severe epilepsy in an adult with partial trisomy 18qdownload.xuebalib.com/xuebalib.com.25520.pdf ·...
Post on 17-Mar-2019
225 Views
Preview:
TRANSCRIPT
�
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, ItalyManuscript 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.
REFERENCES
AllenAS, Berkovic SF, Cossette P,DelantyN,DlugosD, Eichler EE, EpsteinMP, Glauser T, Goldstein DB,Han Y,Heinzen EL, Hitomi Y, Howell KB,JohnsonMR, Kuzniecky R, Lowenstein DH, Lu YF,MadouMR,MarsonAG, Mefford HC, Esmaeeli Nieh S, O’Brien TJ, Ottman R, Petrovski S,Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B,Alldredge BK, Bautista JF, Berkovic SF, BoroA, CascinoGD,ConsalvoD,Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB,French J, FriedmanD,Geller EB,GlauserT,GlynnS,Haut SR,Hayward J,Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH,Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV,Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A,Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven J, SmithMC,Sullivan J, Lin Thio L, Venkat A, Vining EP, VonAllmenGK,WeisenbergJL, Widdess-Walsh P, Winawer MR. 2013. De novo mutations inepileptic encephalopathies. Nature 501:217–221.
Carey JC. 2010. Trisomy 18 and 13 syndromes. In: Allanson J, Cassidy S,editors Management of genetic syndromes. 3rd edition. Hoboken, NJ:John Wiley. & Sons, Inc. pp 807–824.
Ceccarini C, Sinibaldi L, Bernardini L, De Simone R, Mingarelli R, NovelliA, Dallapiccola B. 2007. Duplication 18q21.31-q22.2. Am JMed Genet A143A:343–348.
Cereda A, Carey JC. 2012. The trisomy 18 syndrome. Orphanet J Rare Dis7:81–95.
Cukier HN, Rabionet R, Konidari I, Rayner-Evans MY, Baltos ML,Wright HH, Abramson RK, Martin ER, Cuccaro ML, Pericak-VanceMA, Gilbert JR. 2010. Novel variants identified in methyl-CpG-binding domain genes in autistic individuals. Neurogenetics 11:291–303.
d’Orsi G, Pascarella MG, Pansini A, Buonadonna AL, Trivisano M,Pacillo F, Carapelle E, Demaio V, Minervini M, Gentile M, SpecchioLM. 2013. Partial trisomy 18q and epileptic spasms induced by eatingassociated with bilateral opercular displasia. Am J Med Genet A161A:1194–1195.
Forrest M, Chapman RM, Doyle AM, Tinsley CL,Waite A, Blake DJ. 2012.Functional analysis of TCF4missensemutations that cause Pitt-Hopkinssyndrome. Hum Mutat 33:1676–1686.
Grosso S, Pucci L, Di Bartolo RM, Gobbi G, Bartalini G, Anichini C,Scarinci R, Balestri M, Farnetani MA, Cioni M, Morgese G, Balestri P.2005. Chromosome 18 aberrations and epilepsy: A review. Am J MedGenet A 134A:88–94.
Jones KL. editor. 2006. Trisomy 18 syndrome. In: Smith’s recognizablepatterns of human malformations. 6th edition. Philadelphia, USA:Elsevier Saunders, Inc. pp 13–17.
KinoshitaM,Nakamura Y, Nakano R, Fukuda S. 1989. Thirty-one autopsycases of trisomy 18: Clinical features and pathological findings. PediatrPathol 9:445–457.
Kumada T, Maihara T, Higuchi Y, Nishida Y, Taniguchi Y, Fujii T. 2012.Epilepsy in children with trisomy 18. Am J Med Genet A 9999:1–6.
Kumada T, Nishii R, Higashi T, Oda N, Fujii T. 2010. Epileptic apnea in atrisomy 18 infant. Pediatr Neurol 42:61–64.
Liu ZL, He B, Fang F, Tang CY, Zou LP. 2007. Analysis of single nucleotidepolymorphisms in the melanocortin-4 receptor promoter in infantilespasms. Neuropediatrics 38:304–309.
Ohba C, Okamoto N, Murakami Y, Suzuki Y, Tsurusaki Y, NakashimaM,Miyake N, Tanaka F, Kinoshita T, Matsumoto N, Saitsu H. 2014. PIGNmutations cause congenital anomalies, developmental delay, hypotonia,epilepsy, and progressive cerebellar atrophy. Neurogenetics 15:85–92.
DEL GAUDIO ET AL. 3153
Poulton CJ, Schot R, Kia SK, Jones M, Verheijen FW, Venselaar H, de WitMC, de Graaff E, Bertoli-Avella AM, Mancini GM. 2011. Microcephalywith simplified gyration, epilepsy, and infantile diabetes linked toinappropriate apoptosis of neural progenitors. Am J Hum Genet89:265–276.
Scott Schwoerer J1, Laffin J,Haun J,RacaG, FriezMJ,GiampietroPF. 2014.MECP2 duplication: Possible cause of severe phenotype in females. Am JMed Genet A 164A:1029–1034.
Strathdee G, Zackai E, Shapiro R, Kamholz J, Overhauser J. 1995. Analysisof clinical variation seen in patients with 18q terminal deletions. Am JMed Genet 59:476–483.
Tocco G, Bi X, Vician L, Lim IK, Herschman H, Baudry M. 1996. Twosynaptotagmin genes, Syt1 and Syt4, are differentially regulated in adultbrain and during postnatal development following kainic acid-inducedseizures. Brain Res Mol Brain Res 40:229–239.
Wilson MG, Towner JW, Forsman I, Siris E. 1979. Syndromes associatedwith deletion of the long arm of chromosome 18 [del(18q)]. Am J MedGenet 3:155–174.
Yamanouchi H, Imataka G, Nakagawa E, Nitta A, Naomitsu S, Hirano J,Suzumura H, Watanabe H, Arisaka O, Eguchi M. 2005. An analysis ofepilepsy with chromosomal abnormalities. Brain & Development27:370–377.
本文献由“学霸图书馆-文献云下载”收集自网络,仅供学习交流使用。
学霸图书馆(www.xuebalib.com)是一个“整合众多图书馆数据库资源,
提供一站式文献检索和下载服务”的24 小时在线不限IP
图书馆。
图书馆致力于便利、促进学习与科研,提供最强文献下载服务。
图书馆导航:
图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具
top related