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Epilepsy in Patients With Duplications of Chromosome 14 Harboring FOXG1
Pediatric Neurology 50 (2014) 530e535
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Clinical Observations
Epilepsy in Patients With Duplications of Chromosome 14 Harboring FOXG1 Giuseppe Pontrelli MD a, b, Simona Cappelletti PsyD c, Dianela Claps MD a, Pietro Sirleto MLT d, Laura Ciocca MLS d, Stefano Petrocchi MLT d, Alessandra Terracciano MLS e, Domenico Serino MD a, Lucia Fusco MD, PhD a, Federico Vigevano MD, PhD a, Nicola Specchio MD PhD a, * a
Division of Neurology, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy “Amaducci” Neurology Unit, Department of Neuroscience, University of Bari, Bari, Italy c Unit of Clinical Psychology, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy d Cytogenetics and Molecular Genetics Unit, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy e Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesú Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy b
abstract BACKGROUND: Dup(14q12) harboring FOXG1 has been recently reported in individuals with developmental delay of
variable severity, delayed/absent speech, and epilepsy/infantile spasms. FOXG1 was described as a dosage-sensitive gene encoding G1, a forkhead protein that is a brain-specific transcription factor with a role in brain development. PATIENTS: We extensively reviewed all published cases with dup(14) harboring FOXG1 and highlighted those epileptological features that are more commonly found among such cases. We also describe one new patient, detailing his peculiar clinical and neurophysiological findings. RESULTS: To date, 15 patients with dup(14) including FOXG1 have been reported; within those patients, nine also presented with epilepsy. At onset, the more frequent seizure type in the report and also in our patient is the epileptic spasm. Focal seizures might also be present. Outcomes in patients with epilepsy associated with dup(14) should be considered separately regarding seizures and cognitive and motor development. In the majority of patients (seven of 10, including ours), seizures tend to disappear and motor skills improve; however, instead stagnation of cognitive development is evident in all of them, associated with severe speech difficulties. CONCLUSIONS: There are some common features that should be considered: seizures with onset during the first year of life, particularly clusters of spasms and focal seizures with hypsarrhythmic electroencephalograph pattern; different degrees of cognitive impairment possibly associated with behavior disturbances and severe speech disabilities; and dysmorphic features in the absence of significant microcephaly. Keywords: epilepsy, epileptic spasms, chromosome 14 duplication, FOXG1, genetic
Pediatr Neurol 2014; 50: 530-535 Ó 2014 Elsevier Inc. All rights reserved. Introduction
Rearrangements of chromosome 14 might be responsible for various neurological deficits including mental retardation and epilepsy. About 1000 genes have been identified on Article History: Received November 6, 2013; Accepted in final form January 5, 2014 * Communications should be addressed to: Dr. Specchio; Division of Neurology; Bambino Gesù Children’s Hospital e IRCCS; P.zza S. Onofrio 4; 00165 Rome, Italy. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.022
chromosome 14.1 Among rearrangements, chromosome 14 duplication [dup(14)] is a rare condition; it might be the result of a rearrangement in one parents’ chromosomes or might occur de novo. Dup(14q12) harboring FOXG1 has been recently reported in individuals with developmental delay of variable severity, delayed/absent speech, and epilepsy/infantile spasms.2-7 FOXG1 gene, with location 14q12 and genomic coordinates 29,236,277-29,239,482 (OMIM 164874), has been described as a dosage-sensitive gene encoding G1, a forkhead protein that is a brain-specific transcription factor,
G. Pontrelli et al. / Pediatric Neurology 50 (2014) 530e535
with a role in brain development, corticogenesis, neuronogenesis, and neurite outgrowth.3,8,9 FOXG1 encodes a transcriptional repressor protein exclusively expressed in the fetal and adult brains. The mitosis of Cajal-Retzius cells, the earliest neurons established in cortical layering, is suppressed by FOXG1. It also regulates neurogenesis in the postnatal hippocampus and continues to be expressed at high levels in other areas of postnatal neurogenesis. Therefore the potential role of FOXG1 duplication in determining severe epilepsy, developmental delay, and especially infantile spasms, as a result of increased gene dosage, is an emerging theory.2-7 On the other hand, the clinical picture determined by deletions and inactivating mutations of FOXG1 is represented by Rett-like syndrome (one of the congenital variants) with hypotonia, irritability, severe developmental delay, autism, microcephaly, and late-onset epilepsy.3,9,10 To date, 15 patients with dup(14) including FOXG1 have been reported; within those patients, nine presented also with epilepsy.2-7 The aim of this report is to describe one new case of dup(14) harboring FOXG1 presenting with epilepsy and, through an extensive review of the literature, highlight those epileptological features that are more commonly found among such patients. In this way, we construct a hypothetical patient’s profile, which may help in genetic diagnosis and prognosis. Methods We report one new patient with FOXG1 duplication and we reviewed all published cases focusing on association with epilepsy. To identify published articles we looked for “FOXG1 duplication” on PubMed website (www.ncbi.nlm.nih.gov/pubmed). We evaluated neonatal period, familial history, cytogenetic findings, neurological and morphological assessment, seizures (onset, semiology, and outcome), interictal and ictal electroencephalograph (EEG) findings at baseline and follow-up, treatment, and neuroimaging.
