Topical Review

Epilepsy and Chromosomal Rearrangements in

Smith-Magenis Syndrome [del(17)(p11.2p11.2)]
Alica M. Goldman, MD, PhD; Lorraine Potocki, MD; Katherina Walz, PhD; Jennifer K. Lynch, MD;
Daniel G. Glaze, MD; James R. Lupski, MD, PhD; Jeffrey L. Noebels, MD, PhD

ABSTRACT

Smith-Magenis syndrome is a multiple congenital anomalies/mental retardation syndrome associated with a heterozygous dele-
tion of chromosome 17p11.2. Seizures have not been formally studied in this population. Our objectives were to estimate the
prevalence of seizures and electroencephalographic (EEG) epileptiform abnormalities in patients with Smith-Magenis syn-
drome with defined chromosomal rearrangements and to describe the spectrum of abnormal EEG patterns. Prolonged
video-EEGs were obtained in 60 patients. Eighteen percent of patients reported a seizure history; however, abnormal EEGs
were identified in 31 of the 60 subjects and 27 of 31 were epileptiform. Generalized epileptiform patterns were the most common
(73%). Most patients with either small or large deletions had an abnormal EEG (83%; 75%) in contrast to those with a common
deletion (49%). Our results indicate that epileptiform EEG abnormalities are frequent in patients with Smith-Magenis syndrome.
Considering that close to one third of individuals with Smith-Magenis syndrome with epileptiform abnormalities also had a
history of clinical seizures, cortical hyperexcitability and epilepsy should be considered an important component of the Smith-
Magenis syndrome clinical phenotype. (J Child Neurol 2006;21:93–98; DOI 10.2310/7010.2006.00030).

Smith-Magenis syndrome (Mendelian Inheritance in Man 182290) is
a multiple congenital anomalies/mental retardation syndrome asso-
ciated with an interstitial deletion of chromosome 17p11.2. Smith-
Magenis syndrome was described in 1986,1,2 and, subsequently, more
than 100 patients have been reported.3 A common deletion involving
≈ 4 Mb within the critical interval of chromosome 17p11.2 is observed
in 76% of patients,4 and the estimated birth prevalence of the chro-
mosome 17p11.2 microdeletion is 1 in 25,000.5 Five nondeletion
Received February 4, 2005. Received revised April 1, 2005. Accepted for
publication April 11, 2005.
From the Departments of Neurology (Drs Goldman, Lynch, Glaze, and
Noebels), Peter Kellaway Section of Neurophysiology (Drs Goldman, Lynch,
and Glaze), Molecular and Human Genetics (Drs Potocki, Walz, Lupski, and
Noebels), and Pediatrics (Dr Glaze), Baylor College of Medicine, and Texas
Children’s Hospital (Dr Lupski), Houston, TX.
This work was supported in part by National Institutes of Health grants
T32-NS07399-04 (to A.M.G., J.K.L.) and 29709 (to J.L.N.), the National Institute
of Child Health and Human Development (National Institutes of Health)
(K08 HD01149) (to L.P.), National Cancer Institute grant P01 CA75719 and
National Institute of Child Health and Human Development grant P01
HD39420) (to J.R.L.), the Baylor College of Medicine Mental Retardation
Research Center (HD2406407), and the Texas Children’s Hospital General
Clinical Research Center (M01RR00188).
Address correspondence to Alica M. Goldman, MD, PhD, Department
of Neurology, Baylor College of Medicine, One Baylor Plaza, NB220,
Houston, TX 77030. Tel: 713-798-5862; fax: 713-798-7528; e-mail:
agoldman@bcm.tmc.edu.
patients with Smith-Magenis syndrome were recently found to have
retinoic acid induced 1 (RAI1) heterozygous point mutations.6,7
Smith-Magenis syndrome is characterized by a variable degree
of developmental delay, behavioral and physical abnormalities
such as hearing impairment, and minor skeletal and craniofacial
defects.5,8 Cardiac and renal anomalies commonly observed in
individuals with chromosome 17p11.2 deletions were absent in cases
with RAI1 gene mutations.5–7 Dysfunctional behavior is common
and multifaceted in this patient population. It is frequently char-
acterized by aggressiveness, impulsive outbursts, severe temper
tantrums, limited attention span, and hyperactivity. Self-injurious
tendencies (such as head banging, onychotillomania, and poly-
embolokoilamania) are frequent, as are sleep abnormalities.5,8–13
Seizures are part of the Smith-Magenis syndrome clinical spectrum,
and the reported incidence of epilepsy in this population varies
between 11% and 30%.3,5,8 These data are based on historical and
parental information, and there have been no reported systematic
electroclinical studies of electroencephalographic (EEG) patterns
in Smith-Magenis syndrome.
Our main objectives were to describe the spectrum of EEG
epileptiform abnormalities and to estimate the prevalence of
seizures and epileptiform abnormalities in a group of 60 geno-
typed patients with Smith-Magenis syndrome with underlying chro-
mosomal rearrangements. The uniqueness of this study is the
systematic collection of clinical and electrophysiologic data on an
exceptionally large Smith-Magenis syndrome cohort with a detailed

