Abstract
Purpose
Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES).
Methods and results
Two probands presented with focal motor seizures at 3 months of age, with a limited course. Both children presented, at around 5 years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members.
Conclusion
The mechanism leading to epilepsy and the phenotypic variability of PRRT2 variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in the PRRT2 gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands.
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Data Availability
The data that support the findings of this study are available, upon request, from the corresponding author within a reasonable time after the publication of this article. With possible restrictions due to privacy or ethical concerns.
References
Vigevano F (2005) Benign familial infantile seizures. Brain Dev 27(3 SPEC. ISS):172–177. https://doi.org/10.1016/j.braindev.2003.12.012
Heron SE, Dibbens LM (2013) Role of PRRT2 in common paroxysmal neurological disorders: a gene with remarkable pleiotropy. J Med Genet 50(3):133–139. https://doi.org/10.1136/jmedgenet-2012-101406
Tassinari C et al (2000) Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia. Clin Neurophysiol 111(SUPPL. 2):S94–S102 ([Online])
Labate A, Labate P, Viri M, Mumoli L, Gagliardi M, Romeo A, Zara F, Annesi G, Gambardella A (2012) Homozygous c . 649dupC mutation in PRRT2 worsens the BFIS / PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia 53(12):196–199. https://doi.org/10.1111/epi.12009
Terney D, Kölmel MS, Khinchi M, Olsen TG et al (2016) Clinico-neurophysiological and genetic features of ESES/CSWS in Denmark. Epilepsia 57(suppl. 2):6–225. https://doi.org/10.1111/epi.13609
Lesca G et al (2012) Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia 53(9):1526–1538. https://doi.org/10.1111/j.1528-1167.2012.03559.x
Fruscione F et al (2018) PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain 141(4):1000–1016. https://doi.org/10.1093/brain/awy051
Valente P et al (2016) PRRT2 is a key component of the Ca2+-dependent neurotransmitter release machinery. Cell Rep 15(1):117–131. https://doi.org/10.1016/j.celrep.2016.03.005
Bomben VC, Aiba I, Qian J, Mark XMD, Herlitze S, Noebels XJL (2016) Isolated P / Q calcium channel deletion in layer VI corticothalamic neurons generates absence epilepsy. J Neurosci 36(2):405–418. https://doi.org/10.1523/JNEUROSCI.2555-15.2016
Hasi-Zogaj M et al (2015) A review of 18p deletions. Am J Med Genet C Semin Med Genet 169(3):251–264. https://doi.org/10.1002/ajmg.c.31445
Acknowledgements
We thank the family involved for their participation and cooperation in this study. We also acknowledge the Danish Epilepsy Centre staff members for the help and technical assistance.
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Cossu, A., Santos, J.L., Galati, G. et al. PRRT2 benign familial infantile seizures (BFIS) with atypical evolution to encephalopathy related to status epilepticus during sleep (ESES). Neurol Sci 44, 2173–2176 (2023). https://doi.org/10.1007/s10072-023-06735-7
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DOI: https://doi.org/10.1007/s10072-023-06735-7