Case report This is a 2-year-old boy born at term after normal pregnancy with vaginal delivery; maternal aunt had developmental delay, and distant relatives had an infantile epilepsy history. Head circumference at birth was 35 cm. He passed through the regular neonatal period with no issues. At 4 months (1 week after vaccine), he started to present with clusters of flexor and extensor spasms of increasing frequency, associated with developmental regression (axial hypotonia, reduction of visual pursuit capability, and spontaneous motility). A first EEG performed at 4 months of age documented multifocal slow and epileptiform abnormalities with right parieto-occipital prevalence (Figure, A). Brain magnetic resonance imaging was performed soon after and showed mild atrophy, ventricle enlargement, delayed myelination, and T2hyperintensities in the right caudate head (Figure, G). Treatment with valproic acid and clonazepam was started with partial effect on seizure frequency. At the age of 5 months, focal seizures appeared, manifesting with brief ocular movements and lower limb stiffening. A new EEG revealed the presence of hypsarrhythmia (Figure, B), myoclonic and focal seizures, and epileptic spasms (Figure, C-E). Treatment with ACTH was immediately started, with worsening of focal seizures and without effect on epileptic spasms. Head circumference at 6 months was 49 cm. Over the months, several treatments were attempted (vigabatrin, B6, P5P, folic acid, levetiracetam, topiramate, nitrazepam), with seizures persisting. Even though a significant reduction in seizure frequency was observed when rufinamide was started, a spontaneous and complete resolution was reached at the age of 14 months in concert with psychomotor
531
improvement. Neuropsychological evaluation at the ages of 13 and 19 months revealed a general quotient, respectively, of 44 and 40 (Griffiths scale), with a major impairment of visual attention. Geneticist contribution
A genetic diagnostic panel was performed. Singular genes were assessed (FRA X, chromosome 15 methylation, SLC25A22, STXBP1, CDKL5), with the results normal. G-banded chromosome analysis was performed on phytohemagglutinin-stimulated peripheral blood lymphocytes following standard protocols. We analyzed 50 metaphase cells and found 46,XX[27]/47,XX,þmar[23] (Supplemental Fig 1). Fluorescence in situ hybridization experiments revealed that the small marker chromosome was derived from chromosome 14. To further define the region of the supernumerary derived chromosome 14, single nucleotide polymorphism (SNP) array and microsatellite polymorphism analysis were performed. Array comparative genomic hybridization analysis showed a gain of about 14.8 Mb of the region 14q11.2q12 (19,043,18933,814,746) 2-3 encompassing FOXG1. Single nucleotide polymorphism analysis of the patient, compared with his parents, showed a fatherly uniparental isodisomy, confirmed by microsatellite polymorphism analysis (Supplemental Fig 2, Supplemental Table 1). Review of previously reported patients
The Table shows all previously published cases with dup(14) including FOXG1.2-7 In 15 reported patients, nine presented also with epilepsy. Mean age at onset of epilepsy in all selected patients was 4.9 months (range 3-7 months); seizures were reported as generalized in one patient, focal in two patients, and epileptic spasms in eight patients (spasms with focal signs in two patients). Two patients experienced two types of seizures. Status epilepticus was never reported. Focal seizures were characterized by eyes opening, arrest of suction, and increased respiratory and cardiac rate, or by nocturnal tonic and tonic-vibratory seizures. Six patients were seizure-free during follow-up. Interictal EEG was characterized mainly by the recurrence of focal and bilateral epileptiform abnormalities. In eight patients a hypsarrhythmic EEG pattern was evident at onset or during the follow-up; in two patients, the last follow-up EEG was reported as normal (at 12 and 6 years of age, respectively). Ictal EEG was available in one patient and was characterized by diffuse high-voltage slow wave, followed by low-amplitude fast activity over the frontal and temporal regions with a clinical counterpart of epileptic spasms or by rhythmic fast activity over the occipital and temporal regions associated with subtle seizures. Data on cognitive development were available in all patients but one. Cognitive disability was clear in all patients: in five, it was described as severe; in three it was mild-moderate. None of the patients presented with microcephaly. Motor delay was evident in seven patients; hypotonus/hypertonia, intentional tremor, and stereotyped movements were also reported. Neuroimaging was reported in all patients but one: normal in three of eight patients; two cases of nonspecific white matter alterations of the periventricular and left temporal regions, respectively, one case of thin corpus callosum and one case of small arachnoid cyst. A periventricular nodule of heterotopic gray matter was reported in one patient. Dysmorphic features, such as flat nasal bridge, mild hypotelorism, short palpebral fissures, malformed ears, high-frontal hairline, deep-set eyes, micrognathia, cleft palate, or polydactyly were reported in five of nine patients.
Discussion
The contribution of FOXG1 in the phenotype of reported patients might be related to its function on brain development, particularly as a transcriptional repressor preventing premature neural differentiation.4 Furthermore, this was confirmed through a phenotypeegenotype correlation among patients whose duplication was part of a specific, narrowed-down region. This selection was made in the
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G. Pontrelli et al. / Pediatric Neurology 50 (2014) 530e535
TABLE. Clinical features of patients with FOXG1 duplication Author
Sex
Age
Neonatal
Familial History
Cytogenetic Finding
Sz Onset
Sz Types at Onset
Sz Types During Follow-up
EEG Interictal
Yeung et al., 2009
F
9 yr
BW 3835 g, early feeding difficulties.
NR
Chr 14: 2597-3042. Size 4.45 Mb. Dupl FOXG1 de novo
3 mo
Spasms
Spasms, nocturnal tonic-vibratory, from 6 yr nocturnal tonic.
Hypsarr, cont bil post discharges that occurred synch and asynch.
Brunetti-Pierri et al., 2011
M
4 yr
NR
NR
6 mo
Spasms
Seizure-free on LTG
Hypsarr, R ShW and diffuse slowing
Brunetti-Pierri et al., 2011
F
3 yr
NR
NR
Chr 14: 2690881230254928. Size 3.3-3.4 Mb. Dupl FOXG1 de novo Chr 14: 19582682-29076 500. Size 9.4-11 Mb. Dupl FOXG1 de novo
6 mo
GTC
seizure-free on ZNS at 2 yr.
Multifocal and Gen Sp and SW, slow BA
Brunetti-Pierri et al., 2011
M
6 mo
BW 3317 gr (25-50th c) BL 52.1 cm (75-90th c).
NR
3m
spasms
NR
Modified hypsarr
Brunetti-Pierri et al., 2011
M
3 yr
BW 3000 g (10e25th c).
NR
e
e
e
Normal
Brunetti-Pierri et al., 2011
M
3 yr
NR
Chr 14: 27474978-30603041. Size 3.1 Mb. Dupl FOXG1
5 mo
spasms
Seizure-free
Hypsarr
Brunetti-Pierri et al., 2011
M
Adult
BW 4210 gr (90th c), BL 53.5 cm (90th c), HC 36 cm (90th c). BW appropriate
Unremarkable
Chr 14: 19508845-34063670. Size 14.5 Mb. Dupl FOXG1 de novo
e
e
e
e
Brunetti-Pierri et al., 2011
M
35 yr
NR
Brother with CD
Chr 14: 28257153-35048345. Size 6.8 Mb. Dupl FOXG1
e
e
e
e
Striano et al., 2011
M
3 yr
BW 4210 g (90th c), BL 53.5 cm (75-90th c), HC 36 cm (75th c)
NR
Chr 14: 27409-30603. Size 3.2 Mb. Dupl FOXG1 de novo
5 mo
Spasms
Brief focal with aut signs.
Hypsarr, bil T Sp. Diffuse SW and Sp.
Striano et al., 2011
M
14 yr
NR
Unremarkable
7 mo
Spasms with focal signs.
Seizure-free.
Hypsarr
Tohyama et al., 2011
F
6 yr
BW 2140 g (2.4 SD), BL 48 cm (0.4 SD), HC 28 cm (3.9 SD).
Unremarkable
4 mo
Spasms with focal signs
Seizure-free
Hypsarr
Paciorkowski et al., 2011 Amor et al., 2012
F
14 mo
NR
NR
5.5 mo
Spasms
NR
M
NR
NR
Amor et al., 2012
M
NR
NR
Amor et al., 2012 Present patient
NR M
NR 19 mo
NR HC at 6 mo was 49 cm
Son with the same cytogenetic finding. Father with the same cytogenetic finding. NR Maternal aunt with dev delay, distant relatives with infantile epilepsy history.
