CLINICAL REPORT

Severe Epilepsy in An Adult with Partial Trisomy 18q Luigi del Gaudio,* Salvatore Striano, and Antonietta Coppola Epilepsy Centre, Neurology Department, Federico II University, Naples, Italy

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

Epilepsy is one of the most common presentations associated with chromosome aberrations. Detailed descriptions of some How to Cite this Article: aberration-specific epileptic and electroencephalographic (EEG) del Gaudio L, Striano S, Coppola A. 2014. phenotypes have been reported (i.e., Angelman syndrome, ring Severe Epilepsy in an adult with Partial 20 etc.). However there is limited and mixed information about Trisomy 18q. the characteristics of epilepsy related to trisomy 18. Thus a common seizure phenotype has not been characterized yet. Am J Med Genet Part A 164A:3148–3153. Here we describe in detail a patient with refractory epilepsy and partial 18q trisomy. Ó 2014 Wiley Periodicals, Inc. was 2,700 g (5th–10th centile) and length was 45 cm (<3rd centile). Key words: epilepsy; trisomy 18; edwards syndrome 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 INTRODUCTION dysmorphism of the patient at present, as an adult). Cardiac and abdominal ultrasounds were unremarkable. A metabolic screening The trisomy 18 syndrome, also known as Edwards syndrome, is a test was negative. A brain MRI scan performed at the age of seven common autosomal chromosomal disorder with an overall preva- years showed only mild cerebral atrophy. lence of 1/2,500–1/2,600 and a live born estimated prevalence of He presented with his first seizure at six years old. This was a only 1/6,000–1/8,000; approximately 50% of babies live longer than generalized tonic-clonic (GTC) convulsion occurring during a one week [Cereda and Carey, 2012]. Of these, only 5–10% live febrile illness. Soon after, the patient developed spasms that longer than one year because of the high incidence of congenital occurred daily upon awakening and tonic asymmetric seizures malformations manly affecting the heart, genitourinary, gastroin- occurring during sleep and upon awakening. At that time the testinal and central nervous system. Minor anomalies involve face, interictal electroencephalographic (EEG) showed multiple focal eyes, and limbs. The distinctive phenotype results from full (about discharges over the posterior regions (see Fig. 1c); sleep wors- 94% of cases), mosaic (5% of cases) or partial trisomy 18q (1% of ened these abnormalities (see Fig. 1d); valproic acid (VPA) did cases) [Cereda and Carey, 2012]. The incidence of epilepsy is not improve the seizures’ severity and frequency. From age 12, estimated to be about 25–50% [Carey, 2010] but recently Kumada the spasms disappeared but GTC seizures continued; drop- et al. reported a prevalence of 64% [Kumada et al., 2012]. Although attacks appeared with a daily frequency. None of the antiepilep- Edwards syndrome is the second most common trisomy after Down tic drugs (AEDs) administered (carbamazepine, clobazam, phel- syndrome, and epilepsy is not rare in this condition, there are only bamate, and vigabatrin) improved the frequency or severity of few detailed descriptions about epilepsy associated with Edwards seizures. syndrome. We report on an adult with partial 18q trisomy and He was referred to our department at the age of 30. Neurological severe refractory epilepsy. examination showed severe intellectual disability, a lack of sphinc-

CLINICAL REPORT Conflict of Interest: None. ÃCorrespondence to: This 30-year-old man is the second child of healthy unrelated Luigi del Gaudio, Epilepsy Centre, Neurology Department Federico II parents. Family history is negative for epilepsy and any other University via Pansini 5 Naples, 80131, Italy. neurological condition. Pregnancy was complicated by bleeding E-mail: [email protected] during the second trimester and a reduction of fetal movements was Article first published online in Wiley Online Library noted at that time. He was born at term; the delivery was uneventful. (wileyonlinelibrary.com): 24 September 2014 At birth his head circumference was 32 cm (3rd–5th centile), weight DOI 10.1002/ajmg.a.36743

