Journal of Pediatric Epilepsy 2015; 04(01): 008-016
DOI: 10.1055/s-0035-1554786
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Epilepsies in Children with 2q24.3 Deletion/Duplication

Akihisa Okumura
1  Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
,
Toshiyuki Yamamoto
2  Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan
,
Hirokazu Kurahashi
1  Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
,
Michihiko Takasu
1  Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
› Author Affiliations
Further Information

Address for correspondence

Akihisa Okumura, MD, PhD
Department of Pediatrics, Aichi Medical University School of Medicine
1-1 Yazako Karimata, Nagakute, Aichi 480-1195
Japan   

Publication History

09 September 2014

18 September 2014

Publication Date:
03 July 2015 (online)

 

Abstract

The chromosome 2q24.3 region appears to be important in childhood epilepsy and contains three genes encoding a sodium channel, which are involved in the disorder (SCN1A, SCN2A, and SCN3A). There have been several reports indicating an association between epilepsy and 2q24.3 deletion or duplication. Epilepsy phenotypes markedly differ between patients with 2q24.3 deletion and those with duplication. The majority of patients with 2q24.3 deletion are characterized by severe epilepsy phenotypes such as Dravet syndrome or Dravet syndrome–like intractable epilepsy, which onsets during infancy. This is particularly applicable to patients with SCN1A deletion. In addition, facial dysmorphism (and other dysmorphic features) is observed in all patients with 2q24.3 deletion–associated epilepsy. SCN1A contributes to epileptogenicity; several other genes involved in the deleted region may also play a role in dysmorphism. In all reported cases, patients with 2q24.3 duplication had neonatal- or infantile-onset epilepsy. Although these patients typically experienced multiple daily seizures, seizures were controlled by the appropriate antiepileptic treatment in the majority of cases. SCN2A and SCN3A were duplicated in all patients and are presumed to contribute to epileptogenicity. Facial or other dysmorphic features were infrequent in patients with 2q24.3 duplication. Array comparative genomic hybridization should be considered in patients with neonatal- or infantile-onset epilepsy, because information obtained using this method is likely to be instructive in diagnosis, prognostication, and treatment regimen decisions.


#

Introduction

More than 100 cases of deletions or duplications of the long arm of chromosome 2 have been reported. Deletion and duplication ranges vary markedly among individual patients. The relationship between range of deletion/duplication and phenotype is not well understood, although seizures and facial dysmorphism are observed commonly in patients with 2q21q31 deletions. Array comparative genomic hybridization (CGH) is useful to determine copy number variants (CNVs) and to investigate the relationship between CNV and phenotype. Recent studies using array CGH have provided insight into the genetic origin of the phenotypes of patients with CNV in 2q. The 2q24.3 region has attracted attention because three genes encoding a sodium channel, that is, SCN1A, SCN2A, and SCN3A, are located within this region. Mutations in SCN1A are an established, major genetic determinant of Dravet syndrome (DS), genetic epilepsy with febrile seizure plus (GEFS + ), and other epilepsies mostly refractory against antiepileptic drugs.[1] [2] [3] Mutations in SCN2A have been reported in patients with DS, GEFS + , benign familial neonatal-infantile seizures (BFNIS), and early onset epileptic encephalopathies (EOEE).[4] [5] [6] [7] Mutations in SCN3A have been detected much less frequently in patients with focal epilepsy.[8] [9] Therefore, CNV in the 2q24.3 region is also presumed to cause epilepsy and genetic mutations in these sodium channel genes. However, the effects of CNVs on epileptogenicity can differ from those of genetic mutations. In this review, we focus principally on the relationship between epilepsy and 2q24.3 deletion/duplication, on the basis of array CGH analyses.


#

2q24.3 Deletion and Epilepsy

Patients with 2q24.3 Deletion: Epilepsy and the Genes Involved

We identified 18 patients with deletion of at least one gene in the 2q24.3 region, determined by array CGH ([Table 1]).[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] Patients with chromosomal aberrations, indicating 2q24.3 deletion, but without array CGH analysis results, were not included. The patients comprised nine females and nine males. Epilepsy was documented in 10 of the cases.

