Page 26 - Read Online

Bone et al. J Transl Genet Genom 2022;6:169-78 https://dx.doi.org/10.20517/jtgg.2021.56 Page 177

and prolonged epilepsy monitoring unit studies. Finally, there was a selection bias because only clinically-
obtained EEGs were reviewed. EEGs were obtained in this subpopulation of PTHS patients only when there
was a clinical suspicion for seizure. This selection bias could lead to an over-representation of epilepsy in
our cohort, or conversely, there may be a higher proportion of abnormal EEGs that exist in the total PTHS
population even in the absence of clinical epilepsy. A prospective natural history study would help evaluate
the spectrum of EEG abnormalities along with the evolution of EEG findings and epilepsy with age in PTHS
by standardizing longitudinal data collection.

In conclusion, PTHS is a rare, genetic, neurodevelopmental disorder that presents with a homogenous
phenotype of profound global developmental delay characterized by markedly delayed ambulation and
most patients are unable to use spoken language to communicate. PTHS can have phenotypic similarities
with Angelman syndrome and Rett syndrome; however, they lack a characteristic EEG signature. In a
patient presenting with an Angelman-like phenotype and a normal or a non-characteristic EEG, a diagnosis
of PTHS may be considered. Further, it is of note that breath-holding spells like those seen in Rett
syndrome do not have an epileptic ictal EEG correlate.

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. Further research is
needed to fully understand why a pathological variant in a transcription factor responsible for neuronal
differentiation would yield focal onset seizures.

DECLARATIONS
Acknowledgments
The authors would like to acknowledge the families caring for individuals with Pitt-Hopkins syndrome who
have trusted us with the medical care of their loved ones as well as the support of the UTSW Department of
Pediatrics for support of clinical research in children with rare neurodevelopmental disorders.

Authors’ contributions
Contributed to the conception of the study, data analysis, and drafting of the manuscript: Bone M,
Goodspeed K, Sirsi D

Availability of data and materials
Not applicable.

Financial support and sponsorship
This study was funded in part by support of the UT Southwestern Dedman Family Clinical Scholar
Endowment fund.

Conflicts of interest
KG has received research support from Taysha Gene Therapies and Neurogene, Inc. for work that is
unrelated to that presented in this manuscript. MB has no disclosures to report. DS has no relevant
disclosures to report.

Ethical approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and received institutional review
board approval from the University of Texas Southwestern Medical Center.