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94 Journal of Child Neurology / Volume 21, Number 2, February 2006
molecular characterization of the genotype that allowed for close
genotype-phenotype correlations.
METHODS
Subjects
Sixty patients with Smith-Magenis syndrome [del(17)(p11.2p11.2)] were
enrolled in the multidisciplinary clinical study between December 1990 and
September 1999 through the General Clinical Research Center at the Texas
Children’s Hospital in Houston under a protocol approved by the Baylor Col-
lege of Medicine Institutional Review Board. Informed consent was obtained
from the patient’s parent or legal guardian. The study population consisted
of 27 (45%) male patients, ranging in age from 2 to 31 years, and 33 (55%)
female patients, with an age range of 11 months to 37 years.
Polysomnography and EEG Recording
Seizure history was obtained as part of the comprehensive clinical proto-
col, and all patients underwent a detailed clinical and neurologic evalua-
tion and polysomnographic recordings. Psychotropic medications were
discontinued for a minimum of 2 weeks prior to the study as per standard
protocol. All EEGs were performed as part of an overnight polysomnography
and daytime multiple sleep latency test. Subjects were monitored contin-
uously during the nocturnal session for a minimum of 8 hours with a
21-channel polygraph (Nihon-Kohden model 4421K EEG recorder, Tokyo,
Japan). The following parameters were recorded continuously: eight EEG
channels (Fp1-C3, Fp2-C4, C3-O1, C4-O2, F7-T3, F8-T4, T3-O1, T4-O2) from
surface electrodes placed according to the International 10-20 system,
electro-oculogram, submental electromyogram, single-channel electrocar-
diogram, respiratory effort using thoracic and abdominal strain gauges, res-
piratory airflow using oral and nasal thermocouples, oxygen saturation
using pulse oximetry, end tidal carbon dioxide partial pressure, leg move-
ment using a triaxial accelerometer, and behavioral observations made by
a technologist log and time-synchronized video monitoring. Standard cri-
teria were applied to wake and sleep staging and to EEG pattern classifi-
cation. A multiple sleep latency test followed routine protocol and consisted
of four to five naps at 2 hours each.14 All studies were interpreted by a clin-
ical neurophysiologist physician board certified in sleep medicine (D.G.G.).
Cytogenetic/Molecular Analysis
Cytogenetic evaluation, including fluorescent in situ hybridization, along with
molecular analysis using pulsed field gel electrophoresis, and polymor-
phic markers were performed using methods described previously.3,4
RESULTS
Prevalence of Epilepsy and EEG Abnormalities in
Patients With Smith-Magenis Syndrome
Seizures were reported to occur in 11 of 60 (18.3%) patients. Par-
ents reported staring episodes suggestive of either absence or par-
tial seizures (7/11), generalized convulsions indicative of generalized
tonic-clonic seizures (4/11), and drop attacks, the description of
which corresponded to the usual presentation of atonic seizures
(2/11). There was no detectable correlation between the age of
Smith-Magenis syndrome cases and the onset of seizures. No ictal
events were captured. Of the 11 patients with a reported seizure
history, the EEG was normal in two and abnormal although not def-