Table 1

Patients with 2q24.3 deletion, epilepsy, and involved genes

RefSeq Genes

Patient

Reference

Sex

Age at report

Epilepsy

FIGN

GRB14

COBLL1

SLC38A11

SCN3A

SCN2A

CSRNP3

(TAIP2)

GALNT3

TTC21B

SCN1A

SCN9A

SCN7A

XIRP2

(CMYA3)

B3GALT1

STK39

CERS6

1

Madia et al[10]

Patient 1

Male

4 y

Yes

1/2

l

l

2

Patient 2

Male

7 y

Yes

1/2

l

l

l

l

l

l

l

l

l

3

Patient 3

Female

4 y

Yes

1/2

l

l

l

l

l

l

l

l

l

l

l

4

Pescucci et al[11]

Female

50 mo

Yes

l

l

l

l

l

l

l

l

l

l

l

l

5

Davidsson et al[12]

Male

Not mentioned

Yes

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

6

Chen et al[13]

Female

40 mo

No

l

l

l

l

l

l

1/2

7

Krepischi et al[14]

Patient 3

Female

5 y

Yes

l

l

l

l

l

l

l

l

l

l

l

l

l

8

Takatsuki et al[15]

Female

Not mentioned

Yes

l

l

l

l

l

l

l

l

l

l

l

l

1/2

9

Magri et al[16]

Male

42 mo

No

l

10

Bartnik et al[17]

Female

Not mentioned

Yes

1/2

1/2

11

Nimmakayalu et al[18]

Patient 1

Female

Not mentioned

Yes

l

l

l

l

l

l

l

l

l

l

l

l

12

Patient 2

Male

23 mo

No

l

l

l

13

Traylor et al[19]

Patient 2

Male

8 y

No

l

14

Patient 3

Male

33 mo

No

l

l

l

l

l

l

l

l

l

1/2

15

Patient 4

Male

Not mentioned

Yes

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

16

Celle et al[20]

Male

3 y

No

1/2

l

17

Belengeanu et al[21]

Female

20 mo

No

l

18

Lazier et al[22]

Female

12 mo

No

1/2

l

l

l

Note: Closed circles (l) indicate genes completely deleted in the patient. Open circles (1/2) indicate genes partially deleted in the patient. Shaded cells indicate a patient with epilepsy.


We assigned patients to the following three groups: group A (10 patients [patients 1–5, 7, 8, 11, 14, and 15] with complete or partial SCN1A deletion); group B (three patients [patients 6, 10, and 16] with complete or partial deletion of both SCN2A and SCN3A and no SCN1A deletion); and group C (five patients [patients 9, 12, 13, 17, and 18] with no deletion in SCN1A, SCN2A, or SCN3A). In group A, all but one patient had epilepsy. In contrast, only one patient in group B and no patients in group C had epilepsy. This strongly suggests that SCN1A deletion contributes markedly to epileptogenicity, whereas SCN2A and SCN3A deletion have a comparatively reduced impact.

Differences in epilepsy prevalence may be explained by differences in the pathogenesis of genetic alterations. For SCN1A, truncation mutations are common in patients with DS or other refractory epilepsies. Zuberi et al[23] reported that 133 of 273 SCN1A mutations in epilepsy patients were truncating, including 51 nonsense, 43 frameshift, 24 splice site, and 15 gross rearrangements. In addition, Suls et al[24] reported no SCN1A mutations in 3 of 11 patients with DS (according to sequencing analysis); this suggests that microdeletions involving the SCN1A gene may be common in DS patients. These data further imply that haploinsufficiency of SCN1A can cause severe epilepsy. In contrast, the majority of SCN2A mutations are missense. Shi et al[5] reported SCN2A mutations in patients with BFNIS, GEFS +, DS, and intractable childhood epilepsy, but only one truncating mutation was observed in a patient with intractable childhood epilepsy. Recent studies indicate that SCN2A mutations also occur in EOEE patients.[7] All of the SCN2A mutations in these patients were missense. There have been only two reports of epilepsy associated with SCN3A mutations, both of which were missense.[8] [9] These data suggest that haploinsufficiency is not a major pathomechanism of epilepsy in patients with SCN2A and/or SCN3A aberrations.


