Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation

• Published in: Brain & development (Tokyo. 1979) 2022-02, Vol.44 (2), p.148-152
• Main Authors: Kirikae, Hinako, Uematsu, Mitsugu, Numata-Uematsu, Yurika, Saijo, Naoya, Katata, Yu, Oikawa, Yoshitsugu, Kikuchi, Atsuo, Yanagi, Kumiko, Kaname, Tadashi, Haginoya, Kazuhiro, Kure, Shigeo
• Format: Article
• Language: English
• Subjects: Anticonvulsants - pharmacology; Epileptic encephalopathy; Facies; Humans; Hyperventilation - diagnosis; Hyperventilation - drug therapy; Hyperventilation - genetics; Hyperventilation - physiopathology; Infant; Intellectual Disability - diagnosis; Intellectual Disability - drug therapy; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Male; Migrating seizure; Mutation, Missense; Spasms; Spasms, Infantile - diagnosis; Spasms, Infantile - drug therapy; Spasms, Infantile - genetics; Spasms, Infantile - physiopathology; TCF4; Topiramate; Topiramate - pharmacology; Transcription Factor 4 - genetics
• ISSN: 0387-7604; 1872-7131
• DOI: 10.1016/j.braindev.2021.09.003

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy. The patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy. To our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.