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CLINICAL REPORT

Severe Epilepsy in An Adult with PartialTrisomy 18q

Luigi del Gaudio,* Salvatore Striano, and Antonietta CoppolaEpilepsy Centre, Neurology Department, Federico II University, Naples, Italy

Manuscript Received: 21 January 2014; Manuscript Accepted: 3 July 2014

How to Cite this Article:del Gaudio L, Striano S, Coppola A. 2014.

Severe Epilepsy in an adult with Partial

Trisomy 18q.

Am J Med Genet Part A 164A:3148–3153.

Epilepsy is one of the most common presentations associated

with chromosome aberrations. Detailed descriptions of some

aberration-specific epileptic and electroencephalographic (EEG)

phenotypes have been reported (i.e., Angelman syndrome, ring

20 etc.). However there is limited and mixed information about

the characteristics of epilepsy related to trisomy 18. Thus a

common seizure phenotype has not been characterized yet.

Here we describe in detail a patient with refractory epilepsy

and partial 18q trisomy. � 2014 Wiley Periodicals, Inc.

Key words: epilepsy; trisomy 18; edwards syndrome

INTRODUCTION

The trisomy 18 syndrome, also known as Edwards syndrome, is a

common autosomal chromosomal disorder with an overall preva-

lence of 1/2,500–1/2,600 and a live born estimated prevalence of

only 1/6,000–1/8,000; approximately 50%of babies live longer than

one week [Cereda and Carey, 2012]. Of these, only 5–10% live

longer than one year because of the high incidence of congenital

malformations manly affecting the heart, genitourinary, gastroin-

testinal and central nervous system. Minor anomalies involve face,

eyes, and limbs. The distinctive phenotype results from full (about

94% of cases), mosaic (5% of cases) or partial trisomy 18q (1% of

cases) [Cereda and Carey, 2012]. The incidence of epilepsy is

estimated to be about 25–50% [Carey, 2010] but recently Kumada

et al. reported a prevalence of 64% [Kumada et al., 2012]. Although

Edwards syndrome is the secondmost common trisomyafterDown

syndrome, and epilepsy is not rare in this condition, there are only

few detailed descriptions about epilepsy associated with Edwards

syndrome. We report on an adult with partial 18q trisomy and

severe refractory epilepsy.

Conflict of Interest: None.�Correspondence to:

Luigi del Gaudio, Epilepsy Centre, Neurology Department Federico II

University via Pansini 5 Naples, 80131, Italy.

E-mail: gigi.delgaudio@gmail.com

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 24 September 2014

DOI 10.1002/ajmg.a.36743

CLINICAL REPORT

This 30-year-old man is the second child of healthy unrelated

parents. Family history is negative for epilepsy and any other

neurological condition. Pregnancy was complicated by bleeding

during the second trimester and a reductionof fetalmovementswas

noted at that time.Hewas born at term; the deliverywasuneventful.

At birth his head circumferencewas 32 cm(3rd–5th centile), weight

2014 Wiley Periodicals, Inc.

was 2,700 g (5th–10th centile) and length was 45 cm (<3rd centile).

Feeding problems and delayed psychomotor development were

soon noted. During the first evaluation at 17 months of age, many

dysmorphic features were present including flat face, strabismus,

hyperthelorism, anteverted nostrils, long philtrum, thin upper lip

vermilion, 2–3 toe syndactyly of both feet (Fig. 1a and b show the

dysmorphism of the patient at present, as an adult). Cardiac and

abdominal ultrasounds were unremarkable. A metabolic screening

test was negative. A brain MRI scan performed at the age of seven

years showed only mild cerebral atrophy.

He presented with his first seizure at six years old. This was a

generalized tonic-clonic (GTC) convulsion occurring during a

febrile illness. Soon after, the patient developed spasms that

occurred daily upon awakening and tonic asymmetric seizures

occurring during sleep and upon awakening. At that time the

interictal electroencephalographic (EEG) showed multiple focal

discharges over the posterior regions (see Fig. 1c); sleep wors-

ened these abnormalities (see Fig. 1d); valproic acid (VPA) did

not improve the seizures’ severity and frequency. From age 12,

the spasms disappeared but GTC seizures continued; drop-

attacks appeared with a daily frequency. None of the antiepilep-

tic drugs (AEDs) administered (carbamazepine, clobazam, phel-

bamate, and vigabatrin) improved the frequency or severity of

seizures.