#

Epilepsy Phenotypes Associated with 2q24.3 Deletion

Epilepsy phenotypes differ according to the gene deleted ([Table 2]). Epilepsy was relatively severe in nine patients with SCN1A deletion (patients 1–5, 7, 8, 11, and 15), irrespectively of the involvement of a wide variety of other genes. The age of onset of epilepsy ranged between 8 weeks and 9 months, and was <6 months in seven of the patients. Four patients (patients 1–3 and 5) were diagnosed with DS. The first three patients experienced multiple types of seizures, such as myoclonic, generalized clonic, and complex partial seizures. Seizures were also prolonged, indicative of the typical DS phenotype.[10] The final patient (patient 5) had polymorphic seizures including atonic, hypomotor (with apnea), and clonic seizures, followed by apnea and spasm-like seizures.[12] Ictal electroencephalography (EEG) revealed multiple seizure foci; the authors tentatively diagnosed infant malignant migrating partial seizures. However, this diagnosis was revised, with the authors instead describing an epileptic encephalopathy that resembled DS, subsequent to the patient's death from refractory status epilepticus.[12] The other five patients also had severe epilepsy, characterized by polymorphous seizures. Status epilepticus or prolonged seizures, typically provoked by fever, were documented in three cases (patients 4, 7, and 11); myoclonic seizures or myoclonic jerks were also observed in three patients (patients 4, 7, and 8). These features are similar to those of DS; however, DS was not diagnosed. Seizures in these patients were very frequent and highly refractory to vigorous antiepileptic treatment. These results indicate that SCN1A deletion can cause DS or infantile epileptic encephalopathy with DS-like manifestations, as well as genetic mutations in the SCN1A gene.

Table 2

Characteristics of epilepsy in patients with 2q24.3 deletion

Patient

Reference

Age at onset

Seizure types

Specific diagnosis

Electroencephalography

Magnetic resonance imaging

Remarks

1

Madia et al[10]

Patient 1

8 mo

Febrile and afebrile myoclonic seizures, sometimes followed by generalized clonic seizures, absence seizures

Dravet syndrome

Slowed background activity, high-voltage generalized spike and waves, photosensitivity.

Normal

2

Patient 2

5 mo

Prolonged massive myoclonic or hemiclonic seizures

Dravet syndrome

Slowed background activity, high-voltage generalized spike and waves, photosensitivity.

Normal

3

Patient 3

4 mo

Febrile and afebrile myoclonic seizures either focal or massive, complex partial seizures

Dravet syndrome

Slowed background activity, focal or generalized spike and waves

Mild ventricular dilation

4

Pescucci et al[11]

3 mo

Polymorphic with both focal and generalized seizures, prolonged severe seizures and status epilepticus, sporadic myoclonic jerks

Not mentioned

Slow background, multifocal spikes/spike and waves

Ventricular dilation, diffuse atrophy, incomplete white matter myelination

5

Davidsson et al[12]

8 wk

Atonic seizures, hypomotor seizures with apnea, clonic seizures followed by versive movement and apnea, and spasm-like seizures followed by apnea

Dravet syndrome

Multifocal independent spike and waves

Mild ventricular dilation, myelination delay

Died after a refractory status epilepticus (age at death is not described).