Ó 2014 Wiley Periodicals, Inc. 3148 DEL GAUDIO ET AL. 3149

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. 3150 AMERICAN JOURNAL OF MEDICAL GENETICS PART A ter control, absence of language and inability to walk unaided. At 17–18 translocation and two with 18p trisomy. They described that time the patient still suffered from daily events including epilepsy in seven out of 14 patients; two of them had 18p trisomy absence, tonic and atonic seizures while GTC seizures occurred and epilepsy, presenting with complex partial seizures and EEG at a frequency of 3–4/year. Interictal EEG showed generalized and abnormalities over the posterior regions. They both had a good focal paroxysmal activity mainly over the left temporal and poste- outcome. rior regions (see Fig. 1e); in some occasions the presence of a spike/ Finally, to the best of our knowledge, there are only two polyspike-slow wave complex was clinically related to head drop detailed descriptions of epilepsy in 18q trisomy. The first report (see Fig. 1f). At that time he was on treatment with VPA at the dose is by Ceccarini et al. [2007] who described three siblings carrying of 800 mg/day. Rufinamide was added on up to a dosage of an interstitial duplication of the long arm of chromosome 18 1,200 mg/day obtaining a slight reduction in frequency of tonic (18q21.31-q22.2) inherited from a healthy mosaic carrier and atonic seizures. mother. Theywere presenting with borderline or mild intellectual disability and minor dysmorphicfeatures.Outofthethree siblings only one had a history of epilepsy with generalized CYTOGENETICS and focal seizures. He suffered from generalized seizures from age 19, while focal seizures appeared at the age of 21 years. These Array-CGH analysis using a Human Genome CGH Microarray Kit were characterized by myoclonus of the perioral muscles associ- 8 Â 60 (Agilent) showed a 25.9 MB duplication at 18q12.3-q22.1 ated with a sensation of numbness of the tongue lasting for few (chr18:39,792,312-65,676,291; HG 19) involving 100 protein-cod- seconds. These episodes mostly occurred during a loud reading ing genes (see NCBI Ensembl for information on each gene in the activity, suggesting a “reading epilepsy.” EEG showed isolated, region and Fig. 1). A schematic illustration of the duplication is interictal short (1 sec) saw-tooth theta waves sequences over the shown in Figure 1g. The rearrangement was de novo. fronto-centro-temporal area bilaterally, triggered by hyperpnoea and photic stimulation. The other two siblings never suffered DISCUSSION from seizures; however they both had EEG abnormalities as their epileptic brother. Structural abnormalities of the central nervous system have been The second report is by d’Orsi et al. [2013] who described a reported in about 5% of infants with trisomy 18; the most common 30-year-old man with a trisomy of the 18q12.2q22.3 region. are cerebellar hypoplasia, agenesis of corpus callosum, microgyria, Epilepsy history is characterized by seizure onset at 25 years with hydrocephalus, and myelomeningocele [Carey, 2010; Kinoshita GTC seizures, atonic drop attacks and eating-induced repetitive et al., 1989]. epileptic spasms. The EEG showed symmetric or asymmetric Epilepsy is commonly described in patients with trisomy 18 paroxysmal activity over the posterior regions associated with [Jones, 2006; Carey, 2010] and only few cases can be ascribed to generalized spikes and spike and wave discharges. structural malformations. There is still a lack of detailed descrip- Our patient shares genetic, clinical and EEG features with the tions of epilepsy associated with Edwards syndrome and this is patient described by d’Orsi et al. They both have a partial duplica- probably due to the high mortality of these patients in the first year tion of the long arm of chromosome 18 (18q) and present with of life. Literature reports an overall prevalence ranging from 25 to intellectual disability and a severe epilepsy including spasms, GTC 50% [Carey, 2010] to 64% [Kumada et al., 2012]. The prevalence of and atonic seizures. The EEG showed predominantly paroxysmal epilepsy seems lower in partial trisomy, ranging from 10% [Wilson activity over the posterior regions in both cases. Interestingly they et al., 1979] to 31% [Strathdee et al., 1995]. There are not reported both presented with late onset infantile spasms, although in our data about the prevalence of epilepsy in mosaic trisomy 18. (Table I patient this wasmuch earlier (6 years old compared to 25years old.). reports all data from literature about association of epilepsy with The patient reported by Ceccarini et al. shows a milder phenotype trisomy 18 including the present case). with borderline intellectual functioning and late onset drug-re- A recent report by Kumada et al. [2012] described epilepsy in sponsive epilepsy. Interestingly reflex seizures were present both in seven out of 11 (64%) patients with full trisomy 18 and concluded the case described by Ceccarini (reading epilepsy) and our case that over half of children develop epilepsy during infancy or early (eating epilepsy). childhood, which can be focal as well as generalized; infantile Even if the descriptions are rare, epilepsy in partial trisomy 18 spasms might also occur. Seizures are usually drug-resistant in (18p and 18q) seems to have a common clinical and electroen- half of the children, especially those presenting with generalized cephalographic pattern being characterized by late onset epilepsy epilepsy. The same author [Kumada et al., 2010] described a case of with generalized and focal seizures (18q) or only focal (18p) and an a full trisomy 18 with onset of epilepsy at 10 months characterized EEG pattern with generalized and focal discharges mainly over the by autonomic seizures presenting as epileptic apnea. Yamanouchi posterior regions. Outcome in terms of seizures’ frequency and et al. [2005] found epilepsy in only one out of 29 patients with duration can vary with better prognosis in 18p than 18q trisomy trisomy 18. The patient had full trisomy 18 with onset of epilepsy at [Grosso et al., 2005; d’Orsi et al., 2013]. four years of age; his generalized seizures were poorly controlled More data are available for full trisomy 18: epilepsy appears to be with phenobarbital. characterized by the occurrence of both focal and generalized Grosso et al. [2005] analyzed epilepsy linked to chromosome 18 seizures and an EEG showing focal and generalized discharges; aberrations in 14 patients: five with 18p deletion syndrome onset is usually during infancy, commonly in the first year of life, (18pDS), six with 18q deletion syndrome (18qDS), one with and West syndrome is not unusual. Outcomes can be different: E ADOE AL. ET GAUDIO DEL