initely epileptiform in three, and epileptiform patterns were
recorded in six.
Table 1. Summary of the Electroencephalographic Abnormalities
Identified in the Smith-Magenis Syndrome Cohort
Generalized patterns on EEG (73%)
Bursts or runs of generalized slow waves
Runs of generalized spike-and-wave complexes at 3 Hz
Runs of generalized frontally or occipitally dominant
spike-and-wave complexes < 3.5 Hz
Bursts of generalized spikes and polyspikes
Focal patterns on EEG (43%)
Focal occipital, central, centrotemporal, or temporal spikes
and sharp waves
Runs of central spikes at 6–8 Hz
Rhythmic high-voltage occipital 4 Hz waves
Rhythmic bilateral high-voltage frontal theta activity
EEG = electroencephalogram.
To define the total prevalence of epileptiform abnormalities,
we reviewed EEG tracings of the entire cohort and found that 31
of the 60 patients with Smith-Magenis syndrome (52%) had abnor-
mal EEG studies. Twenty-seven of the 31 EEGs (87%) were epilep-
tiform. Nine of the 31 cases had a positive seizure history.
Generalized epileptiform patterns were found to be the most com-
mon abnormality (73%). Focal epileptiform abnormalities were
detected in 43% of the records (Table 1 and Figure 1). Epileptiform
discharges restricted to a wake state were detected only in one
patient. Fifty-two percent (14/27) of abnormalities were confined
exclusively to various sleep states, and 44% (12/27) were present
in both wake and sleep tracings (Figure 2). The prevalence of
EEG abnormalities in male and female patients was comparable
(55% in male patients).
Twelve patients were being treated with an anticonvulsant at
the time of the study, yet only two were taking the medications for
seizure control. The remaining 10 were prescribed antiepileptic
drugs for management of behavioral problems but not epilepsy.
Seven of these were found to display generalized and/or focal
epileptiform patterns.
Twenty-three patients had imaging studies of the brain that
were reported previously.8 There was no statistically significant dif-
ference between patients with an abnormal brain imaging and
epileptiform EEG compared with those with a normal study.
Genotypic Characteristics of Patients
With Smith-Magenis Syndrome
The mechanism leading to the microdeletion is an unequal cross-
ing over owing to homologous recombination between flanking
repeat gene clusters.15–20 The chromosomal extent of this deletion
could be determined in 51 individuals. Thirty-nine patients (≈76%)
had the common Smith-Magenis syndrome deletion spanning
≈4 Mb within chromosome 17p11.2.4 Other patients had smaller or
larger deletions involving the Smith-Magenis syndrome critical
interval, and in one case, deletion of the Smith-Magenis syndrome
region was the result of a complex chromosomal rearrangement.
Of all of the Smith-Magenis syndrome cases, patients with
either small or large deletions were more likely to have an abnor-
mal EEG than the individuals with common deletions (83% and 75%
vs 49%, respectively) (Figure 3); however, this association did not
reach statistical significance. In an attempt to define a possible chro-
mosomal region involved in the development of epileptiform activ-
ity, we examined the genetic data of six patients with small deletions
 Epilepsy and Smith-Magenis Syndrome / Goldman et al 95