7

Krepischi et al[14]

Patient 3

2 mo

Absence seizures, generalized tonic seizures, myoclonic seizures, epileptic spasms, febrile prolonged seizures

Not mentioned

Diffuse disorganization, multifocal spikes/slow-waves, photosensitivity

Normal

8

Takatsuki et al[15]

3 mo

Generalized tonic clonic seizures, continuous myoclonic jerks

Not mentioned

Not mentioned

Not mentioned

10

Bartnik et al[17]

Uncertain

Zone out, absent, or shiver-like episodes

Not mentioned

Generalized abnormal electroencephalography, not clearly epileptiform

Not mentioned

Seizures resolved spontaneously

11

Nimmakayalu et al[18]

Patient 1

9 mo

Brief startle responses progressing to tonic–clonic episodes, prolonged severe seizures and status epilepticus

Not mentioned

Grade II dysrhythmia

Myelination delay, mild ventricular dilation, cortical atrophy

Died at 15 years of age in hospice care

15

Traylor et al[19]

Patient 4

11 wk

Staring with a jerking of extremities and nystagmoid movements preceded by crying

Not mentioned

Slow background pattern, multifocal sharp waves

Chiari I malformation

Died at 16 months of age while asleep

The interictal EEGs of these nine patients were characterized by nonspecific abnormalities. Background abnormalities, indexed principally by slowed activity, were described in seven cases; generalized or multifocal epileptiform discharges were also described in seven cases and photosensitivity in three cases. These EEG findings were consistent with DS.[25]

It is notable that three of the SCN1A patients died. Patient 5 died following a refractory status epilepticus, as mentioned above; patient 11 died at 15 years of age while in hospice care; and patient 15 died at 16 months of age while sleeping, suggesting sudden unexpected death in epilepsy. It is well known that DS is associated with significant mortality, and that death may occur at any age.[26] The mortality rate of DS is between 14 and 20%.[26] [27] [28] Death of DS patients is usually associated with status epilepticus or infection, or is otherwise sudden and unexpected. Our recent study demonstrated that acute encephalopathy occasionally presents in DS, and it resulted in the death of 4 of 15 patients.[29] It is important to be aware that patients with SCN1A deletion are at risk for sudden and unexpected death even when they are not diagnosed with classical DS.

In contrast to patients with SCN1A deletion, epilepsy was mild and self-limiting in the female patient 10 with SCN2A and SCN3A deletions.[17] The parents of patient 10 reported that she had a 3- to 4-month history of “zone out,” absence, and “shiver-like” episodes at 1 year of age, and further that the episodes resolved spontaneously without medication. The clinical course and seizure semiology of this patient were similar to those of benign infantile epilepsy.[30] [31] The patient had generalized abnormal EEG, but this was not obviously epileptiform. Detailed information regarding EEG abnormalities was not provided.


#

Developmental and Other Neurological Symptoms

All patients with SCN1A deletion were characterized by developmental delay, and at least six of the patients had severe developmental delay ([Table 3]). Autistic features were reported in three cases (patients 3–5). Developmental delay occurs in the large majority of DS patients.[26] Several authors also report that autism spectrum disorders are not uncommon in DS patients.[26] [32] Recent genetic studies that used whole-exome sequencing for parent–child trios exhibiting sporadic autism spectrum disorders suggested that SCN1A might be a genetic determinant of autism spectrum disorders.[33] [34] An experimental study demonstrated that mice with SCN1A haploinsufficiency exhibited autism-like behavioral abnormalities such as hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory.[35]

Table 3

Development, other neurological symptoms, and dysmorphic features in patients with 2q24.3 deletion

Patient

Reference

Development

Other neurological symptoms

Facial dysmorphism

Other symptoms

1

Madia et al[10]

Patient 1

Delayed

Not mentioned

Bulbous nose, bow-shaped mouth, hypotonic face

Not mentioned

2

Patient 2

Delayed

Mild generalized hypotonia, uncoordinated gait

Down-slanting palpebral fissures, low-implanted ears, broad nasal bridge

Not mentioned

3

Patient 3

Severely delayed, autistic features

Clumsy gait, mild generalized hypotonia

Bitemporal narrowing, frontal bossing, tubular nose, anterior open bite

Cleft palate, central precocious puberty

4

Pescucci et al[11]