Chr 14: 19365-30359. Size 11 Mb. Dupl FOXG1. Small extranumerary marker (with part of duplication) from maternal balanced translocation involving chr 14 and 15. Parental CGH array normal. Chr 14: 14q11.2-q12. Dupl FOXG1. Mosaic dupl. Maternal uniparental disomy 14 and mosaic small marker of paternal origin containing the proximal long arm of chr 14. Chr 14: 27165797-30192375. Size: 3.3 Mb. Dupl FOXG1 de novo. Chr 14: 28236716- 28325210. Size: 88 Kb.
Abbreviations: abn ¼ Abnormalities asynch ¼ Asynchronous BA ¼ Background activity bil ¼ Bilateral BL ¼ Body length BW ¼ Body weight cont ¼ Continuous F ¼ Female c ¼ Centile CD ¼ Cognitive disabilities chr ¼ Chromosome CLB ¼ Clobazam dev ¼ Development dupl ¼ Duplication FA ¼ Fast activity fr ¼ Frontal gen ¼ Generalized GQ ¼ General quotient GTC ¼ Generalized tonic-clonic seizure HC ¼ Head circumference hem ¼ Hemisphere hypsarr ¼ Hypsarrhythmia KD ¼ Ketogenic diet
Chr 14: 19582682-33275 612. Size 13.7-18.4 Mb. Dupl FOXG1. Chr 3:191 656 626-199 287 624. Size 7.6-8.4 Mb. Parental studies: Mother: chr 3; 14 translocation. Chr 14: 28217364-34635622. Size 6.4 Mb. Dupl FOXG1 de novo
e
e
Seizure-free at 14 mo e
Chr 14: 28236716 28325210. Size: 88 Kb.
e
e
e
e
Chr 14: 27861440- 30208129. Size: 2.3 Mb. Chr 14: 19043189-33814746. Size: 14.8 Mb. Dupl FOXG1 de novo.
e 4 mo
e Spasms
e Brief focal, tonic, myoclonic.
e Multifocal slow and epileptiform abn with R P-O prevalence.
L LEV LTG M NR NZP O P PA post R SD ShW synch sp SW Sz T TPM VGB VPA W ZNS
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
Left Levetiracetam Lamotrigine Male Not reported Nitrazepam Occipital Parietal Paroxysmal activity Posterior Right Standard deviation Sharp wave Synchronous Spike Slow wave Seizure Temporal Topiramate Vigabatrin Valproic acid Wave Zonisamide
e
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TABLE. Clinical features of patients with FOXG1 duplication (Continued) EEG Interictal Follow-up
EEG Ictal
7 yr: multifocal NR discharges, gen sp 4-5 Hz. 9 yr: BA slowing, bi Fr sp W 2.5-3 Hz. NR R ShW, R hem slowing; last EEG: normal. NR NR
Treatment
Neurological Features
Neuropsychological Assessment
Associated Features
Neuroimaging
VGB, KD, steroids, LEV
3-6 mo: dev regression, poor head control, walked 21 mo. 9 yr: no speaking, hypotonia
Behavior: affectionate and not disruptive. Occasional hand flapping. Able to feed herself.
9 yr: HC 51.5 cm (25th c). Minor dysmorphisms: upslanting palpebral fissures, bil single palmar creases, mild 2-3 syndactyly.
Periventricular nodule of heterotopic gray matter. Positron emission tomography (9 yr): bil T and Fr hypometabolism.
ACTH, LTG
Lack of speech, nystagmus, walking at 3 yr, frequent falls, broad-based gait, stereotyped hand movements. 1 yr: unable to sit, 30 mo: inability to walk. Speech delayed.
Global dev delay, inappropriate laughing. No history of regression. Dev delay.
Unilateral postaxial polydactyly, strabismus, HD 49.1 cm (3 SD), nondysmorphic. HD 48 cm (25th c). Dysmorphic facies, flat nasal bridge, mild hypotelorism, short palpebral fissures, bil malformed ears, bil fifth finger clinodactyly, R fifth finger brachydactyly. Mild dysmorphisms: small palpebral fissures, simplified ears, a L accessory nipple, and a R club foot.
Mild foreshortened frontal lobes.
ZNS
Mild small posterior fossa and foreshortening of the corpus callosum.
BA slowing, L T SW with Sp and SW discharges.
NR
ACTH, Prednisone, TPM
Truncal and axial hypotonia, brisk reflexes, absence of speech (13 m)
Dev delay.
e
e
e
18 mo: started walking.
Mild dysmorphic facial features.
Bil T abn.
NR
ACTH, TPM
Stereotyped hand movements, severe speech involvement.
Communicative difficulties, hyperactivity, severe attention deficits, IQ 72 (Griffiths scale). Dev regression and autistic spectrum disorders.
Normocephalic and nondysmorphic.
Abnormal alteration of the white matter signal in the L T region.
e
e
e
No focal signs, lack of speech, inability to walk unsupported at the age 4 yr.
Dev delay, severely CD.
Not executed.
e
e
e
Poor eye contact 35 yr: able to say a few words.
Asynch bil T PA, bil O and T SW and PA.
Normal
Normal
Spasms: bil diffuse NZP, ACTH, SW with attenuation VPA, TPM and Fr-T FA. Focal: O-T rhythmic FA. NR ACTH, VGB
33 yr: HD 53.5 cm (10-25th c). Dysmorphic features: high frontal hairline, hyperplastic supra-orbital ridges, deep-set eyes, asymmetric anteverted ears, short philtrum, micrognathia, cutaneous II-III syndactyly on the L foot, cleft palate. Prominent jaw, one irregular café-au-lait spot, horizontal striae on back, and short large toes. No facial dysmorphisms.
Normal
NR
NR
NR
e e e Hypsarr
Severe CD: stereotyped behavior, anxiety, self-injuries, aggressive behavior. Attenuated responsiveness to verbal Early dev was reported and visual stimuli and discontinuous as normal; Bayley Scales eye contact, absence of language. revealed moderate CD.
Thin corpus callosum, incomplete myelination, and areas of signal abnormality in the central/periventricular white matter, L caudate nucleus porencephalic cyst. Small arachnoid cyst.
Not executed.
Clumsiness and broad-based gait.
Dev was delayed: hyperactive and attended the school with support.
No facial dysmorphisms.
Normal
VPA, ZNS, ACTH, CLB
5 mo: mild hypotonia, 6 yr: able to speak few words.
Mild psychomotor delay. 5 yr, 8 mo: IQ 40 (Binnet).
Normal
NR
NR
NR
e
TPM, VPA, ACTH e
5 mo: HD was 41 cm (þ0.2 SD), mild dysmorphic features: frontal bossing, small mouth, small hands, hemangioma on the L forehead. NR
Normal
Normal
Hemifacial microsomia.