He was referred to our department at the age of 30. Neurological

examination showed severe intellectual disability, a lack of sphinc-

3148

FIG. 1. (a) facial and (b) foot dysmorphism of the patient as an adult; (c) interictal EEG recorded at six years old showing multiple focal

discharges over the posterior regions with worsening during sleep (d); (e) interictal electroencephalographic (EEG) recorded at the age of 30

showing generalized and focal paroxysmal activity mainly over the left temporal and posterior regions; (f) ictal EEG recorded at 30 years old

showing spike/polispike-slow wave complexes clinically related to a head drop; (g) Schematic of the duplication affecting the long arm of the

chromosome 18. The red box indicates the duplication of the present case.

DEL GAUDIO ET AL. 3149

3150 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

ter control, absence of language and inability to walk unaided. At

that time the patient still suffered from daily events including

absence, tonic and atonic seizures while GTC seizures occurred

at a frequency of 3–4/year. Interictal EEG showed generalized and

focal paroxysmal activity mainly over the left temporal and poste-

rior regions (see Fig. 1e); in some occasions the presence of a spike/

polyspike-slow wave complex was clinically related to head drop

(see Fig. 1f). At that time he was on treatment with VPA at the dose

of 800mg/day. Rufinamide was added on up to a dosage of

1,200mg/day obtaining a slight reduction in frequency of tonic

and atonic seizures.

CYTOGENETICS

Array-CGH analysis using a Human Genome CGHMicroarray Kit

8� 60 (Agilent) showed a 25.9MB duplication at 18q12.3-q22.1

(chr18:39,792,312-65,676,291; HG 19) involving 100 protein-cod-

ing genes (see NCBI Ensembl for information on each gene in the

region and Fig. 1). A schematic illustration of the duplication is

shown in Figure 1g. The rearrangement was de novo.

DISCUSSION

Structural abnormalities of the central nervous system have been

reported in about 5%of infants with trisomy 18; themost common

are cerebellar hypoplasia, agenesis of corpus callosum, microgyria,

hydrocephalus, and myelomeningocele [Carey, 2010; Kinoshita

et al., 1989].

Epilepsy is commonly described in patients with trisomy 18

[Jones, 2006; Carey, 2010] and only few cases can be ascribed to

structural malformations. There is still a lack of detailed descrip-

tions of epilepsy associated with Edwards syndrome and this is

probably due to the high mortality of these patients in the first year

of life. Literature reports an overall prevalence ranging from 25 to

50% [Carey, 2010] to 64% [Kumada et al., 2012]. The prevalence of

epilepsy seems lower in partial trisomy, ranging from 10% [Wilson

et al., 1979] to 31% [Strathdee et al., 1995]. There are not reported

data about the prevalence of epilepsy inmosaic trisomy 18. (Table I

reports all data from literature about association of epilepsy with

trisomy 18 including the present case).

A recent report by Kumada et al. [2012] described epilepsy in

seven out of 11 (64%) patients with full trisomy 18 and concluded

that over half of children develop epilepsy during infancy or early

childhood, which can be focal as well as generalized; infantile

spasms might also occur. Seizures are usually drug-resistant in

half of the children, especially those presenting with generalized

epilepsy. The same author [Kumada et al., 2010] described a case of

a full trisomy 18 with onset of epilepsy at 10 months characterized

by autonomic seizures presenting as epileptic apnea. Yamanouchi

et al. [2005] found epilepsy in only one out of 29 patients with

trisomy 18. The patient had full trisomy 18 with onset of epilepsy at

four years of age; his generalized seizures were poorly controlled

with phenobarbital.

Grosso et al. [2005] analyzed epilepsy linked to chromosome 18

aberrations in 14 patients: five with 18p deletion syndrome

(18pDS), six with 18q deletion syndrome (18qDS), one with

17–18 translocation and two with 18p trisomy. They described

epilepsy in seven out of 14 patients; two of them had 18p trisomy

and epilepsy, presenting with complex partial seizures and EEG

abnormalities over the posterior regions. They both had a good

outcome.

Finally, to the best of our knowledge, there are only two

detailed descriptions of epilepsy in 18q trisomy. The first report

is by Ceccarini et al. [2007] who described three siblings carrying

an interstitial duplication of the long arm of chromosome 18

(18q21.31-q22.2) inherited from a healthy mosaic carrier

mother. Theywere presentingwith borderline ormild intellectual

disability and minor dysmorphic features. Out of the three

siblings only one had a history of epilepsy with generalized

and focal seizures. He suffered from generalized seizures from

age 19, while focal seizures appeared at the age of 21 years. These

were characterized by myoclonus of the perioral muscles associ-

ated with a sensation of numbness of the tongue lasting for few

seconds. These episodes mostly occurred during a loud reading

activity, suggesting a “reading epilepsy.” EEG showed isolated,

interictal short (1 sec) saw-tooth theta waves sequences over the

fronto-centro-temporal area bilaterally, triggered by hyperpnoea

and photic stimulation. The other two siblings never suffered

from seizures; however they both had EEG abnormalities as their

epileptic brother.

