Epilepsy, electroclinical features, and long-term outcomes in Pitt–Hopkins syndrome due to pathogenic variants in the TCF4 gene

Sara Matricardi, Paolo Bonanni, Giulia Iapadre, Maurizio Elia, Elisabetta Cesaroni, Alberto Danieli, Susanna Negrin, Luca Zagaroli, Francesca Felicia Operto, Marco Carotenuto, Francesco Pisani, Emanuela Claudia Turco, Alessandro Orsini, Alice Bonuccelli, Salvatore Savasta, Daniela Concolino, Giuseppe Di Cara, Pasquale Striano, Alberto Verrotti

Research output: Contribution to journalArticlepeer-review


Background and purpose: Pitt–Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. Methods: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. Results: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5–8). The median time of follow-up was 7.9 years (range = 2–27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003–0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. Conclusions: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Original languageEnglish
JournalEuropean Journal of Neurology
Publication statusAccepted/In press - 2021


  • antiseizure medications
  • epilepsy
  • Pitt–Hopkins syndrome
  • seizures
  • TCF4 gene

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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