Severely delayed, autistic features

Sleep disturbance with breath holding

Hypotelorism, down-slanting palpebral fissures, long eye lashes, ptosis, high nasal bridge with large nose, thick helices and ear lobule, mild micrognathia, cupid bow mouth

Cleft palate, gastroesophageal reflux, hand and foot anomalies, failure to thrive

5

Davidsson et al[12]

Severely delayed, autistic features

Hypotonia, brisk tendon reflexes

Small eyes, slight bilateral ptosis, micrognathia, low set small ears

Cleft palate, high anal atresia, atrial septal defect, pansynostosis, syndactyly

7

Krepischi et al[14]

Patient 3

Severely delayed

Swallowing difficulty

Micro/brachycephaly, thin nose with depressed and broad nasal bridge, anteverted nares, short philtrum

Hypothyroidism, tapered fingers and anteriorly displaced anus, left eye iris coloboma, right eye choroid, and retina coloboma

8

Takatsuki et al[15]

Delayed

Generalized hypotonia

Thick arched eyebrows, upslanting palpebral fissures, long eyelashes, flat nasal bridge, short nose, long philtrum, small mouth, micrognathia, low-set ears

Pulmonary emphysema, fetal growth retardation

10

Bartnik et al[17]

Severely delayed, autistic features

Hypotonia, bipolar disorder, ocular motor apraxia

Short palpebral fissures, mild dental crowding, short neck

Central obesity

11

Nimmakayalu et al[18]

Patient 1

Severely delayed

Hypotonia, microcephaly, feeding difficulty, irritability, hypoplastic optic nerves

Narrow palpebral fissures, deep set eyes, full cheeks, small mandible, prominent lateral palatine ridges, prominent frenulum between upper central incisors, tented upper lip with downturned corners of mouth, bitemporal narrowing, short nose with bulbous tip, dimple at the end of the nose

Fetal growth retardation, gastroesophageal reflux, poor growth, short sternum, small hands short slender tapered fingers

15

Traylor et al[19]

Patient 4

Severely delayed

Chiari I malformation

Small downslanting palpebral fissures, posteriorly rotated ears, uveal coloboma, coloboma of the choroid and retina

Fetal growth retardation, wide-spaced nipples, chordee of penis, brachydactyly, single transverse palmar crease, bridged palmar crease, craniosynostosis, failure to thrive

It is notable that patient 10, who had SCN2A and SCN3A deletions, was also characterized by severe developmental delay, autistic features, and neurological symptoms, such as hypotonia, bipolar disorder, and ocular motor apraxia, despite the fact that epilepsy was comparatively mild and self-limited. It is also of note that the other two patients with SCN2A and SCN3A deletions (patients 6 and 16) had autism spectrum disorders but no seizures.[13] [20] Several genetic studies that used whole-exome sequencing and whole-genome sequencing have indicated that SCN2A might be a causal factor in autism spectrum disorders.[36] [37] The role of SCN3A in autism remains to be clarified.


#

Dysmorphic Features

All patients with 2q24.3 deletion were characterized by various dysmorphic features, and facial dysmorphism was present in all cases. Abnormalities of the nose (n = 7), mouth (n = 6), eyes (n = 5), and ears (n = 5) were observed. Other manifestations of dysmorphism were noted in eight patients as follows: hand/foot abnormalities (n = 4), cleft palate (n = 3), fetal growth retardation (n = 3), and failure to thrive (n = 2). Dysmorphic features due to SCN1A mutations are unusual in DS patients. When dysmorphic features are present in DS patients or in other infantile refractory epilepsies, array CGH can be used to determine the cause of epilepsy. Dysmorphism in patients with 2q24.3 deletion will differ according to the genes deleted ([Table 3]).