The second report is by d’Orsi et al. [2013] who described a

30-year-old man with a trisomy of the 18q12.2q22.3 region.

Epilepsy history is characterized by seizure onset at 25 years with

GTC seizures, atonic drop attacks and eating-induced repetitive

epileptic spasms. The EEG showed symmetric or asymmetric

paroxysmal activity over the posterior regions associated with

generalized spikes and spike and wave discharges.

Our patient shares genetic, clinical and EEG features with the

patient described by d’Orsi et al. They both have a partial duplica-

tion of the long arm of chromosome 18 (18q) and present with

intellectual disability and a severe epilepsy including spasms, GTC

and atonic seizures. The EEG showed predominantly paroxysmal

activity over the posterior regions in both cases. Interestingly they

both presented with late onset infantile spasms, although in our

patient thiswasmuchearlier (6yearsold compared to25yearsold.).

The patient reported by Ceccarini et al. shows a milder phenotype

with borderline intellectual functioning and late onset drug-re-

sponsive epilepsy. Interestingly reflex seizures were present both in

the case described by Ceccarini (reading epilepsy) and our case

(eating epilepsy).

Even if the descriptions are rare, epilepsy in partial trisomy 18

(18p and 18q) seems to have a common clinical and electroen-

cephalographic pattern being characterized by late onset epilepsy

with generalized and focal seizures (18q) or only focal (18p) and an

EEG pattern with generalized and focal discharges mainly over the

posterior regions. Outcome in terms of seizures’ frequency and

duration can vary with better prognosis in 18p than 18q trisomy

[Grosso et al., 2005; d’Orsi et al., 2013].

More data are available for full trisomy 18: epilepsy appears to be

characterized by the occurrence of both focal and generalized

seizures and an EEG showing focal and generalized discharges;

onset is usually during infancy, commonly in the first year of life,

and West syndrome is not unusual. Outcomes can be different:

TABLE

I.Clinical

Dataof

theReported18Trisom

yCasesIncludingthePresentCase

Pt

Genetic

Onset

ofepi.

Gender

Maintype

ofseizures

Brain

MRI

Interictal

EEG

Outcome

Article

1Fulltrisom

y18

4years

Male

Brief

tonicconvulsion

Cerebellarhypogenesis,

dysplastic

hyppocam

pus

Multifocalspikesinthe

rightparietal

and

lefttemporalareas

Poorly

controlled

Yamanouchi

etal.[2005]

2Fulltrisom

y18

10months

Female

Epilepticapnea,

GTC,tonic

Mild

atrophy

Focal(right

parietal,

lefttemporal)and

generalized

paroxysm

alactivity

Good

Kum

ada

etal.[2010]

3Fulltrisom

y18

2years9months

Female

Complex

Partial

n.d.

Normal

Good

Kum

ada

etal.[2012]

4Fulltrisom

y18

1months

Female

GTC

Severe

atrophy

Spikes

onleftfrontal

andrightparietal

Good

Kum

ada

etal.[2012]

5Fulltrisom

y18

4months

Female

Spasms,tonic,

absence

Mild

atrophy

MultipleIndipendent

SpikeFoci

Poorly

controlled

Kum

ada

etal.[2012]

6Fulltrisom

y18

3years

6months

Female

Tonic

Severe

atrophy

DiffuseHighVoltage

Slow

Waves

Poorly

controlled

Kum

ada

etal.[2012]

7Fulltrisom

y18

2years

5months

Female

Spasms

Mild

atrophy

Hypsarrhytm

iaGood

Kum

ada

etal.[2012]

8Fulltrisom

y18

11months

Male

Spasms,tonic,

myoclonic

Severe

atrophy

Hypsarrhytm

iaPoorly

controlled

Kum

ada

etal.[2012]

9Fulltrisom

y18

10months

Female

Epileptic

encephalophaty

Cerebellarhypoplasia,

enlargem

ent

ofventricular

system

Paroxysm

alactivity

prevalentover

the

posteriorregions

Good

Elia,Sueri

unpublished

data

10

18ptrisom

y4years

Male

Complex

Partial

Normal

Generalized

andbi-

occipitalSpikeand

Spike-Waves

Good

Grossoet

al.