NR
e
e
Normal
Normal
Hemifacial microsomia.
NR
e Diffuse low voltage, or focal discharges
e ACTH, B6, P5P, VGB, folic acid, LEV, TPM, NZP
Normal Dev regression (axial hypotonia, reduction of visual pursuit capability and spontaneous motility)
Normal No 13 and 19 mo: GQ of 44 and 40, No respectively (Griffiths scale), major impairment of visual attention.
NR Mild atrophy and ventricles enlargement, delayed myelination and T2-hyperintensities in the R caudate head.
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G. Pontrelli et al. / Pediatric Neurology 50 (2014) 530e535
FIGURE. (A) Interictal awake electroencephalograph showing disorganized background activity associated with multiple slow waves intermingled with low-voltage spikes over the right posterior region. Diffuse low-voltage fast activity is also evident with predominance over the right parieto-temporo-occipital region. (B) During sleep, an increase of epileptiform abnormalities is evident with diffuse epileptiform discharges. (C) Diffuse spike-and-wave complexes followed by massive myoclonia involving the upper limbs. A decremental activity is also evident associated with an increase of muscle tone. (D) Brief infraclinical focal discharges involving bilateral central and posterior areas during sleep. (E) Spasm-tonic seizure with an electroencephalograph counterpart characterized by diffuse slow waves intermingled with spikes and followed by low-voltage fast activity. (F) Array comparative genomic hybridization and single nucleotide polymorphism were performed using, respectively, the SurePrint G3 Human comparative genomic hybridization þ single nucleotide polymorphism Microarray 4 180 K (Agilent Technologies, Santa Clara, CA) and 3130XL Genetic Analyzer (Applied Biosystems, Foster City, CA). Profile of the chromosome 14 showing the mosaicism of the duplication of proximal part of chromosome 14 is evident. Fragment analysis at D14S1071 showed a higher peak of paternal inheritance, indicating the mosaic status of the der(14). (G) Axial and coronal T2-weighted image magnetic resonance images showing mild atrophy, ventricles enlargement, and delayed myelination.
attempt of reducing the spectrum of possible candidate genes. Although FOXG1 represents the most interesting candidate to explain this phenotype, the role of additional genes in the large duplicated regions cannot be excluded, considering the hypothesis of regulatory mutations to explain the wide phenotypic variability.2,7-9
Within all reported patients, one had a mosaic dup(14) associated to maternal uniparental disomy of chromosome 14, a similar condition found in our patient with a mosaic dup(14) associated to paternal uniparental disomy. The condition of uniparental disomy is usually associated to dysmorphisms such as facial abnormalities, a small, bell-
G. Pontrelli et al. / Pediatric Neurology 50 (2014) 530e535
shaped thorax, abdominal wall defects, polyhydramnios, and cognitive disability.11 In both patients with uniparental disomy, the occurrence of severe epileptic encephalopathy with spasms and focal seizures without the typical body alterations seems to be related to FOXG1 gain of function more than to the uniparental disomy per se. The epileptological features of the reported patients seem to be quite similar, because the most frequent type of seizure experienced in the report and also in our patient is the epileptic spasm. Also focal seizures might be present, in both reported patients, and in our patient. In particular, spasms are reported in nine of 10 patients (including the present patient); focal seizures were evident in three of 10 patients. Mean age at onset is 4.85 1.33 months (range 37 months) regarding all seizures. All patients but one presented at onset with epileptic spasms with hypsarrhythmic interictal EEG pattern. These patients might be considered in the ample context of West syndrome, even if in all of them early developmental delay was evident before onset of seizures. This finding should be related to the genetic condition per se more than a regression from seizures and interictal EEG abnormalities. It is noteworthy that in two patients EEGs were reported as normal during follow-up: this finding could be related to the age of patients (12 and 6 years, respectively), and it could be expected also in other patients at the same age. Neuroimaging findings are mainly not specific. Outcome in patients with epilepsy associated to dup(14) should be considered separately regarding seizures and cognitive and motor development. In the majority of patients (seven of 10 including the present patient), seizures tend to disappear during the follow-up, motor skills improve, and all patients might walk and stand alone. Regarding cognitive development, stagnation is evident in all of them with mild to severe disabilities associated to severe speech difficulties. Rett-like syndrome and other types of haploinsufficiency of FOXG1 (mutations or deletions) have similarities as well as notable differences with respect to duplications. In both situations, normal perinatal growth, developmental slowing or regression, intellectual deficits, absent speech, and epilepsy are common features, but in the case of duplications we recognize some peculiar element: seizure onset during the first year of life typically represented by spasms, ability to walk within the first 2 years, absence of microcephaly, and stereotypic hand movements.2-4,6,9 These differences indicate that overexpression of FOXG1 may have a specific role in the pathogenesis of infantile spasms in these patients.9 Even for MECP2, duplications lead to clinical features that are similar to those of FOXG1 duplication.4 These similarities are intellectual disabilities and severely impaired speech. Nevertheless, early-onset epilepsy and
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infantile spasms are typical of FOXG1 duplication but have not been described in MECP2 duplication. In our patient and in those previously reported with FOXG1 duplication, there are common features that should be considered for an early diagnosis: seizures with onset during the first year of life, particularly clusters of spasms and focal seizures with hypsarrhythmic EEG pattern; different degrees of cognitive impairment, possibly associated to behavior disturbances and severe speech disabilities; and dysmorphic features in the absence of significant microcephaly. The authors thank the patients’ families for their contribution to this research.
Supplementary material
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.022. References 1. Heilig R, Eckenberg R, Petit JL, et al. The DNA sequence and analysis of human chromosome 14. Nature. 2003;421:601-607. 2. Brunetti-Pierri N, Paciorkowski AR, Ciccone R, et al. Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet. 2011;19:102-107. 3. Striano P, Paravidino R, Sicca F, et al. West syndrome associated with 14q12 duplications harboring FOXG1. Neurology. 2011;76: 1600-1602. 4. Yeung A, Bruno D, Scheffer IE, et al. 4.45 Mb microduplication in chromosome band 14q12 including FOXG1 in a girl with refractory epilepsy and intellectual impairment. Eur J Med Genet. 2009;52: 440-442. 5. Paciorkowski AR, Thio LL, Rosenfeld JA, et al. Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. Eur J Hum Genet. 2011;19:1238-1245. 6. Tohyama J, Yamamoto T, Hosoki K, et al. West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am J Med Genet A. 2011;155A: 2584-2588. 7. Amor DJ, Burgess T, Tan TY, Pertile MD. Questionable pathogenicity of FOXG1 duplication. Eur J Hum Genet. 2012;20:595-596. 8. Falace A, Vanni N, Mallamaci A, Striano P, Zara F. Do regulatory regions matter in FOXG1 duplications? Eur J Hum Genet. 2013;21: 365-366. 9. Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-geneerelated encephalopathies. Epilepsia. 2012;53:2067-2078. 10. Kortum F, Das S, Flindt M, et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet. 2011;48:396-406. 11. Kagami M, Sekita Y, Nishimura G, et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet. 2008; 40:237-242.