TABLE I. Clinical Data of the Reported 18 Trisomy Cases Including the Present Case

Onset Main type Interictal Pt Genetic of epi. Gender of seizures Brain MRI EEG Outcome Article 1 Full trisomy 18 4 years Male Brief tonic convulsion Cerebellar hypogenesis, Multifocal spikes in the Poorly Yamanouchi dysplastic right parietal and controlled et al. [2005] hyppocampus left temporal areas 2 Full trisomy 18 10 months Female Epileptic apnea, Mild atrophy Focal (right parietal, Good Kumada GTC, tonic left temporal) and et al. [2010] generalized paroxysmal activity 3 Full trisomy 18 2 years 9 months Female Complex Partial n.d. Normal Good Kumada et al. [2012] 4 Full trisomy 18 1 months Female GTC Severe atrophy Spikes on left frontal Good Kumada and right parietal et al. [2012] 5 Full trisomy 18 4 months Female Spasms, tonic, Mild atrophy Multiple Indipendent Poorly Kumada absence Spike Foci controlled et al. [2012] 6 Full trisomy 18 3 years 6months Female Tonic Severe atrophy Diffuse High Voltage Poorly Kumada Slow Waves controlled et al. [2012] 7 Full trisomy 18 2 years 5 months Female Spasms Mild atrophy Hypsarrhytmia Good Kumada et al. [2012] 8 Full trisomy 18 11 months Male Spasms, tonic, Severe atrophy Hypsarrhytmia Poorly Kumada myoclonic controlled et al. [2012] 9 Full trisomy 18 10 months Female Epileptic Cerebellar hypoplasia, Paroxysmal activity Good Elia, Sueri encephalophaty enlargement prevalent over the unpublished of ventricular system posterior regions data 10 18p trisomy 4 years Male Complex Partial Normal Generalized and bi- Good Grosso et al. occipital Spike and [2005] Spike-Waves 11 18p trisomy 5 years Male Complex Partial Agenesis of the Generalized and bi- Good Grosso Seizures splenium of the occipital Spike and et al. [2005] corpus callosum Spike-Waves 12 18q trisomy 19 years Male GTC, Reflex Enlarged cisterna Saw-tooth theta waves Good Ceccarini magna and sequences in fronto- et al. [2007] cerebellar hypoplasia temporo-central area bilaterally. 13 18q trisomy 25 years Male Atonic, GTCS, Reflex, Bilateral opercula dysplasia Focal and generalized Poorly d’Orsi epileptic spasms and corpun paroxysmal activity controlled et al. callosum hypoplasia with prevalence over [2013] the posterior regions 14 18q trisomy 6 years Male Spams, GTC Mild Atrophy Generalized, Focal Poorly Present Case Tonic, Atonic discharge over controlled posterior regions

