Epilepsy and electroencephalography in Pitt-Hopkins syndrome

Abstract

Aim: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by mono-allelic loss of function variants of transcription factor 4 (TCF4), which plays a key role in early brain developmental and neuronal differentiation. Up to one-half of patients with PTHS will have epilepsy; however, little is known about the characteristic electroencephalogram (EEG) findings in this population. Because there is significant phenotypic overlap between PTHS and other neurodevelopmental disorders such as Angelman syndrome and Rett syndrome, which have characteristic EEG patterns, exploration of a potential EEG signature in patients with PTHS was warranted.

Methods: We conducted a retrospective review of clinical EEGs in patients with PTHS.

Results: In this cohort of patients with PTHS (n = 16), over half had abnormal EEGs; however, no characteristic EEG signature was identified. Further, all patients with epilepsy (5/16) had focal onset seizures with or without secondary generalization, and all five had focal abnormalities on EEG. There was no specific correlation between EEG results and developmental trajectories or age in our patient group, and there was no clear genotype-phenotype correlation.

Conclusion: Although a distinctive EEG signature was not identified, all individuals with epilepsy in our cohort had focal onset seizures with corresponding focal epileptiform discharges or focal slowing on EEG. Future studies are needed to fully elucidate the spectrum of EEG findings in PTHS and explore the pathogenesis of focal seizures in a disorder of neuronal differentiation and development.

Keywords

Pitt-Hopkins syndrome / epilepsy / EEG / TCF4

References

[1] GoodspeedK,MorrisMA,EvansP.Pitt-Hopkins syndrome: a review of current literature, clinical approach, and 23-patient case series.J Child Neurol2018;33:233-44 PMCID:PMC5922265

[2] SweattJD.Pitt-Hopkins syndrome: intellectual disability due to loss of TCF4-regulated gene transcription.Exp Mol Med2013;45:e21 PMCID:PMC3674405

[3] MatricardiS,IapadreG.Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.Eur J Neurol2022;29:19-25

[4] ZollinoM,VanBalkom ID.Diagnosis and management in Pitt-Hopkins syndrome: first international consensus statement.Clin Genet2019;95:462-78

[5] WatkinsA,MossJ.Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes.J Neurodev Disord2019;11:24 PMCID:PMC6778364

[6] TanA,EdgarVB.Pitt-Hopkins syndrome: a unique case study.J Int Neuropsychol Soc2018;24:995-1002

[7] CurròA,BruttiniM.CDKL5 mutations may mimic Pitt-Hopkins syndrome phenotype.Eur J Med Genet2021;64:104102

[8] PearsonE,OliverC,Clayton-SmithJ.The adaptive functioning profile of Pitt-Hopkins syndrome.Eur J Med Genet2021;64:104279

[9] Balkom ID, Vuijk PJ, Franssens M, Hoek HW, Hennekam RC. Development, cognition, and behaviour in Pitt-Hopkins syndrome.Dev Med Child Neurol2012;54:925-31

[10] CarotenutoM,PisaniF.Polysomnographic findings in fragile x syndrome children with EEG abnormalities.Behav Neurol2019;2019:5202808 PMCID:PMC6915005

[11] MainiI,TurcoEC.Clinical and polygraphic improvement of breathing abnormalities after valproate in a case of Pitt-Hopkins syndrome.J Child Neurol2012;27:1585-8

[12] KirikaeH,Numata-UematsuY.Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation.Brain Dev2022;44:148-52

[13] BedeschiMF,CalvelloMR.Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.Eur J Med Genet2017;60:565-71

[14] LaanLA.Angelman syndrome: is there a characteristic EEG?.Brain Dev2005;27:80-7

[15] KennedyAJ,PaulukaitisBS.Tcf4 regulates synaptic plasticity, DNA methylation, and memory function.Cell Rep2016;16:2666-85 PMCID:PMC5710002

[16] SeppM,EesmaaA,TimmuskT.Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5’ exon usage and splicing.PLoS One2011;6:e22138 PMCID:PMC3137626

[17] ForrestM,DoyleAM,WaiteA.Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.Hum Mutat2012;33:1676-86

[18] SeppM,TimmuskT.Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.Hum Mol Genet2012;21:2873-88

[19] SabyJN,RobertsTPL,MarshED.Evoked potentials and EEG analysis in Rett syndrome and related developmental encephalopathies: towards a biomarker for translational research.Front Integr Neurosci2020;14:30 PMCID:PMC7271894