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Clinical Observations
Epilepsy in Patients With Duplications of Chromosome 14 Harboring FOXG1 Giuseppe Pontrelli MD a, b, Simona Cappelletti PsyD c, Dianela Claps MD a, Pietro Sirleto MLT d, Laura Ciocca MLS d, Stefano Petrocchi MLT d, Alessandra Terracciano MLS e, Domenico Serino MD a, Lucia Fusco MD, PhD a, Federico Vigevano MD, PhD a, Nicola Specchio MD PhD a, * a
Division of Neurology, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy “Amaducci” Neurology Unit, Department of Neuroscience, University of Bari, Bari, Italy c Unit of Clinical Psychology, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy d Cytogenetics and Molecular Genetics Unit, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy e Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesú Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy b
abstract BACKGROUND: Dup(14q12) harboring FOXG1 has been recently reported in individuals with developmental delay of
variable severity, delayed/absent speech, and epilepsy/infantile spasms. FOXG1 was described as a dosage-sensitive gene encoding G1, a forkhead protein that is a brain-specific transcription factor with a role in brain development. PATIENTS: We extensively reviewed all published cases with dup(14) harboring FOXG1 and highlighted those epileptological features that are more commonly found among such cases. We also describe one new patient, detailing his peculiar clinical and neurophysiological findings. RESULTS: To date, 15 patients with dup(14) including FOXG1 have been reported; within those patients, nine also presented with epilepsy. At onset, the more frequent seizure type in the report and also in our patient is the epileptic spasm. Focal seizures might also be present. Outcomes in patients with epilepsy associated with dup(14) should be considered separately regarding seizures and cognitive and motor development. In the majority of patients (seven of 10, including ours), seizures tend to disappear and motor skills improve; however, instead stagnation of cognitive development is evident in all of them, associated with severe speech difficulties. CONCLUSIONS: There are some common features that should be considered: seizures with onset during the first year of life, particularly clusters of spasms and focal seizures with hypsarrhythmic electroencephalograph pattern; different degrees of cognitive impairment possibly associated with behavior disturbances and severe speech disabilities; and dysmorphic features in the absence of significant microcephaly. Keywords: epilepsy, epileptic spasms, chromosome 14 duplication, FOXG1, genetic
Pediatr Neurol 2014; 50: 530-535 Ó 2014 Elsevier Inc. All rights reserved. Introduction
Rearrangements of chromosome 14 might be responsible for various neurological deficits including mental retardation and epilepsy. About 1000 genes have been identified on Article History: Received November 6, 2013; Accepted in final form January 5, 2014 * Communications should be addressed to: Dr. Specchio; Division of Neurology; Bambino Gesù Children’s Hospital e IRCCS; P.zza S. Onofrio 4; 00165 Rome, Italy. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.022
chromosome 14.1 Among rearrangements, chromosome 14 duplication [dup(14)] is a rare condition; it might be the result of a rearrangement in one parents’ chromosomes or might occur de novo. Dup(14q12) harboring FOXG1 has been recently reported in individuals with developmental delay of variable severity, delayed/absent speech, and epilepsy/infantile spasms.2-7 FOXG1 gene, with location 14q12 and genomic coordinates 29,236,277-29,239,482 (OMIM 164874), has been described as a dosage-sensitive gene encoding G1, a forkhead protein that is a brain-specific transcription factor,
G. Pontrelli et al. / Pediatric Neurology 50 (2014) 530e535
with a role in brain development, corticogenesis, neuronogenesis, and neurite outgrowth.3,8,9 FOXG1 encodes a transcriptional repressor protein exclusively expressed in the fetal and adult brains. The mitosis of Cajal-Retzius cells, the earliest neurons established in cortical layering, is suppressed by FOXG1. It also regulates neurogenesis in the postnatal hippocampus and continues to be expressed at high levels in other areas of postnatal neurogenesis. Therefore the potential role of FOXG1 duplication in determining severe epilepsy, developmental delay, and especially infantile spasms, as a result of increased gene dosage, is an emerging theory.2-7 On the other hand, the clinical picture determined by deletions and inactivating mutations of FOXG1 is represented by Rett-like syndrome (one of the congenital variants) with hypotonia, irritability, severe developmental delay, autism, microcephaly, and late-onset epilepsy.3,9,10 To date, 15 patients with dup(14) including FOXG1 have been reported; within those patients, nine presented also with epilepsy.2-7 The aim of this report is to describe one new case of dup(14) harboring FOXG1 presenting with epilepsy and, through an extensive review of the literature, highlight those epileptological features that are more commonly found among such patients. In this way, we construct a hypothetical patient’s profile, which may help in genetic diagnosis and prognosis. Methods We report one new patient with FOXG1 duplication and we reviewed all published cases focusing on association with epilepsy. To identify published articles we looked for “FOXG1 duplication” on PubMed website (www.ncbi.nlm.nih.gov/pubmed). We evaluated neonatal period, familial history, cytogenetic findings, neurological and morphological assessment, seizures (onset, semiology, and outcome), interictal and ictal electroencephalograph (EEG) findings at baseline and follow-up, treatment, and neuroimaging.
