Brain & Development 27 (2005) 370–377
www.elsevier.com/locate/braindev

Original article

An analysis of epilepsy with chromosomal abnormalities*
Hideo Yamanouchia,*, George Imatakaa, Eiji Nakagawaa, Akihisa Nittaa, Naomitsu Suzukia,
Jun-ichi Hiranoa, Hiroshi Suzumuraa, Hiroshi Watanabeb, Osamu Arisakaa, Mitsuoki EguchiaaDepartments of Pediatrics and Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japanb
Obstetrics, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
Received 14 July 2003; received in revised form 12 April 2004; accepted 14 April 2004

Abstract
We retrospectively reviewed the medical records of neonates with chromosomal abnormalities and epilepsy who had been admitted to theneonatal intensive care unit (NICU) and followed up at the outpatient clinic of Dokkyo University School of Medicine. Chromosomal
anomalies were diagnosed in 128 of 5789 patients admitted from 1978 through 2001. Seventy-one neonates had trisomy 21, 29 had trisomy
18, 8 had trisomy 13, and 20 had other chromosomal anomalies. Seizures occurred in five patients with trisomy 21 and in one patient eachwith trisomy 18, 6qK, 13qK, 21qK, and mosaicism trisomy 13. Two patients with 4p- [Wolf–Hirschhorn syndrome] were admitted to the
NICU, but were not followed up at our outpatient clinic. The boy with 6qK (46,XY,-6, Cder(6)t(6;11)(q25.1;q23.3)mat) had agenesis of the
corpus callosum and multiple congenital anomalies as well as intractable epilepsy. The girl with 13qK (46, XX, t(2,4)(q24.2;p14), del(13)(q21.2q31.2)) had infantile spasms at 12 months, which were well controlled with nitrazepam and vitamin B6. The girl with mosaic
trisomy 8q; (46, XX, der(8) (qter/q11.2::p23.3/qter)/46, XX), was not born at our hospital, but showed unique clinical features. She had
intractable epilepsy characterized by episodes of vomiting and staring with astatic seizures. Computed tomography of the brain revealed
bilateral calcification in the globus pallidus, associated with bursts of high-amplitude slow waves on electroencephalography. One of the twopatients with del(15)(q12)[Angelman syndrome] had giant-amplitude visual evoked potential, suggesting hyperexcitability of the visualcortex.
q 2005 Elsevier B.V. All rights reserved.
Keywords: Epilepsy; Chromosome; Cytogenetics; Trisomy 21; Trisomy 18; Trisomy 13; Monosomy

1. Introduction
Various chromosomal abnormalities have been found inpatients with epilepsy and epileptic syndromes. Genetic
linkage and karyotype analysis may provide cytogenetic
clues leading to the identification of genes linked to specifictypes of epilepsy. The Human Genome Project has
identified most human genes, including many with unclear
functions. The compilation of clinical data on the association between epilepsy and chromosomal abnormalities islikely to improve our understanding of the functions andmechanisms of genes related to epilepsy. To date, little*
The paper is based on the lecture given at the 6th annual meeting of the
Infantile Seizure Society, Tokyo, March 15–16, 2003.
* Corresponding author. Tel.: C81 282 86 1111; fax: C81 282 86-2947.
E-mail address: yhideo@dokkyomed.ac.jp (H. Yamanouchi).

0387-7604/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2004.04.012

attention has been paid to cytogenetic studies examining
clinical features of epilepsy and epileptic syndromes. In thisreport, we review the clinical features and course of children
with epilepsy associated with chromosomal anomalies who
were admitted to our neonatal intensive care unit (NICU)
over the past 24 years. Many of the patients were
subsequently followed up as outpatients.

