Page 20 - Read Online

Bone et al. J Transl Genet Genom 2022;6:169-78 https://dx.doi.org/10.20517/jtgg.2021.56 Page 171

been proposed that terminal variants occurring in exons 9-19 cause the full PTHS clinical phenotype, while
[13]
variants which occur earlier in the gene may have a more variable or mild presentation . However, there is
a case report of an individual with a single base-pair deletion in exon 19 who has only mild intellectual
[6]
disability, speaks in full sentences, and achieves motor milestones on time . However, These studies are
limited by small sample sizes, and in a relatively large case series, there was no clear correlation between
[1]
disease severity and the type or location of the variant .
As in many other single-gene disorders, precision therapies are in development for PTHS, though only
supportive care is available currently. With potential therapies on the horizon, clinical assessments that may
track disease severity over time are needed. EEG is a potential biomarker that is often utilized in other
neurodevelopmental disorders and genetic epilepsies. Systematic evaluation of EEGs in the PTHS
population is very limited. In this study, we reviewed the available clinical EEGs and qualitative reports
from our Pitt-Hopkins Syndrome Specialty Clinic to assess electrographic signatures that may be unique to
[14]
PTHS, as demonstrated in other disorders, including Angelman syndrome .

METHODS
We conducted a retrospective chart review of the patients with PTHS seen in our Pitt-Hopkins Specialty
Clinic at the University of Texas Southwestern and Children’s Health Dallas Center for Autism and
Developmental Disabilities from 2016 to 2021. There are a total of 32 patients with PTHS in the database,
and 16 had a clinical EEG report available to review. We reviewed clinical data, including demographics,
neurological manifestations of PTHS, developmental abilities, brain imaging reports, and EEGs. 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.

Clinically obtained magnetic resonance imaging (MRI) of the brain was reviewed where available. The
MRIs performed at our center were read and reported by board-certified pediatric neuroradiologists. For
brain imaging performed at outside institutions, only reports were available for review. Imaging reports
were classified as normal or abnormal. For abnormal studies, findings were categorized as microcephaly,
gliosis, myelination abnormalities, hypoplasia or atrophy, and dysplasia of the corpus callosum.

EEGs were obtained for clinical indications. The most common clinical indication was clinical seizures or
events concerning seizures. EEGs obtained at our institution were recorded using a video EEG machine
(Stellate Harmonie, 2009-2011 and Natus Xltek NeuroWorks, 2011-2021). Electrodes were applied with
paste utilizing the 10-20 international system. A single-lead electrocardiogram was included for all
recordings. All EEG recordings performed at our center were read and reported by board-certified pediatric
epileptologists. Some of the EEGs were performed at outside institutions, reports of these EEGs were
reviewed, and results were analyzed. EEGs included in the study were either continuous long-term video
EEGs (> 23 h) or routine (< 2 h) recordings. EEG recordings were sorted by type (long-term or routine), age
of the patient at the time of the study, and normal or abnormal impression. If EEGs were abnormal, they
were grouped into epileptiform abnormalities, background abnormalities, or both. EEG characteristics were
analyzed in relation to the developmental profile, imaging findings, and epilepsy characteristics.

Descriptive statistics were used to describe the demographics of the cohort, genotype, clinical
characteristics, and qualitative findings on brain imaging and EEG. Fisher’s exact test was used to compare
rates of abnormal EEG, abnormal MRI brain, and delay of ambulation by greater than 1 year and greater
than 3 years. This test was used because of the small sample size and the likelihood that there would be 5 or
fewer observations in any given cell. The data analysis for this paper was generated using SAS software,