#
#

2q24.3 Duplication and Epilepsy

Epilepsy Associated with 2q24.3 Duplication

To date, 10 cases of 2q24.3 duplication (6 sporadic patients and 1 family; 3 males and 7 females), as indicated by array CGH, have been reported ([Table 4]).[38] [39] [40] [41] [42] [43] All patients had neonatal- or infantile-onset epilepsy. SCN2A and SCN3A were part of the duplicated region in all patients; SCN1A was involved in all but one case ([Table 4]). However, the clinical features did not differ according to the presence or absence of SCN1A duplication. Therefore, epilepsy in patients with 2q24.3 duplication is apparently attributable to an increase in the number of SCN2A and SCN3A copies.

Table 4

Patients with 2q24.3 duplication and involved genes

RefSeq Genes

Patient

Reference

Sex

Age at report

FIGN

GRB14

COBLL1

SLC38A11

SCN3A

SCN2A

CSRNP3

(TAIP2)

GALNT3

TTC21B

SCN1A

SCN9A

SCN7A

XIRP2

(CMYA3)

B3GALT1

STK39

CERS6

19

Heron et al[38]

Patient 1

Male

10 y

l

l

l

l

l

l

l

l

l

20

Patient 2

Female

9 y

l

l

l

l

l

l

l

l

l

21

Patient 3

Female

8 y

l

l

l

l

l

l

l

l

l

22

Patient 4

Female

Not mentioned

l

l

l

l

l

l

l

l

l

23

Raymond et al[39]

Female

Not mentioned

1/2

l

l

l

l

l

l

l

l

l

24

Okumura et al[40]

Female

10 mo

l

l

l

l

l

l

l

l

l

l

l

l

25

Vecchi et al[41] [a]

Male

7 y

l

l

l

l

l

l

26

Goeggel Simonetti et al[42]

Patient 1

Female

6 y

l

l

l

l

l

l

l

l

l

l

l

l

l

27

Patient 2

Female

2 y

l

l

l

l

l

l

l

l

l

l

l

l

1/2

28

Lim et al[43]

Male

8 mo

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

Note: Closed circles (l) indicate genes completely duplicated in the patient. Open circles (1/2) indicate genes partially duplicated in the patient.


a This patient had the mosaicism of the duplication.


Epilepsy phenotypes are relatively similar among patients with 2q24.3 duplication ([Table 5]), although the region of duplication differs markedly among patients. Onset occurred during the neonatal period in seven cases (patients 19–22, 24, 26, 27) and within the first 3 months of life in the remaining three patients (patients 23, 25, 28). The most prevalent seizure types were focal followed by generalized tonic–clonic and myoclonic seizures; spasms were also observed in several patients. A cluster of seizures was observed frequently, but status epilepticus was not noted in any patients.

Table 5

Characteristics of epilepsy in patients with 2q24.3 duplication

Patient

Reference

Age at onset

Seizure types

Electroencephalography

Magnetic resonance imaging

Outcome

Antiepileptic drugs presumed to be effective

19

Heron et al[38]

Patient 1 (III-2, a proband)

18 d

Apnea, generalized stiffening, tonic seizure, clonic seizure with cyanosis, absence seizure, myoclonic seizure

Diffuse slowing, focal and generalized spikes/sharp/spike and waves

Normal

Seizure cessation at 20 mo. Drug cessation by 5 y

Vigabatrin

20

Patient 2 (III-4)

2 d

Generalized tonic, myoclonic or tonic with eye deviation and apnea

Sharp and slow in the right temporal area

Normal

Seizure cessation by 5 mo

Phenobarbital + phenytoin

21

Patient 3 (III-5)

3 d

Generalized tonic, myoclonic or tonic with eye deviation and apnea

Normal

Normal

Seizure cessation by 5 mo

Phenobarbital + phenytoin

22

Patient 4 (II-2)

2 d (possible seizures from 6 mo of gestation)

Myoclonic seizures and generalized seizures

Not mentioned

Not mentioned

Seizure cessation at 2 wk

Phenobarbital + phenytoin

23

Raymond et al[39]

2–3 wk

Sudden facial flushing, head turning, eye deviation, arm jerking, followed by a cry