Figure 1. Examples of epileptiform pat-

terns identified in patients with Smith-
Magenis syndrome. A, Generalized
spike-and-wave complex (patient 1090).
B, Generalized 3 Hz spike-and-wave
complexes (patient 1365).

B
96 Journal of Child Neurology / Volume 21, Number 2, February 2006
Figure 2. Diagram summarizing the prevalence of epileptiform abnor-
malities in relation to wake and sleep states. Twenty-two percent of
all epileptiform patterns were present in the wake state (W), non–rapid
eye movement (REM) (NR), and REM (R) sleep and are represented
by the light gray portion of the diagram, section 1:W+NR+R. Nineteen
percent of all epileptiform abnormalities occurred in the wake state
and non-REM sleep, medium gray section 2:W+NR, and 4% in the wake
state and REM sleep, darker gray section 3:W+R. Thirty-three percent
of epileptiform patterns were restricted to non-REM sleep, striped sec-
tion 4:NR; 11% to REM sleep, dotted section 5:R; and 7% were found
in both non-REM and REM sleep, section 6 with squares:NR+R. Only
4% of all epileptiform abnormalities were found confined to the wake
state, white section 7:W.
(Figure 4). All patients were deleted for areas within the Smith-
Magenis syndrome critical region thought to be required for the
development of typical Smith-Magenis syndrome.15,21,22 Four of the
six cases shared the proximal breakpoints; however, the distal
breakpoints were variable within this group and did not permit a
more refined definition of genes involved in the epileptiform com-
ponent of the Smith-Magenis syndrome phenotype.
DISCUSSION
Although seizures have been reported in up to 30% of patients
with Smith-Magenis syndrome,5 these figures are based solely on
historical and parental information. In our cohort of 60 genotyped
patients with Smith-Magenis syndrome, recurring stereotypic clin-
ical events strongly suggestive of seizures were reported in 18.3%,
yet only 2 of 6 cases that had epileptiform findings during our
EEG study carried a formal diagnosis of epilepsy and were treated
with anticonvulsants. The remaining four cases that were not
treated were reported to have staring episodes. We can only spec-
ulate that these events were considered to be part of their "com-
mon" behavior and thus went on undiagnosed and untreated. The
extended EEG recording studies showed that the overall prevalence
of epileptiform abnormalities was 45%. Twenty-nine percent of
cases with epileptiform EEG had seizures by history. The great
majority of all epileptiform abnormalities were expressed either
exclusively during sleep (52%) or both in wake and sleep states
(44%). This proportion is in general concordance with the EEG char-
acteristics of other patients with epilepsy. It is possible that the
prevalence of epileptiform abnormalities was underestimated in
our study because we relied on sampling from only eight EEG chan-
nels of the polysomnographic recordings. The electrophysiologic
data were originally collected to evaluate the sleep characteristics
of patients with Smith-Magenis syndrome rather than to examine
their epileptiform abnormalities.12 It was the finding of seizures in
our Smith-Magenis syndrome mouse model that prompted us to
reevaluate the clinical cohort and scrutinize their polysomno-
graphic recordings for seizures and epileptiform patterns.23 Despite
the limitations of EEG recordings, the precise delineation of geno-
type in our study population provided a unique opportunity to
correlate distinct chromosomal aberrations with the clinical and
electrographic phenotypes. Seventy-six percent of the evaluated
Figure 3. Spectrum of mutations in
patients with Smith-Magenis syn-
drome.The clustered bar diagram com-
pares the frequency of the identified
mutation types across Smith-Magenis
syndrome patient groups. Five distinct
mutational categories (white bars =
common deletions; solid black bars =
small deletions; vertical striped bars =
large deletions; solid gray bars = com-
plex rearrangements; speckled white
bars = undetermined mutations) are
shown and compared among all
patients with Smith-Magenis syn-
drome, patients with Smith-Magenis
syndrome with a normal electro-
encephalogram (EEG-N), and patients
with Smith-Magenis syndrome
with an abnormal/epileptiform EEG
(EEG-AN).