2. Patients and Methods
From 1978 through 2001, a total of 13,716 babies wereborn at our hospital. Among them, 3120 premature or
critically ill neonates were admitted to our NICU. In addition,
2669 babies were transferred to our NICU from otherhospitals. The total number of admitted neonates during thestudy period was 5789.We searched the hospital NICU andcytogenetic laboratory databases to identify newborns
with chromosomal anomalies. A total of 128 patients

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371

Table 1
Patients with chromosomal abnormality found in NICU

3.2. Trisomy 18 (Edwards syndrome)

Chromosomal abnormality

Number ofpatients

Number of patientswith epilepsy

Trisomy 21
Trisomy 18
Trisomy 13
Trisomy 22
Trisomy 10, mosaic
Trisomy 8, mosaicdel (22)(q11.2)
del(4)(p16.3)
del(13)(q21.2q31.2)t(2;4)(q24.2;p14)
del(9)(q22.3q32)
del(8)(q13.1q21.2)
21qK
r (12)(p13;q24)
46, XY, -6, Cder(6)t(6;11)(q25.1;q23.3)
46, XY/46, XY, t(2:13)(q31;q21.2)
ins(14;16)(p12;p13.3)
47 XX, Cder 15 t(3:15)(q23:q11.2)
mat
Add(7)(p22)
Add (6)(q25.3)
Total

71
29
8
1
1
1
3
2
1

5
1
1
0
0
0
0
na
1

1
1
1
1
1

0
0
1
0
1

1
1
2

0
0
0

Only 1 of the 29 patients with trisomy 18 had
epilepsy. Her karyotype was 47, XX, C18. Clinicalfeatures included severe mental retardation, thinness, andshort stature. She had a large ventricular septal defectand a patent ductus arteriosus. Other anomalies included
low-set ears, short sternum, overlapping fingers, and‘rocker-bottom’ feet. The patient had a history ofgeneralized convulsions since the age of 4 years. She
had brief tonic seizures lasting 10 seconds, commonlyoccurring during sleep, at a frequency of about once per
week. Electroencephalography (EEG) showed multifocal
spikes in the right parietal and left temporal areas.
Magnetic resonance imaging (MRI) showed cerebellar
hypogenesis, a thin corpus callosum, and a dysplastic
hippocampus (Fig. 1). She was treated with phenobarbital, but seizures were poorly controlled. She died ofpneumonia at the age of 6 years.

1
1
128

0
0
10

3.3. Trisomy 13 (Patau syndrome)na: data not available due to a lack of follow up study.

had such anomalies, including 71 (55%) with trisomy 21, 29(23%) with trisomy 18, 8 (6%) with trisomy 13, and 20 (16%)
with other anomalies. A review of medical records fromthe outpatient clinic showed that 10 of these patients
had epilepsy. Five patients had trisomy 21, and one each
had trisomy 18, mosaic trisomy 13, 6qK (46, XY, -6,
Cder(6)t(6;11)(q25.1;q23.3)mat), 13qK (46, XX,t(2,4)(q24.2;p14), del (13)(q21.2q31.2)), and 21qK
(Table 1).

3. Results
3.1. Trisomy 21 (Down syndrome)
Five patients with trisomy 21 had a diagnosis of epilepsy.
In 3 patients, seizures were caused by hypoxic-ischemic
encephalopathy due to respiratory failure, cardiac failure, orboth in neonatal period or early infancy. Another patient had
hemiconvulsions associated with infarction due to moyamoya disease, a vascular abnormality commonly occurringin children with Down syndrome. The other patient had
cryptogenic infantile spasms. He was initially treated with a
combination of nitrazepam and valproic acid, and thespasms resolved. Subsequently, atypical absence and tonic
seizures developed, and Lennox–Gastaut syndrome wasdiagnosed. He received zonisamide, ethosuximide, nitrazepam and valproic acid. He is now 15 years old and has been
seizure free for more than 3 years (Table 2).