[2005]

11

18ptrisom

y5years

Male

Complex

Partial

Seizures

Agenesisof

the

splenium

ofthe

corpus

callosum

Generalized

andbi-

occipitalSpikeand

Spike-Waves

Good

Grosso

etal.[2005]

12

18qtrisom

y19years

Male

GTC,Reflex

Enlarged

cisterna

magnaand

cerebellarhypoplasia

Saw-tooth

thetawaves

sequencesinfronto-

temporo-central

area

bilaterally.

Good

Ceccarini

etal.[2007]

13

18qtrisom

y25years

Male

Atonic,GTCS,

Reflex,

epilepticspasms

Bilateralopercula

dysplasia

andcorpun

callosum

hypoplasia

Focalandgeneralized

paroxysm

alactivity

withprevalence

over

theposteriorregions

Poorly

controlled

d’Orsi

etal.

[2013]

14

18qtrisom

y6years

Male

Spam

s,GTC

Tonic,Atonic

Mild

Atrophy

Generalized,Focal

dischargeover

posteriorregions

Poorly

controlled

PresentCase

GTCS,generalized

tonicclonicseizures;CPS,complex

partialseizure.

DEL GAUDIO ET AL. 3151

3152 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

some patients may respond well to one type of AED, while others

can be resistant to all therapies.

It is possible that the different phenotype of these conditions

(18q, 18p and full trisomy 18) reflect the different gene content of

the aberration. The rearrangement occurring in our patient encom-

passes 100 protein coding genes. Among these, eight genesmight be

implicated in seizures’ pathophysiology: SYP4 encodes synaptoga-

min 4, a protein that plays a crucial role in synaptic transmission;

expression of synaptotagmin-4 is induced in the rat hippocampus

after systemic kainic acid treatment [Tocco et al., 1996]; IER3IP1

encodes the immediate early response 3 interacting protein 1.

Homozygous mutations have been found in patients suffering

from myoclonic epilepsy occurring with other clinical conditions

[Poulton et al., 2011]; MBD1 and MBD2, code for methyl-CpG

binding domain protein 1 and 2. They belong to a family of nuclear

proteins related by the presence in each of a methyl-CpG binding

domain (MBD). This family also includes MECP2, a gene whose

deletions result in Rett syndrome, a well known epileptic encepha-

lopathy [Cukier et al., 2010]; duplicationof the samegenehavebeen

associated with a clinical picture characterized by infantile hypo-

tonia, severe to profound intellectual disability, autism or autistic-

like features, spasticity [Scott Schwoerer et al., 2014].TCF4 encodes

a protein called transcription factor 4;mutations of this gene lead to

Pitt–Hopkins Syndrome, an encephalopathy that also includes

severe epilepsy. This gene is dosage sensitive. [Forrest et al.,

2012]; NEDD4L codify for the neural precursor cell expressed,

developmentally down-regulated 4-like. De novomutations of this

gene have been recently found in patients affected by epileptic

encephalopathy [Allen et al., 2013]; MC4R encodes the melano-

cortin 4 receptor which is activated by ACTH, the first line drug

used to treat infantile spasms. This gene is dosage sensitive: the

homozygous knock-out mouse develops maturity onset obesity

syndrome associated with hyperphagia, iperinsulinemia, and hy-

perglycemia. The heterozygous mice have an intermediate pheno-

type. [Liu et al., 2007]; PIGN encodes the phosphatidylinositol

glycan anchor biosynthesis. Mutations have been found in a

syndrome called multiple congenital anomalies-hypotonia-seiz-

ures syndrome [Ohba et al., 2014].

It is difficult to state, which of these genes play amajor role in the

pathophysiology of epilepsy for this condition. It is possible that the

overall burden of the duplicated products and their interactions

lead to the disease. Although the function of the proteins encoded

by these genes make them promising as candidate genes for the

pathophysiologyof epilepsy in this condition, functional studies are

needed to clarify their exact role.

Accordingly the clinical phenotype cannot be characterized

based on only three detailed reports. The description of single or

group cases is essential to understand if a unified phenotype exists

and, if it does then its characteristics should be studied in detail for

further prognosis.

ACKNOWLEDGMENTS

Wewould like to thank the patient’s family for giving us permission

to report their son’s case.We also thankDrKrishnaChinthapalli for

language support.

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