Figure 4. Schematic representation of small deletions in our patients
with Smith-Magenis syndrome. A, An ideogram illustrating chromo-
some 17. The 17p11.2 and 17p12 chromosome regions are indicated
by white and solid vertical bars, respectively. B, Schematic illustration
of the ≈4 Mb common deletion region (SMS CDR) within chromosome
17p11.2 that is deleted in 80% to 90% of patients with Smith-Magenis
syndrome.5,16,17,31 Large deletions extend beyond the common deletion
region, whereas small deletions are confined within the 4 Mb inter-
val, as shown in this figure. SMS CR = Smith-Magenis syndrome crit-
ical region, a minimal deletion interval responsible for the full
Smith-Magenis syndrome phenotype.15 The relative position of 10 of
20 genes residing in the Smith-Magenis syndrome common deletion
region is shown.15 PMP22 and KCNJ12 genes are located outside the
Smith-Magenis syndrome common deletion region. SMS-REPD, SMS-
REPM, SMS-REPP = distal, middle, and proximal low-copy repeat
gene clusters, respectively, which are the substrates for nonallelic
homologous recombination in Smith-Magenis syndrome. 17 C,
Schematic representation of the small deletions documented in our
Smith-Magenis syndrome cohort. Solid lines indicate nondeleted
areas, whereas dotted lines represent deleted regions. Detailed maps
of the respective breakpoints are reported elsewhere.15,16
patients with Smith-Magenis syndrome harbored a common dele-
tion.3,4 Interestingly, we recorded epileptiform patterns in five of
six cases carrying small deletions and in four of five cases with large
deletions. However, statistical analysis of these subgroups did not
reach the threshold of significance, and confirmation of a possi-
ble relationship between the deletion size and the presence of
EEG abnormalities will require a larger clinical sample. We also ana-
lyzed the breakpoints of all small deletions. A candidate epilepsy
gene, Kcnj12, coding for Kir2.2, the alpha subunit of an inward rec-
tifier potassium channel, held great promise as a causative gene
for the epilepsy in Smith-Magenis syndrome; however, we confirmed
that it is located outside the Smith-Magenis syndrome deletion
region in our patients.24 Moreover, the epileptic chromosome
17p11.2 deletion mouse model recently described by our group indi-
cated that genes other than Kcnj12 can contribute to the genera-
tion of seizures in Smith-Magenis syndrome.23 Owing to considerable
variability in the distal breakpoints, we were unable to define con-
sistent chromosomal areas/genes that could be involved in the
generation of the epileptiform trait of the syndrome. It is also pos-
sible that the observed relationship between the seizure phenotype
and deletion size could be due to a “position effect” and is not solely
a result of genetic haploinsufficiency, as suggested by the animal
studies of Yan et al.25 In this regard, continuing analysis of murine
models of Smith-Magenis syndrome will be important in further
refining the genetic basis for seizures in this syndrome.
Epilepsy and Smith-Magenis Syndrome / Goldman et al 97
Walz et al reported an epileptic phenotype of a Smith-Magenis
syndrome mouse model [Df(11)17/+] generated by chromosomal
engineering.23 The engineered mouse chromosomal deletions
included the murine homologue of the retinoic acid induced 1
(RAI1) gene. Five of six mutant mice displayed epileptiform spike-
and-waves and polyspikes on their EEGs, predominantly during
behavioral sleep. One third also manifested frequent overt gener-
alized tonic-clonic seizures. It is of interest that one of the five
patients whose phenotype was due to mutation of RAI1 had a
reported seizure history, although no further clinical or electro-
physiologic details of his epilepsy were available.6 The chromosome
17p11.2 deletion mouse model also suggested a strain-dependent
increase in vulnerability to seizures during postnatal develop-
ment.23 We studied this phenomenon in our Smith-Magenis syn-
drome cohort, but the analysis of mean age difference between
groups with and without epileptiform EEG was not statistically sig-
nificant. Moreover, the male mouse deletion mutants were also
behaviorally hypoactive,26 a characteristic that is in contrast to the
usual behavioral phenotype of patients in our study.
In summary, epileptiform EEG patterns are common in patients
with Smith-Magenis syndrome, and when present, close to one third
of individuals can be expected to manifest clinical seizures. It has
been shown that untreated epilepsy can contribute to a variety of
sleep disturbances, as well as to maladaptive daily functioning.27–29
Disordered sleep and behavioral problems pose frequent man-
agement challenges in patients with Smith-Magenis syndrome,
and their basis is multifactorial.11–13,30 Careful history taking, along
with EEG studies, might help identify patients in whom unrecog-
nized seizure disorder associated with haploinsufficient genes
within the chromosome 17p11.2 microdeletion interval might be
contributory to psychosocial dysfunction.
Acknowledgments
We thank the patients and their families for their participation.
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