GTCS, generalized tonic clonic seizures; CPS, complex partial seizure. 3151 3152 AMERICAN JOURNAL OF MEDICAL GENETICS PART A some patients may respond well to one type of AED, while others REFERENCES can be resistant to all therapies. It is possible that the different phenotype of these conditions Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein (18q, 18p and full trisomy 18) reflect the different gene content of MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, the aberration. The rearrangement occurring in our patient encom- Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, O’Brien TJ, Ottman R, Petrovski S, passes 100 protein coding genes. Among these, eight genes might be SYP4 Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, implicated in seizures’ pathophysiology: encodes synaptoga- Alldredge BK, Bautista JF, Berkovic SF, Boro A, Cascino GD, Consalvo D, min 4, a protein that plays a crucial role in synaptic transmission; Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, expression of synaptotagmin-4 is induced in the rat hippocampus French J, Friedman D, Geller EB, Glauser T, Glynn S, Haut SR, Hayward J, after systemic kainic acid treatment [Tocco et al., 1996]; IER3IP1 Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, encodes the immediate early response 3 interacting protein 1. Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A, Homozygous mutations have been found in patients suffering Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven J, Smith MC, from myoclonic epilepsy occurring with other clinical conditions Sullivan J, Lin Thio L, Venkat A, Vining EP, Von Allmen GK, Weisenberg [Poulton et al., 2011]; MBD1 and MBD2, code for methyl-CpG JL, Widdess-Walsh P, Winawer MR. 2013. De novo mutations in binding domain protein 1 and 2. They belong to a family of nuclear epileptic encephalopathies. Nature 501:217–221. proteins related by the presence in each of a methyl-CpG binding Carey JC. 2010. Trisomy 18 and 13 syndromes. In: Allanson J, Cassidy S, domain (MBD). This family also includes MECP2, a gene whose editors Management of genetic syndromes. 3rd edition. Hoboken, NJ: deletions result in Rett syndrome, a well known epileptic encepha- John Wiley. & Sons, Inc. pp 807–824. lopathy [Cukier et al., 2010]; duplication of the same gene have been Ceccarini C, Sinibaldi L, Bernardini L, De Simone R, Mingarelli R, Novelli associated with a clinical picture characterized by infantile hypo- A, Dallapiccola B. 2007. Duplication 18q21.31-q22.2. Am J Med Genet A 143A:343–348. tonia, severe to profound intellectual disability, autism or autistic- like features, spasticity [Scott Schwoerer et al., 2014]. TCF4 encodes Cereda A, Carey JC. 2012. The trisomy 18 syndrome. Orphanet J Rare Dis a protein called transcription factor 4; mutations of this gene lead to 7:81–95. Pitt–Hopkins Syndrome, an encephalopathy that also includes Cukier HN, Rabionet R, Konidari I, Rayner-Evans MY, Baltos ML, severe epilepsy. This gene is dosage sensitive. [Forrest et al., Wright HH, Abramson RK, Martin ER, Cuccaro ML, Pericak-Vance NEDD4L MA, Gilbert JR. 2010. Novel variants identified in methyl-CpG- 2012]; codify for the neural precursor cell expressed, binding domain genes in autistic individuals. Neurogenetics 11: developmentally down-regulated 4-like. De novo mutations of this 291–303. gene have been recently found in patients affected by epileptic MC4R d’Orsi G, Pascarella MG, Pansini A, Buonadonna AL, Trivisano M, encephalopathy [Allen et al., 2013]; encodes the melano- Pacillo F, Carapelle E, Demaio V, Minervini M, Gentile M, Specchio cortin 4 receptor which is activated by ACTH, the first line drug LM. 2013. Partial trisomy 18q and epileptic spasms induced by eating used to treat infantile spasms. This gene is dosage sensitive: the associated with bilateral opercular displasia. Am J Med Genet A homozygous knock-out mouse develops maturity onset obesity 