Case report This is a 2-year-old boy born at term after normal pregnancy with vaginal delivery; maternal aunt had developmental delay, and distant relatives had an infantile epilepsy history. Head circumference at birth was 35 cm. He passed through the regular neonatal period with no issues. At 4 months (1 week after vaccine), he started to present with clusters of flexor and extensor spasms of increasing frequency, associated with developmental regression (axial hypotonia, reduction of visual pursuit capability, and spontaneous motility). A first EEG performed at 4 months of age documented multifocal slow and epileptiform abnormalities with right parieto-occipital prevalence (Figure, A). Brain magnetic resonance imaging was performed soon after and showed mild atrophy, ventricle enlargement, delayed myelination, and T2hyperintensities in the right caudate head (Figure, G). Treatment with valproic acid and clonazepam was started with partial effect on seizure frequency. At the age of 5 months, focal seizures appeared, manifesting with brief ocular movements and lower limb stiffening. A new EEG revealed the presence of hypsarrhythmia (Figure, B), myoclonic and focal seizures, and epileptic spasms (Figure, C-E). Treatment with ACTH was immediately started, with worsening of focal seizures and without effect on epileptic spasms. Head circumference at 6 months was 49 cm. Over the months, several treatments were attempted (vigabatrin, B6, P5P, folic acid, levetiracetam, topiramate, nitrazepam), with seizures persisting. Even though a significant reduction in seizure frequency was observed when rufinamide was started, a spontaneous and complete resolution was reached at the age of 14 months in concert with psychomotor
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improvement. Neuropsychological evaluation at the ages of 13 and 19 months revealed a general quotient, respectively, of 44 and 40 (Griffiths scale), with a major impairment of visual attention. Geneticist contribution
A genetic diagnostic panel was performed. Singular genes were assessed (FRA X, chromosome 15 methylation, SLC25A22, STXBP1, CDKL5), with the results normal. G-banded chromosome analysis was performed on phytohemagglutinin-stimulated peripheral blood lymphocytes following standard protocols. We analyzed 50 metaphase cells and found 46,XX[27]/47,XX,þmar[23] (Supplemental Fig 1). Fluorescence in situ hybridization experiments revealed that the small marker chromosome was derived from chromosome 14. To further define the region of the supernumerary derived chromosome 14, single nucleotide polymorphism (SNP) array and microsatellite polymorphism analysis were performed. Array comparative genomic hybridization analysis showed a gain of about 14.8 Mb of the region 14q11.2q12 (19,043,18933,814,746) 2-3 encompassing FOXG1. Single nucleotide polymorphism analysis of the patient, compared with his parents, showed a fatherly uniparental isodisomy, confirmed by microsatellite polymorphism analysis (Supplemental Fig 2, Supplemental Table 1). Review of previously reported patients
The Table shows all previously published cases with dup(14) including FOXG1.2-7 In 15 reported patients, nine presented also with epilepsy. Mean age at onset of epilepsy in all selected patients was 4.9 months (range 3-7 months); seizures were reported as generalized in one patient, focal in two patients, and epileptic spasms in eight patients (spasms with focal signs in two patients). Two patients experienced two types of seizures. Status epilepticus was never reported. Focal seizures were characterized by eyes opening, arrest of suction, and increased respiratory and cardiac rate, or by nocturnal tonic and tonic-vibratory seizures. Six patients were seizure-free during follow-up. Interictal EEG was characterized mainly by the recurrence of focal and bilateral epileptiform abnormalities. In eight patients a hypsarrhythmic EEG pattern was evident at onset or during the follow-up; in two patients, the last follow-up EEG was reported as normal (at 12 and 6 years of age, respectively). Ictal EEG was available in one patient and was characterized by diffuse high-voltage slow wave, followed by low-amplitude fast activity over the frontal and temporal regions with a clinical counterpart of epileptic spasms or by rhythmic fast activity over the occipital and temporal regions associated with subtle seizures. Data on cognitive development were available in all patients but one. Cognitive disability was clear in all patients: in five, it was described as severe; in three it was mild-moderate. None of the patients presented with microcephaly. Motor delay was evident in seven patients; hypotonus/hypertonia, intentional tremor, and stereotyped movements were also reported. Neuroimaging was reported in all patients but one: normal in three of eight patients; two cases of nonspecific white matter alterations of the periventricular and left temporal regions, respectively, one case of thin corpus callosum and one case of small arachnoid cyst. A periventricular nodule of heterotopic gray matter was reported in one patient. Dysmorphic features, such as flat nasal bridge, mild hypotelorism, short palpebral fissures, malformed ears, high-frontal hairline, deep-set eyes, micrognathia, cleft palate, or polydactyly were reported in five of nine patients.
Discussion
The contribution of FOXG1 in the phenotype of reported patients might be related to its function on brain development, particularly as a transcriptional repressor preventing premature neural differentiation.4 Furthermore, this was confirmed through a phenotypeegenotype correlation among patients whose duplication was part of a specific, narrowed-down region. This selection was made in the
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TABLE. Clinical features of patients with FOXG1 duplication Author
Sex
Age
Neonatal
Familial History
Cytogenetic Finding
Sz Onset
Sz Types at Onset
Sz Types During Follow-up
EEG Interictal
Yeung et al., 2009
F
9 yr
BW 3835 g, early feeding difficulties.
NR
Chr 14: 2597-3042. Size 4.45 Mb. Dupl FOXG1 de novo
3 mo
Spasms
Spasms, nocturnal tonic-vibratory, from 6 yr nocturnal tonic.
Hypsarr, cont bil post discharges that occurred synch and asynch.
Brunetti-Pierri et al., 2011
M
4 yr
NR
NR
6 mo
Spasms
Seizure-free on LTG
Hypsarr, R ShW and diffuse slowing
Brunetti-Pierri et al., 2011
F
3 yr
NR
NR
Chr 14: 2690881230254928. Size 3.3-3.4 Mb. Dupl FOXG1 de novo Chr 14: 19582682-29076 500. Size 9.4-11 Mb. Dupl FOXG1 de novo
6 mo
GTC
seizure-free on ZNS at 2 yr.
Multifocal and Gen Sp and SW, slow BA
Brunetti-Pierri et al., 2011
M
6 mo
BW 3317 gr (25-50th c) BL 52.1 cm (75-90th c).
NR
3m
spasms
NR
Modified hypsarr
Brunetti-Pierri et al., 2011
M
3 yr
BW 3000 g (10e25th c).
NR
e
e
e
Normal
Brunetti-Pierri et al., 2011
M
3 yr
NR
Chr 14: 27474978-30603041. Size 3.1 Mb. Dupl FOXG1
5 mo
spasms
Seizure-free
Hypsarr
Brunetti-Pierri et al., 2011
M
Adult
BW 4210 gr (90th c), BL 53.5 cm (90th c), HC 36 cm (90th c). BW appropriate
Unremarkable
Chr 14: 19508845-34063670. Size 14.5 Mb. Dupl FOXG1 de novo
e
e
e
e
Brunetti-Pierri et al., 2011
M
35 yr
NR
Brother with CD
Chr 14: 28257153-35048345. Size 6.8 Mb. Dupl FOXG1
e
e
e
e
Striano et al., 2011
M
3 yr
BW 4210 g (90th c), BL 53.5 cm (75-90th c), HC 36 cm (75th c)
NR
Chr 14: 27409-30603. Size 3.2 Mb. Dupl FOXG1 de novo
5 mo
Spasms
Brief focal with aut signs.
Hypsarr, bil T Sp. Diffuse SW and Sp.
Striano et al., 2011
M
14 yr
NR
Unremarkable
7 mo
Spasms with focal signs.
Seizure-free.
Hypsarr
Tohyama et al., 2011
F
6 yr
BW 2140 g (2.4 SD), BL 48 cm (0.4 SD), HC 28 cm (3.9 SD).
Unremarkable
4 mo
Spasms with focal signs
Seizure-free
Hypsarr
Paciorkowski et al., 2011 Amor et al., 2012
F
14 mo
NR
NR
5.5 mo
Spasms
NR
M
NR
NR
Amor et al., 2012
M
NR
NR
Amor et al., 2012 Present patient
NR M
NR 19 mo
NR HC at 6 mo was 49 cm
Son with the same cytogenetic finding. Father with the same cytogenetic finding. NR Maternal aunt with dev delay, distant relatives with infantile epilepsy history.