Ictal electroencephalography: diffuse attenuation followed by bilateral frontal-central rhythmic α/β

Not mentioned

Seizure persistence

Phenobarbital

24

Okumura et al[40]

2 d

Mild convulsive movement and staring

Markedly abnormal background activities

Normal

Seizure cessation by 6 mo. Drug cessation by 40 mo

Valproate

25

Vecchi et al[41]

3 mo

Focal seizures with secondary generalization, atonic seizures, absence seizures

Multifocal polyspikes, multiple spikes

Not mentioned

Seizure free at 7 y

Carbamazepine, valproate

26

Goeggel Simonetti et al[42]

Patient 1

0 d

Staring with an unusual cry, wide eye opening, flushing and bulbar and head deviation

Excessive spikes/sharp on the right central-temporal area.

Normal

Seizure cessation at 8 months. Drug cessation by 2.5 y

Carbamazepine

27

Patient 2

2 d

Cyanosis, head deviation, followed by multifocal clonic movements

Multifocal sharp waves

Mild callosal hypoplasia

Seizure cessation, and drug discontinuation by 1.5 y

Oxcarbazepine + phenobarbital + valproate

28

Lim et al[43]

40 d

Spasms

Burst suppression

Normal

Seizure free at 8 mo

Vigabatrin

Interictal EEGs were abnormal in eight of the nine patients for whom information was available. Focal or generalized epileptiform discharges were reported frequently. These nonspecific EEG abnormalities are observed frequently in neonatal-onset or early-infantile-onset epilepsy patients. Magnetic resonance imaging (MRI) data were obtained from seven patients. Although one patient had mild hypoplasia of the corpus callosum, the others were not characterized by any MRI abnormalities.

The most notable feature in patients with 2q24.3 duplication was a relatively favorable seizure outcome compared with 2q24.3 deletion patients. At the time of report, only one patient failed to achieve seizure freedom, and medication had been discontinued in seven patients. The antiepileptic drugs presumed to be effective for epilepsy include phenobarbital, phenytoin, vigabatrin, valproate, carbamazepine, and oxcarbazepine. The data indicate that antiepileptic treatment should be considered particularly in neonatal-onset to early-infantile-onset epileptic patients with 2q24.3 duplication. Seizure cessation can improve the quality of life in such patients significantly, although the efficacy of drug treatment varies among individual patients.

These features are not consistent with the literature regarding the established types of epilepsies in patients with SCN2A mutations. The duration of seizure persistence in these patients was relatively similar to that of BFNIS, a typical epilepsy phenotype related to SCN2A mutations. The response to antiepileptic drugs was less favorable in these patients compared with BFNIS patients. DS and EOEE, which represent other typical epilepsy phenotypes associated with SCN2A mutations, are markedly more refractory than are epilepsies associated with 2q24.3 duplication. Although increased numbers of SCN2A and SCN3A copies are presumed to affect the function of sodium channels, the precise pathomechanism underlying this effect remains to be elucidated.


#

Developmental and Other Features

In contrast to seizure outcome, the developmental outcome was not favorable in the majority of the patients. Only one patient did not exhibit any degree of developmental delay. Autistic features were documented in one patient. Other neurological symptoms reported were hypotonia (n = 1), mild dystonic movement (n = 1), and swallowing difficulty (n = 1) ([Table 6]).

Table 6

Development, other neurological symptoms, and dysmorphic features in patients with 2q24.3 duplication

Patient

Reference

Development

Other neurological symptoms

Facial dysmorphism

Other symptoms

19

Heron et al[38] Patient 1 (III-2, a proband)

Delayed, autistic features

None

None

Not mentioned

20

Patient 2 (III-4)

Delayed

Not mentioned

Not mentioned

Not mentioned

21

Patient 3 (III-5)

Delayed

Not mentioned

Not mentioned

Not mentioned

22

Patient 4 (II-2)

Borderline intellect

Not mentioned

Not mentioned

Not mentioned

23

Raymond et al[39]

