07.011. View

12.

Yoo J, Marcuse L, Fields M, Rosengard J, Traversa M, Gaspard N . Brief Potentially Ictal Rhythmic Discharges [B(I)RDs] in Noncritically Ill Adults. J Clin Neurophysiol. 2017; 34(3):222-229. DOI: 10.1097/WNP.0000000000000357. View

13.

Szczaluba K, Rydzanicz M, Walczak A, Kosinska J, Koppolu A, Biernacka A . Brain Tissue Low-Level Mosaicism for Mutation Causes Smith-Kingsmore Phenotype with Recurrent Hypoglycemia-A Novel Phenotype and a Further Proof for Testing of an Affected Tissue. Diagnostics (Basel). 2021; 11(7). PMC: 8303645. DOI: 10.3390/diagnostics11071269. View

14.

Grabiner B, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S . A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 2014; 4(5):554-63. PMC: 4012430. DOI: 10.1158/2159-8290.CD-13-0929. View