Only one of the eight patients with trisomy 13 wasfollowed up at our outpatient clinic. The other sevenpatients died neonatally. The surviving patient was a boyborn after 38 weeks’ gestation and weighing 3366 g atbirth. He was admitted for meconium aspiration syndrome. Gastrointestinal malrotation was noted and surgically corrected in the neonatal period. He had a small
ventricular septal defect, which later spontaneously
closed. Minor anomalies included a capillary hemangiomaon the forehead, frontal alopecia, a narrow palate,cryptorchidism, and penis palmatus. Fluorescence in situ
hybridization (FISH) analysis showed that 73% of
cultured cells had a karyotype of 47, XY, C13. The
remainder had a normal karyotype, suggesting a mosaic
form of trisomy 13. Seizures developed neonatally. Most
seizures were multifocal clonic type, and the EEG showed
multifocal spikes in the right temporal and left parietal
areas, independently. Seizures initially occurred several
times a day, but were well controlled by treatment withclonazepam. He died of pneumonia at the age of 7 years.
Autopsy showed olfactory aplasia and fenestration of the
septum pellucidum as well as an atrophic brain with a thin
corpus callosum.
3.4. 6qK/11qC syndrome
This neonate was born at 38 weeks’ gestation as the firstchild of non-consanguineous parents. Body weight at birth
was 2300 g. Multiple congenital anomalies were noted atbirth, including hypertelorism, epicanthic folds, low-set
ears, micrognathia, cleft palate, overlying fingers, andposterior prominence of the heels. His karyotype was 46,
XY, -6, Cder(6)t(6;11)(q25.1;q23.3)mat. EEG showed
multiple spikes in the occipital, central, and frontal areas,

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Table 2
Summary of clinical features of patients with chromosomal abberations and epilepsies
Patient

Chromosomal
abnormalities

Onset

GenderMain types of seizure

Etiology of seizure/structuralabnormality

Treatment

Outcome1

Trisomy 21

1y

Male

Mild cerebral atrophy

NZP, VPA, ZNS,
ESM

Well controlled

2
3

Trisomy 21
Trisomy 21

1y
3y

FemaleMale

Well controlled
Well controlled

Trisomy 21

11m

Male

PB, VPA, PHT

Poorly controlled

5

Trisomy 21

5m

Male

PB

Well controlled

6

Trisomy 18

4y

Male

PB

Poorly controlled

7

Trisomy 13,
mosaic0m

Male

Neonatal convulsion

CZP

Well controlled

86qK/11qC

2y

Male

VPA, CZP

Well controlled

9
10

13qK
21qK

1m
3y

FemaleMale

VPA, CBZ, CZP
PB

Well controlled
Well controlled

11

Trisomy 8q,
mosaic3y

FemalePoorly controlled

Angelmansyndrome
Angelmansyndrome

2yFemaleCalcification in the globus
pallidus, mild cerebral atrophy(Fig. 5)
Mild cerebral atrophy

CZP, VPA, ZNS

12VPA, CZP

Well controlled

1yFemaleGeneralized
convulsion
Infantile spasms
Prolonged febrile
convulsion
Complex partial
seizure, astatic
seizureAstatic seizure,
myoclonic seizure
Myoclonic seizure

Moyamoya diesease
Hypoxic ischemic
encephalopathy
Hypoxic ischemic
encephalopathy
Hypoxic ischemic
encephalopathy
Cerebellar hypogenesis,
dysplasitic hippocampus (Fig.1)
Olfactory aplasia, dysplasia of
septum pellucidum, cerebral
atrophy
Callosal agenesis, colpocephaly, small cerebellum (Fig. 3)
Mild cerebral atrophy
Normal brain

PB
PB

4

Infantile spasms
followed by Lennox–
Gastaut syndrome
Hemiconvulsion
Generalized
convulsion
Generalized tonic
convulsion
Generalized
convulsion
Brief tonic convulsion

Mild cerebral atrophy

VPA

Well controlled

13

The judgement of ‘well controlled’ is made when the patient has no seizure for over 2 years. Frequency of seizures in patient 3 was 2–3 times or more a day. See
the text for more detailed information of seizures. Patients 11, 12 and 13 were not born nor admitted in our hospital in neonatal period. NZP: nitrazepam, VPA:
valproic acid, ZNS: zonisamide, ESM: ethosuximide, PB: phenobarbital, PHT: phenytoin, CZP: clonazepam.

with secondary generalized spike-wave discharges (Fig. 2).
Generalized convulsions initially occurred at 2 years of age,and three times of episodes of status convulsivus lasting for
more than 1–h appeared at 6 years. He is now 15 years old,and his seizures are relatively well controlled by valproic
acid and clonazepam. MRI at 3 years showed callosal
agenesis associated with colpocephaly, a disproportionately
small cerebellum, and a flattened pons (Fig. 3).