161A:1194–1195. syndrome associated with hyperphagia, iperinsulinemia, and hy- Forrest M, Chapman RM, Doyle AM, Tinsley CL, Waite A, Blake DJ. 2012. perglycemia. The heterozygous mice have an intermediate pheno- Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins type. [Liu et al., 2007]; PIGN encodes the phosphatidylinositol syndrome. Hum Mutat 33:1676–1686. glycan anchor biosynthesis. Mutations have been found in a Grosso S, Pucci L, Di Bartolo RM, Gobbi G, Bartalini G, Anichini C, syndrome called multiple congenital anomalies-hypotonia-seiz- Scarinci R, Balestri M, Farnetani MA, Cioni M, Morgese G, Balestri P. ures syndrome [Ohba et al., 2014]. 2005. Chromosome 18 aberrations and epilepsy: A review. Am J Med Genet A 134A:88–94. It is difficult to state, which of these genes play a major role in the pathophysiology of epilepsy for this condition. It is possible that the Jones KL. editor. 2006. Trisomy 18 syndrome. In: Smith’s recognizable patterns of human malformations. 6th edition. Philadelphia, USA: overall burden of the duplicated products and their interactions Elsevier Saunders, Inc. pp 13–17. lead to the disease. Although the function of the proteins encoded by these genes make them promising as candidate genes for the Kinoshita M, Nakamura Y, Nakano R, Fukuda S. 1989. Thirty-one autopsy cases of trisomy 18: Clinical features and pathological findings. Pediatr pathophysiology of epilepsy in this condition, functional studies are Pathol 9:445–457. needed to clarify their exact role. Kumada T, Maihara T, Higuchi Y, Nishida Y, Taniguchi Y, Fujii T. 2012. Accordingly the clinical phenotype cannot be characterized Epilepsy in children with trisomy 18. Am J Med Genet A 9999: based on only three detailed reports. The description of single or 1–6. group cases is essential to understand if a unified phenotype exists Kumada T, Nishii R, Higashi T, Oda N, Fujii T. 2010. Epileptic apnea in a and, if it does then its characteristics should be studied in detail for trisomy 18 infant. Pediatr Neurol 42:61–64. further prognosis. Liu ZL, He B, Fang F, Tang CY, Zou LP. 2007. Analysis of single nucleotide polymorphisms in the melanocortin-4 receptor promoter in infantile ACKNOWLEDGMENTS spasms. Neuropediatrics 38:304–309. Ohba C, Okamoto N, Murakami Y, Suzuki Y, Tsurusaki Y, Nakashima M, We would like to thank the patient’s family for giving us permission Miyake N, Tanaka F, Kinoshita T, Matsumoto N, Saitsu H. 2014. PIGN to report their son’s case. We also thank Dr Krishna Chinthapalli for mutations cause congenital anomalies, developmental delay, hypotonia, language support. 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 Wit Tocco G, Bi X, Vician L, Lim IK, Herschman H, Baudry M. 1996. Two MC, de Graaff E, Bertoli-Avella AM, Mancini GM. 2011. Microcephaly synaptotagmin genes, Syt1 and Syt4, are differentially regulated in adult with simplified gyration, epilepsy, and infantile diabetes linked to brain and during postnatal development following kainic acid-induced inappropriate apoptosis of neural progenitors. Am J Hum Genet seizures. Brain Res Mol Brain Res 40:229–239. 89:265–276. Wilson MG, Towner JW, Forsman I, Siris E. 1979. Syndromes associated Scott Schwoerer J1, Laffin J, Haun J, Raca G, Friez MJ, Giampietro PF. 2014. with deletion of the long arm of chromosome 18 [del(18q)]. Am J Med MECP2 duplication: Possible cause of severe phenotype in females. Am J Genet 3:155–174. Med Genet A 164A:1029–1034. Yamanouchi H, Imataka G, Nakagawa E, Nitta A, Naomitsu S, Hirano J, Strathdee G, Zackai E, Shapiro R, Kamholz J, Overhauser J. 1995. Analysis Suzumura H, Watanabe H, Arisaka O, Eguchi M. 2005. An analysis of of clinical variation seen in patients with 18q terminal deletions. Am J epilepsy with chromosomal abnormalities. Brain & Development Med Genet 59:476–483. 27:370–377. 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。

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