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Page 172 Bone et al. J Transl Genet Genom 2022;6:169-78 https://dx.doi.org/10.20517/jtgg.2021.56

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RESULTS
At the time of their initial EEG, patients ranged in age from 15 months to 9 years (mean 3.75 years, standard
deviation 2.25 years). All individuals had developmental delay, five had epilepsy, and seven had breath-
[1]
holding spells, as previously reported [Table 1] . We reviewed a total of 29 EEG reports, representing 16
unique individual patients. EEG recordings were available for 12 of the 29 EEGs, representing 6 of the 16
individual patients, and no additional abnormalities were identified beyond those identified in the clinical
report. Of the EEG recordings reviewed, which were reported as normal, all parameters including posterior
dominant rhythm, sleep-wake transitions, and sleep architecture were normal when accounting for age at
the time of the EEG. Seventeen of the 29 EEGs reviewed were abnormal, and nine out of sixteen individual
patients had at least one abnormal EEG (56%). Most EEGs were obtained to characterize seizure-like events.
Median age at first EEG was 3.5 years, and among children with an abnormal EEG, median age at first
abnormal EEG was 4.5 years. Abnormalities included interictal epileptiform discharges (4/9, 44%),
generalized slowing (5/9, 56%), and focal slowing (4/9, 44%), [Table 2]. Three of the four individuals with
epileptiform abnormalities had focal spikes only, and one patient had both multifocal and generalized
spikes. Focal spikes were seen most often over the centrotemporal and occipital regions [Figure 1]. All four
children who had epileptiform abnormalities also had background slowing: three (75%) had generalized
slowing, and one (25%) had focal slowing. There were four patients (4/9, 44%) who had abnormal EEG with
background slowing without epileptiform abnormalities. One patient with an initial normal EEG had
subsequent abnormal EEG with focal slowing and focal spikes. Once a patient had an abnormal EEG,
findings were consistently demonstrated on repeat studies. Of the five patients with epilepsy, all had focal
onset seizures with or without impaired awareness, and some had secondary bilateral tonic-clonic seizures.
All four individuals with interictal epileptiform discharges had clinical seizures, and one individual with
clinical seizures had focal slowing on a routine EEG [Table 2]. There were two EEGs that captured typical
hyperventilation spells with oxygen desaturation that did not have EEG correlate.

Brain MRIs were available in 13 of the 16 patients who had EEGs performed, and the majority were
abnormal (9/13). Abnormalities included hypoplasia or atrophy of brain parenchyma (6/9), corpus callosal
dysplasia (4/9), abnormalities of the white matter, or myelination patterns (2/9), gliosis (2/9), and
microcephaly (1/9), [Table 2]. Of the four patients with a normal brain MRI, two patients had a prior study
with abnormalities, one had delayed myelination, and the other had thinning of the corpus callosum.

Developmentally, all individuals demonstrated delays in the achievement of motor and language milestones.
With regards to gross motor milestones, those with an abnormal EEG (n = 9) attained rolling at a median of
4.5 months (range 3 to 28 months), sitting at a median of 14 months (range 6 to 32 months), standing at a
median of 36 months (range 24 to 36 months), cruising at a median of 39 months (range 30 to 48 months),
and walking at a median of 48 months (range 15 to 108 months). Five of the nine were able to babble at a
median age of 12 months (range 6 to 40 months), but none of the individuals had words at their most recent
follow-up (age range 2 to 25 years). Those with abnormal EEGs attained motor milestones at similar ages as
those with normal EEGs but are markedly delayed compared to the average age of motor skill acquisition in
typically developing children [Figure 2].

Fisher’s exact test was used to examine the relationship between EEG abnormalities and clinical features of
PTHS, including abnormal MRI brain imaging and delayed ambulation. There was a higher rate of