Fig. 1. Magnetic resonance image in a 4-year-old girl with trisomy 18, showing cerebellar hypogenesis (arrow in A), a thin corpus callosum (small arrow in A),
and a dysplastic hippocampus (arrowhead in B).

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373

Fig. 2. Electroencephalography in a 3-year-old boy with 6qK/11qC syndromes, showing multiple spikes in the occipital, central, and frontal areas, withsecondary generalized spike-wave discharges. Calibration 50 mV, 1 s.

3.5. 13qK syndrome
This patient had a deletion between q21.2 and q31.2 ofchromosome 13 as well as a translocation between
chromosomes 2 and 4; 46, XX, t(2,4)(q24.2;p14), del(13)(q21.2q31.2). She was born at 39 weeks’ gestation,delivered spontaneously, and weighed 2500 g. She underwent surgery in the neonatal period for intestinal malrotation. Tonic spasms started at the age of 1 month. An EEG

showed hypsarrythmia, leading to the diagnosis of infantile
spasms. Computed tomography showed mild atrophy of thebrain. Spasms were controlled by nitrazepam and vitamin
B6. She had dysmorphic facies with large auricles and aflexed right ring finger. The range of motion of theextremities was restricted with moderate joint contractures.
Neurological examination showed brisk deep tendon
reflexes. An EEG at 5 years of age showed spikes in theright occipital area.

Fig. 3. Magnetic resonance image in a 3-year-old boy with 6qK/11qC syndrome, showing callosal agenesis associated with colpocephaly, adisproportionately small cerebellum, and a flattened pons.

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H. Yamanouchi et al. / Brain & Development 27 (2005) 370–377

Two patients were given a diagnosis of 4pK [Wolf–
Hirschhorn syndrome] in the neonatal period, but were notfollowed up at our outpatient clinic. The patients’ clinicalcourse therefore could not be evaluated.

9 months of age. She was not able to speak even single words
at 5 years. She had a round face and thick lips. No visceralorgan anomaly was noted. She was given a diagnosis oftrisomy 8q; 46, XX, der(8)(qter/q11.2::p23.3/qter)/46,
XX. Mosaicism was found in 53% of cultured cells, asconfirmed by FISH analysis. She had an episode ofgeneralized convulsions at 3 years of age. Three months
later, she started to have episodes of sudden unconsciousness
with staring and frequent vomiting, lasting from 30 min to
1 h. Astatic episodes also sometimes occurred. Interictal
EEG showed polyspike or spike-wave complexes in the rightfrontal and anterior temporal areas as well as bursts ofparoxysmal high voltage slow waves (Fig. 4). Laboratory
studies, including an assessment of parathyroid function,
showed no relevant findings. Computed tomography of thebrain showed bilateral high-density areas in the globus
pallidus (Fig. 5). MRI revealed non-specific cerebral
atrophy. The astatic episodes and generalized convulsions
disappeared after she started to receive zonisamide, but
episodes of staring and vomiting persisted despite treatment
with several anticonvulsant drugs, including zonisamide,clonazepam, and carbamazepine.

3.8. Trisomy 8q

3.9. Angelman syndrome

This child was born and admitted to the NICU at a local
hospital, and later followed up at our outpatient clinic fordelayed psychomotor development and epilepsy. She wasborn at 39 weeks’ gestation and had a birth weight of 3285 g.
The neonatal period was uneventful. Developmental milestones were delayed: she could sit without support at
9 months, stood alone at 2 years, and walked at 2 years

Two patients with Angelman syndrome, diagnosed on
the basis of FISH analysis showing 46, XX, ish del(15)(q11.2q11.2)(SNRPN-), were followed up at our outpatient clinic. They were not admitted to our hospital in the
neonatal period, but were observed for psychomotor
retardation associated with hypotonia. Generalized clonic
convulsions and myoclonic seizures appeared at 2 to 3 years