Delayed

Not mentioned

None

Not mentioned

24

Okumura et al[40]

Severely delayed

Hypotonia

None

None

25

Vecchi et al[41]

Delayed

Not mentioned

None

Not mentioned

26

Goeggel Simonetti et al[42]

Patient 1

Mildly delayed

Not mentioned

Not mentioned

Not mentioned

27

Patient 2

Normal

Mild dystonic movement

None

Fetal growth retardation, CAKUT

28

Lim et al[43]

Delayed

Swallowing difficulty

None

Hypoplastic left heart syndrome

Abbreviation: CAKUT, congenital anomalies of the kidney and the urinary tract.


It is notable that facial dysmorphism was not described in any patient. Sporadic visceral anomalies were present in two patients (congenital anomalies of the kidney and the urinary tract in patient 27 and hypoplastic left heart syndrome in patient 28). The lack of dysmorphic features and specific neurological symptoms implies that 2q24.3 duplication is difficult to diagnose without the use of array CGH.


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A Representative Patient

Patient 24 has been discussed previously in a patient report.[40] This female was born at term following an uncomplicated pregnancy. She was the first child of unrelated, healthy parents. The patient exhibited no dysmorphic features but experienced seizures characterized by staring and mild convulsive movements, 10 to 20 seconds in duration, since the third day of life. The patient was admitted to a neonatal intensive care unit at 9 days of age. Physical examination revealed mild hypotonia but was otherwise unremarkable. Head MRI and blood examination, including metabolic screening of amino acids and organic acid analyses, revealed no abnormalities. Interictal EEG revealed markedly abnormal background activity with spiky transients. The patient was treated with phenobarbital and midazolam; seizures were attenuated transiently at 23 days of age. Seizures recurred at 2 months of age, at which time the patient was admitted to our hospital, after which she experienced between 10 and 50 seizures per day. Treatment with phenobarbital and levetiracetam was ineffective. Array CGH analysis was performed at 5 months of age and revealed duplication of 2q24.2q24.3. On the basis of this result, phenobarbital and levetiracetam were substituted for valproate monotherapy; seizures were completely controlled by 50 mg/kg/day valproate after 6 months of age. Seizures provoked by fever were not documented. The patient remained free of seizures even following valproate discontinuation at 40 months of age. The patient's development was delayed severely. At the final follow-up at 44 months of age, the patient could walk only with support. She could communicate using certain simple words but could not produce two-word sentences. Generalized hypotonia was observed with normal deep tendon reflexes.


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Summary

Epilepsy is a common neurological disorder in patients with 2q24.3 deletion/duplication. Sodium channel genes (i.e., SCN1A, SCN2A, and SCN3A) in this region are highly likely to contribute to epileptogenicity. The fact that both an increase and a decrease in the number of copies of these genes are associated closely with the presence of epilepsy indicates that balance among sodium channel genes is essential for normal brain function and development.

Epilepsy phenotypes differ between patients with 2q24.3 deletion and those with 2q24.3 duplication. Severe epilepsy phenotypes, such as DS, manifest frequently in patients with 2q24.3 deletion, particularly in those with SCN1A deletion. Dysmorphic features are also common in these patients. In contrast, epilepsy in patients with 2q24.3 duplication is relatively mild; furthermore, cessation of seizures can be achieved in a large majority of such patients. Dysmorphic features are usually absent.

Neonatal- and infantile-period onset epilepsy is common in patients with 2q24.3 deletion/duplication. Array CGH should be considered in such patients, because information obtained using array CGH is useful in the diagnosis, prognostication, and treatment regimen decisions. At present, the number of reported cases of 2q24.3 deletion/duplication is limited. Additional data will likely improve our understanding of epilepsy related to 2q24.3 deletion/duplication.


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Address for correspondence

Akihisa Okumura, MD, PhD
Department of Pediatrics, Aichi Medical University School of Medicine
1-1 Yazako Karimata, Nagakute, Aichi 480-1195
Japan