Chr 14: 19365-30359. Size 11 Mb. Dupl FOXG1. Small extranumerary marker (with part of duplication) from maternal balanced translocation involving chr 14 and 15. Parental CGH array normal. Chr 14: 14q11.2-q12. Dupl FOXG1. Mosaic dupl. Maternal uniparental disomy 14 and mosaic small marker of paternal origin containing the proximal long arm of chr 14. Chr 14: 27165797-30192375. Size: 3.3 Mb. Dupl FOXG1 de novo. Chr 14: 28236716- 28325210. Size: 88 Kb.
Abbreviations: abn ¼ Abnormalities asynch ¼ Asynchronous BA ¼ Background activity bil ¼ Bilateral BL ¼ Body length BW ¼ Body weight cont ¼ Continuous F ¼ Female c ¼ Centile CD ¼ Cognitive disabilities chr ¼ Chromosome CLB ¼ Clobazam dev ¼ Development dupl ¼ Duplication FA ¼ Fast activity fr ¼ Frontal gen ¼ Generalized GQ ¼ General quotient GTC ¼ Generalized tonic-clonic seizure HC ¼ Head circumference hem ¼ Hemisphere hypsarr ¼ Hypsarrhythmia KD ¼ Ketogenic diet
Chr 14: 19582682-33275 612. Size 13.7-18.4 Mb. Dupl FOXG1. Chr 3:191 656 626-199 287 624. Size 7.6-8.4 Mb. Parental studies: Mother: chr 3; 14 translocation. Chr 14: 28217364-34635622. Size 6.4 Mb. Dupl FOXG1 de novo
e
e
Seizure-free at 14 mo e
Chr 14: 28236716 28325210. Size: 88 Kb.
e
e
e
e
Chr 14: 27861440- 30208129. Size: 2.3 Mb. Chr 14: 19043189-33814746. Size: 14.8 Mb. Dupl FOXG1 de novo.
e 4 mo
e Spasms
e Brief focal, tonic, myoclonic.
e Multifocal slow and epileptiform abn with R P-O prevalence.
L LEV LTG M NR NZP O P PA post R SD ShW synch sp SW Sz T TPM VGB VPA W ZNS
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
Left Levetiracetam Lamotrigine Male Not reported Nitrazepam Occipital Parietal Paroxysmal activity Posterior Right Standard deviation Sharp wave Synchronous Spike Slow wave Seizure Temporal Topiramate Vigabatrin Valproic acid Wave Zonisamide
e
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TABLE. Clinical features of patients with FOXG1 duplication (Continued) EEG Interictal Follow-up
EEG Ictal
7 yr: multifocal NR discharges, gen sp 4-5 Hz. 9 yr: BA slowing, bi Fr sp W 2.5-3 Hz. NR R ShW, R hem slowing; last EEG: normal. NR NR
Treatment
Neurological Features
Neuropsychological Assessment
Associated Features
Neuroimaging
VGB, KD, steroids, LEV
3-6 mo: dev regression, poor head control, walked 21 mo. 9 yr: no speaking, hypotonia
Behavior: affectionate and not disruptive. Occasional hand flapping. Able to feed herself.
9 yr: HC 51.5 cm (25th c). Minor dysmorphisms: upslanting palpebral fissures, bil single palmar creases, mild 2-3 syndactyly.
Periventricular nodule of heterotopic gray matter. Positron emission tomography (9 yr): bil T and Fr hypometabolism.
ACTH, LTG
Lack of speech, nystagmus, walking at 3 yr, frequent falls, broad-based gait, stereotyped hand movements. 1 yr: unable to sit, 30 mo: inability to walk. Speech delayed.
Global dev delay, inappropriate laughing. No history of regression. Dev delay.
Unilateral postaxial polydactyly, strabismus, HD 49.1 cm (3 SD), nondysmorphic. HD 48 cm (25th c). Dysmorphic facies, flat nasal bridge, mild hypotelorism, short palpebral fissures, bil malformed ears, bil fifth finger clinodactyly, R fifth finger brachydactyly. Mild dysmorphisms: small palpebral fissures, simplified ears, a L accessory nipple, and a R club foot.
Mild foreshortened frontal lobes.
ZNS
Mild small posterior fossa and foreshortening of the corpus callosum.
BA slowing, L T SW with Sp and SW discharges.
NR
ACTH, Prednisone, TPM
Truncal and axial hypotonia, brisk reflexes, absence of speech (13 m)
Dev delay.
e
e
e
18 mo: started walking.
Mild dysmorphic facial features.
Bil T abn.
NR
ACTH, TPM
Stereotyped hand movements, severe speech involvement.
Communicative difficulties, hyperactivity, severe attention deficits, IQ 72 (Griffiths scale). Dev regression and autistic spectrum disorders.
Normocephalic and nondysmorphic.
Abnormal alteration of the white matter signal in the L T region.
e
e
e
No focal signs, lack of speech, inability to walk unsupported at the age 4 yr.
Dev delay, severely CD.
Not executed.
e
e
e
Poor eye contact 35 yr: able to say a few words.
Asynch bil T PA, bil O and T SW and PA.
Normal
Normal
Spasms: bil diffuse NZP, ACTH, SW with attenuation VPA, TPM and Fr-T FA. Focal: O-T rhythmic FA. NR ACTH, VGB
33 yr: HD 53.5 cm (10-25th c). Dysmorphic features: high frontal hairline, hyperplastic supra-orbital ridges, deep-set eyes, asymmetric anteverted ears, short philtrum, micrognathia, cutaneous II-III syndactyly on the L foot, cleft palate. Prominent jaw, one irregular café-au-lait spot, horizontal striae on back, and short large toes. No facial dysmorphisms.
Normal
NR
NR
NR
e e e Hypsarr
Severe CD: stereotyped behavior, anxiety, self-injuries, aggressive behavior. Attenuated responsiveness to verbal Early dev was reported and visual stimuli and discontinuous as normal; Bayley Scales eye contact, absence of language. revealed moderate CD.
Thin corpus callosum, incomplete myelination, and areas of signal abnormality in the central/periventricular white matter, L caudate nucleus porencephalic cyst. Small arachnoid cyst.
Not executed.
Clumsiness and broad-based gait.
Dev was delayed: hyperactive and attended the school with support.
No facial dysmorphisms.
Normal
VPA, ZNS, ACTH, CLB
5 mo: mild hypotonia, 6 yr: able to speak few words.
Mild psychomotor delay. 5 yr, 8 mo: IQ 40 (Binnet).
Normal
NR
NR
NR
e
TPM, VPA, ACTH e
5 mo: HD was 41 cm (þ0.2 SD), mild dysmorphic features: frontal bossing, small mouth, small hands, hemangioma on the L forehead. NR
Normal
Normal
Hemifacial microsomia.
NR
e
e
Normal
Normal
Hemifacial microsomia.