3.6. 21qK syndrome
This boy was born after 40 weeks’ gestation, deliveredvaginally, and weighed 2340 g. Multiple congenital
anomalies were noted neonatally, including a narrow nasal
root, downward slanted palpebral fissures, and cryptorchidism. Early motor milestones were normal: he obtained head
control at 4 months, sat without support at 8 months, andstood alone at 11 months. Language development wasdelayed; he could not speak words at 4 years of age. He had
an episode of status convulsivus associated with fever at
3 years. EEG showed no spike discharges. No further
seizures occurred during the next 6 years of observation at
our outpatient clinic. A detailed karyotype was not available
for this patient.
3.7. Wolf–Hirschhorn syndrome

Fig. 4. Electroencephalography in a patient with trisomy 8q, showing paroxysmal high voltage slow wave bursts. Calibration 50 mV, 1 s.

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375

was attributed primarily to impaired cerebral perfusion,associated with hypoxic-ischemic encephalopathy or moyamoya disease. Epilepsy was directly ascribed to Down
syndrome in only one patient with infantile spasms; thus theprimary prevalence of epilepsy directly due to Down
syndrome was estimated to be 1.5% in our study. Anytype of epilepsy can be associated with Down syndrome, butWest syndrome/infantile spasms are most common [3,4].
4.2. Trisomy 18 (Edwards syndrome)

Fig. 5. Computed tomogram of the brain in a patient with trisomy 8q,
showing bilateral high-density areas in the globus pallidus as well as
cerebral atrophy.

of age and were controlled by treatment with valproic acidand clonazepam. Visual evoked potential testing was donein one patient and showed markedly increased interpeak
amplitude between waves III and IV as well as IV and V,
suggesting hyperexcitability of the visual cortex to photic
stimulation (Fig. 6).

4. Discussion

Trisomy 18 is the second most common chromosomal
disorder occurring in neonates. Postnatal survival is very
poor because of critical visceral anomalies. Survival for
longer than several months is rare. Few patients with thissyndrome have been reported to have epilepsy, because
most die of severe complications shortly after birth. The
precise incidence of epilepsy associated with trisomy 18 isunclear. Most reported cases have been associated with amosaic form or partial trisomy [5–7], with relatively mild
clinical features.
4.3. Trisomy 13 (Patau syndrome)
The major structural brain anomaly of trisomy 13 isholoprosencephaly, frequently accompanied by cerebellar
dysplasia. Convulsions in the neonatal period or early
infancy are relatively common [8]. Our patient had neonatal
convulsions with subsequent epilepsy, both of which wererelatively easy to control. This mild picture of epilepsy
probably correlates with the relatively minor cerebral
anomalies, i.e. olfactory aplasia and fenestration of the
septum pellucidum.

4.1. Down syndrome
4.4. 6qK/11qC syndrome
In our study, the overall prevalence of epilepsy
associated with Down syndrome was 7%. Previous studies
have reported a prevalence of 6% [1] to 16% [2]. These
differences probably arise from the ages of the study groups.
In four of our five patients with Down syndrome, epilepsy

Fig. 6. Visual evoked potentials in a 2-year-old girl with Angelman
syndrome. Note giant amplitudes of waves III–IV (58 mV) and IV–V
(45 mV). Calibration 10 mV, 30 msec. LO: left occipital point, MO: middle
oocipital point, RO: right occipital point. The reference electrode waspalced on the midfrontal point.

Our patient had distal monosomy of the long arm ofchromosome 6 as well as trisomy of the long arm ofchromosome 11, inherited by maternal translocationt(6;11)(q25.1;q23.3). To our knowledge, epilepsy has beenreported in 5 out of 20 patients with distal terminal deletionof the long arm of chromosome 6 (Table 3) [9–12]. Most
distal deletions associated with epilepsy are located from
6q25 to the terminus. Most patients have ventricular
dilatation, microcephaly, and brachycephaly. Seizures arecontrolled well, although precise types of seizures arepoorly documented [9–12]. Our patient had agenesis of the
corpus callosum. The etiology of agenesis of the corpus
callosum is diverse, and many syndromic forms have beenpresented. As for chromosome 6, agenesis of the corpus
callosum has been associated with a deletion in 6q25 [13].
4.5. 13 q-syndrome
Our series included a patient with partial deletion of thelong arm of chromosome 13, del(13)(q21.2q31.2), as well as376

H. Yamanouchi et al. / Brain & Development 27 (2005) 370–377

Table 3
Literature survey of patients with terminal deletion of the long arm of chromosome 6, associated with epilepsy
Authors

Deletion

Ventriculomegaly

Microcephaly

Brachycephaly

Seizures

Reference

Liberfarb RM, et al.
Stevens CA, et al.
Oliveira-Duarte, et al. (case 1)
Oliveira-Duarte, et al. (case 2)
Mcleod DR, et al.
Our case

6q25/qter(?)
6q25/qter
6q25/qter
6q25/qter
6q26/qter
6q25.1/qter

na
C
C
C
na
C

C
C
C
C
C
C

C
na
C
C
na
C

Controlled well
Controlled well
Controlled well
Controlled wellnaControlled well

[9]
[10]
[11]
[11]
[12]

na: data not available.

translocation between chromosome 2 and chromosome 4with a breakpoint in 2q24.1 and 4p14. Two patients withdel(13)(q21–q34) and del(13)(q22–q33) have been reported
to have holoprosencephaly as well as Dandy–Walker
malformation [14]. A variant form of late infantile neuronal
ceroid lipofuscinosis (NCL) is mapped on 13q21.1–q32[15]. Our patient had no findings suggestive of NCL. She
had normal fundi and showed no evidence of progressive
myoclonus epilepsy or regression of psychomotor development. Computed tomographic examination showed mild
brain atrophy, but no malformation. A search of the Pub
Med website of the National Library of Medicine revealed
no reported case of West syndrome or related intractabletypes of epilepsy with onset in infancy associated with thischromosomal aberration.
4.6. Trisomy 8q
Trisomy 8q is a relatively common chromosomal
aberration, but its association with epilepsy is poorly
defined [16]. Our patient showed unique clinical features:calcification of the globus pallidus, astatic seizures andcomplex partial seizures with alterations in consciousness,staring and vomiting, and interictal EEG polyspikes or
spike-wave complexes in the frontal and anterior temporal
areas, as well as paroxysmal high voltage slow wave bursts.
Although the clinical and radiological features of trisomy 8q
remain uncertain, our findings may be characteristic of thissyndrome.

this patient had never had photosensitive epilepsy, ourfindings suggest that patients with Angelman syndrome may
have hyperexcitability of the visual cortex.

5. Conclusion
Epileptic syndromes may have unique features related tothe specific underlying chromosomal disorder. This report
described the clinical characteristics of patients withtrisomy 13 and trisomy 18 who survived for relatively
prolonged periods (7 years and 6 years at death, respectively). Although both of these trisomy syndromes arecommonly encountered, little is known about the features of
epilepsy associated with these syndromes. The patient withterminal deletion of 6q had callosal agenesis withcolpocephalic ventricular dilatation and had episodes ofstatus convulsivus. The patient with trisomy 8q had
complex partial seizures and astatic seizures, as well as asymmetrically calcified globus pallidus on CT scans.
Episodes with staring were associated with frequent
vomiting. Infantile spasms developed in patients with
13qK and Down syndrome, but were well controlled with
anticonvulsants. Further studies are needed to delineate theclinical features of epileptic syndromes and to understandthe mechanisms of epilepsy associated with chromosomal
abnormalities.

4.7. Angelman syndrome

Acknowledgements

Angelman syndrome is a neurogenetic disorder resulting
from lack of genetic contribution of the maternal chromosome 15q11-13. Patients with this syndrome present withsevere mental retardation, poor language skills, inappropriate laughter, and epileptic seizures, including spasms,
partial seizures, atypical absences, and myoclonic absences.
The 15q11–13 region codes b3 subunit of gammaaminobutyric acidA/benzodiazepine receptor, suggestingthat reduced GABAergic inhibition may cause cortical
hyperexcitability. Motor cortex hyperexcitability has beensuggested by the results of the burst-locked EEG averagemethod [17]. One of our patients with Angelman syndrome
showed giant-amplitude visual evoked potentials. Although

The authors would like to thank Prof.Yukio Fukuyama
for his helpful comments and suggestions.

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