NR
e Diffuse low voltage, or focal discharges
e ACTH, B6, P5P, VGB, folic acid, LEV, TPM, NZP
Normal Dev regression (axial hypotonia, reduction of visual pursuit capability and spontaneous motility)
Normal No 13 and 19 mo: GQ of 44 and 40, No respectively (Griffiths scale), major impairment of visual attention.
NR Mild atrophy and ventricles enlargement, delayed myelination and T2-hyperintensities in the R caudate head.
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FIGURE. (A) Interictal awake electroencephalograph showing disorganized background activity associated with multiple slow waves intermingled with low-voltage spikes over the right posterior region. Diffuse low-voltage fast activity is also evident with predominance over the right parieto-temporo-occipital region. (B) During sleep, an increase of epileptiform abnormalities is evident with diffuse epileptiform discharges. (C) Diffuse spike-and-wave complexes followed by massive myoclonia involving the upper limbs. A decremental activity is also evident associated with an increase of muscle tone. (D) Brief infraclinical focal discharges involving bilateral central and posterior areas during sleep. (E) Spasm-tonic seizure with an electroencephalograph counterpart characterized by diffuse slow waves intermingled with spikes and followed by low-voltage fast activity. (F) Array comparative genomic hybridization and single nucleotide polymorphism were performed using, respectively, the SurePrint G3 Human comparative genomic hybridization þ single nucleotide polymorphism Microarray 4 180 K (Agilent Technologies, Santa Clara, CA) and 3130XL Genetic Analyzer (Applied Biosystems, Foster City, CA). Profile of the chromosome 14 showing the mosaicism of the duplication of proximal part of chromosome 14 is evident. Fragment analysis at D14S1071 showed a higher peak of paternal inheritance, indicating the mosaic status of the der(14). (G) Axial and coronal T2-weighted image magnetic resonance images showing mild atrophy, ventricles enlargement, and delayed myelination.
attempt of reducing the spectrum of possible candidate genes. Although FOXG1 represents the most interesting candidate to explain this phenotype, the role of additional genes in the large duplicated regions cannot be excluded, considering the hypothesis of regulatory mutations to explain the wide phenotypic variability.2,7-9
Within all reported patients, one had a mosaic dup(14) associated to maternal uniparental disomy of chromosome 14, a similar condition found in our patient with a mosaic dup(14) associated to paternal uniparental disomy. The condition of uniparental disomy is usually associated to dysmorphisms such as facial abnormalities, a small, bell-
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shaped thorax, abdominal wall defects, polyhydramnios, and cognitive disability.11 In both patients with uniparental disomy, the occurrence of severe epileptic encephalopathy with spasms and focal seizures without the typical body alterations seems to be related to FOXG1 gain of function more than to the uniparental disomy per se. The epileptological features of the reported patients seem to be quite similar, because the most frequent type of seizure experienced in the report and also in our patient is the epileptic spasm. Also focal seizures might be present, in both reported patients, and in our patient. In particular, spasms are reported in nine of 10 patients (including the present patient); focal seizures were evident in three of 10 patients. Mean age at onset is 4.85 1.33 months (range 37 months) regarding all seizures. All patients but one presented at onset with epileptic spasms with hypsarrhythmic interictal EEG pattern. These patients might be considered in the ample context of West syndrome, even if in all of them early developmental delay was evident before onset of seizures. This finding should be related to the genetic condition per se more than a regression from seizures and interictal EEG abnormalities. It is noteworthy that in two patients EEGs were reported as normal during follow-up: this finding could be related to the age of patients (12 and 6 years, respectively), and it could be expected also in other patients at the same age. Neuroimaging findings are mainly not specific. Outcome in patients with epilepsy associated to dup(14) should be considered separately regarding seizures and cognitive and motor development. In the majority of patients (seven of 10 including the present patient), seizures tend to disappear during the follow-up, motor skills improve, and all patients might walk and stand alone. Regarding cognitive development, stagnation is evident in all of them with mild to severe disabilities associated to severe speech difficulties. Rett-like syndrome and other types of haploinsufficiency of FOXG1 (mutations or deletions) have similarities as well as notable differences with respect to duplications. In both situations, normal perinatal growth, developmental slowing or regression, intellectual deficits, absent speech, and epilepsy are common features, but in the case of duplications we recognize some peculiar element: seizure onset during the first year of life typically represented by spasms, ability to walk within the first 2 years, absence of microcephaly, and stereotypic hand movements.2-4,6,9 These differences indicate that overexpression of FOXG1 may have a specific role in the pathogenesis of infantile spasms in these patients.9 Even for MECP2, duplications lead to clinical features that are similar to those of FOXG1 duplication.4 These similarities are intellectual disabilities and severely impaired speech. Nevertheless, early-onset epilepsy and
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infantile spasms are typical of FOXG1 duplication but have not been described in MECP2 duplication. In our patient and in those previously reported with FOXG1 duplication, there are common features that should be considered for an early diagnosis: seizures with onset during the first year of life, particularly clusters of spasms and focal seizures with hypsarrhythmic EEG pattern; different degrees of cognitive impairment, possibly associated to behavior disturbances and severe speech disabilities; and dysmorphic features in the absence of significant microcephaly. The authors thank the patients’ families for their contribution to this research.
Supplementary material
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.022. References 1. Heilig R, Eckenberg R, Petit JL, et al. The DNA sequence and analysis of human chromosome 14. Nature. 2003;421:601-607. 2. Brunetti-Pierri N, Paciorkowski AR, Ciccone R, et al. Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet. 2011;19:102-107. 3. Striano P, Paravidino R, Sicca F, et al. West syndrome associated with 14q12 duplications harboring FOXG1. Neurology. 2011;76: 1600-1602. 4. Yeung A, Bruno D, Scheffer IE, et al. 4.45 Mb microduplication in chromosome band 14q12 including FOXG1 in a girl with refractory epilepsy and intellectual impairment. Eur J Med Genet. 2009;52: 440-442. 5. Paciorkowski AR, Thio LL, Rosenfeld JA, et al. Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. Eur J Hum Genet. 2011;19:1238-1245. 6. Tohyama J, Yamamoto T, Hosoki K, et al. West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am J Med Genet A. 2011;155A: 2584-2588. 7. Amor DJ, Burgess T, Tan TY, Pertile MD. Questionable pathogenicity of FOXG1 duplication. Eur J Hum Genet. 2012;20:595-596. 8. Falace A, Vanni N, Mallamaci A, Striano P, Zara F. Do regulatory regions matter in FOXG1 duplications? Eur J Hum Genet. 2013;21: 365-366. 9. Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-geneerelated encephalopathies. Epilepsia. 2012;53:2067-2078. 10. Kortum F, Das S, Flindt M, et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet. 2011;48:396-406. 11. Kagami M, Sekita Y, Nishimura G, et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet. 2008; 40:237-242.