1. Introduction

Malignant migrating partial seizures of infancy (MMPSI) is a rare and usually an unrecognized epileptic syndrome of infancy. The International League Against Epilepsy defines this form of epilepsy as follows: seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, combined with multifocal ictal EEG discharges, and progressive deterioration of psychomotor development [1–3]. Exact criteria of MMPSI are not defined and are being developed. According to the draft of the Classification of the Epilepsies 2001, this syndrome refers to presumably symptomatic neocortical focal epilepsy. In the new Classification of the Epilepsies 2017 (ILAE 2017), MMPSI has not found a separate place, but it is implied that it includes in a group of developmental and epileptic encephalopathy.

This severe form of epilepsy was recently described. The first publication about migrating partial seizures of infancy was presented by Coppola and colleagues in 1995 [1], and then personal observations were done by Gerard et al. [4] and by Okuda et al. [5]. Veneselli et al. summarized previous observations and added three own cases [6]. Coppola et al. in their remarkable report (1995) based on neuropediatric department at the René Descartes University (Paris) presented 14 clinical cases of infants of both sexes with previously undescribed epileptic syndrome characterized by virtually continuous multifocal seizures. According to the classical authors description, the first seizures occurred average at the age of 3 months without any significant previous events. During the period from 1 to 10 months, seizures became very frequent. Seizures were focal and had different clinical characteristics; EEG revealed multiple epileptiform discharges arising independently and with migration during subsequent seizures from one cortical region to another. Patients had regression of psychomotor development, tetraparesis and severe muscular hypotonia of axial muscles. Three of 14 patients died: one at the age of 7 months, and other at the age of 7 and 8 years. Seizures were completely ceased only in two patients. In most cases the cause of the disease was not identified; and there were no family cases [1].

In 2005, Dulac summarized 24 patients' follow-up (the largest number of verified cases in the world) in the Saint Vincent de Paul Hospital in Paris. Marsh et al. [25] reported another six cases of MMPSI observed in the Philadelphia Children's Hospital University of Pennsylvania who met the criteria described by Coppola. Presented clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy for the whole world epileptology [3].

Synonyms of this epileptic syndrome in the world scientific literature are malignant migrating partial seizures of infancy, migrating partial seizures of infancy, malignant epilepsy of infancy with migrating multifocal seizures, Coppola-Dulac syndrome, and most genetic verified cases, which can be referred to early infantile epileptic encephalopathy type 14 (EIEE14).

## 2. Etiology

In most MMPSI cases, etiology remains unknown; familial cases are rare. In observation by Dulac, relatives in 3 of 24 patients had febrile convulsions, and 4 patients had family history of epilepsy [3]. Multiple tests for inherited metabolism defects had negative results [7].

### 2.1 Monogenic mutations with Mendelian type of inheritance

The first genetic sequencing for identification mutations specific for MMPSI was carried out by Coppola et al. [8]. Was performed automatic sequencing of genes of potassium (KCNQ2, KCNQ3) and sodium (SCN1A, SCN2A) ion channels in three children with MMPSI but no mutation have been found. Mutational screening of chloride (CLCN2) ion channel gene revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. But the same variation has been found in 38 out of 100 control alleles [8].

2.1.1 Early infantile epileptic encephalopathy type 3 (EIEE6; 609304)

Monogenic mutations as etiological factors of malignant migrating partial seizures of infancy

Phenotype OMIM classification

Early infantile epileptic encephalopathy type 3 (EIEE3)

Early infantile epileptic encephalopathy type 6 (EIEE6)

Early infantile epileptic encephalopathy type 13 (EIEE13)

Early infantile epileptic encephalopathy type 14 (EIEE14)

Early infantile epileptic encephalopathy type 16 (EIEE16)

Progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA)

Table 1.

109

Phenotype OMIM number

DOI: http://dx.doi.org/10.5772/intechopen.82838

Gene/ locus

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome)

Gene OMIM number

609304 SLC25A22 609302 11p15.5 gly110arg;

607208 SCN1A 182389 2q24.3 ala1669gly

614959 KCNT1 608167 9q34.3 arg428glm

615338 TBC1D24 613577 16p13.3 phe229ser

615760 QARS 603727 3p21.31 tyr57his

Location Mutation

614558 SCN8A 600702 12q13.13 phe846ser AD Ohba et al.

variants

(.0003)

(.0023) arg862gly (.0024)

(.0001) ala934thr (.0002) arg474his (.0003) ile760met (.0004) phe932ile (.0009) gly288ser (.0010)

(.0005) + cys156ter (.0006)

(.0003) + arg515trp (.0004)

Inheritance References

AR Poduri

AD Freilich

AD Barcia

AR Milh et al. [18]

AR Zhang et al. [19]

et al. [9]

et al. [10] Carranza Rojo et al. [11]

[12]

et al., [13] Vanderver et al. [14] Ishii et al. [15]

Poduri et al. [9] reported about two sibs (brother and sister), born of consanguineous Saudi Arabian parents, with EIEE3 presenting MMPSI phenotype. EEG showed abnormal spikes in various brain regions. Neurological signs included hypotonia and brisk tendon reflexes; psychomotor development was delayed and subsequently arrested. Brain MRI was normal in the boy but showed delayed myelination and diffuse thinning of the corpus callosum in his sister. Two sibs had polymorphic seizures including bilateral and hemiclonic convulsions, flushing of the face, "staring," and eventually bilateral eyelid blinking. The seizures in both children were refractory to treatment. The boy developed seizure onset at 1 week of age and died at 14 months; the girl presented first seizures at 2 weeks of age and died at 47 months of age. They also had two healthy brothers. The research team

At present time a number of monogenic mutations were identified in patients with malignant migrating partial seizures of infancy. In catalog of human genes and genetic disorders – Online Mendelian Inheritance in Man (OMIM), we could find the following positions for MMPSI phenotype (Table 1):


### Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome) DOI: http://dx.doi.org/10.5772/intechopen.82838

### Table 1.

This severe form of epilepsy was recently described. The first publication about migrating partial seizures of infancy was presented by Coppola and colleagues in 1995 [1], and then personal observations were done by Gerard et al. [4] and by Okuda et al. [5]. Veneselli et al. summarized previous observations and added three

own cases [6]. Coppola et al. in their remarkable report (1995) based on

there were no family cases [1].

Epilepsy - Advances in Diagnosis and Therapy

whole world epileptology [3].

defects had negative results [7].

2. Etiology

108

epileptic encephalopathy type 14 (EIEE14).

neuropediatric department at the René Descartes University (Paris) presented 14 clinical cases of infants of both sexes with previously undescribed epileptic syndrome characterized by virtually continuous multifocal seizures. According to the classical authors description, the first seizures occurred average at the age of 3 months without any significant previous events. During the period from 1 to 10 months, seizures became very frequent. Seizures were focal and had different clinical characteristics; EEG revealed multiple epileptiform discharges arising independently and with migration during subsequent seizures from one cortical region to another. Patients had regression of psychomotor development, tetraparesis and severe muscular hypotonia of axial muscles. Three of 14 patients died: one at the age of 7 months, and other at the age of 7 and 8 years. Seizures were completely ceased only in two patients. In most cases the cause of the disease was not identified; and

In 2005, Dulac summarized 24 patients' follow-up (the largest number of verified cases in the world) in the Saint Vincent de Paul Hospital in Paris. Marsh et al. [25] reported another six cases of MMPSI observed in the Philadelphia Children's Hospital University of Pennsylvania who met the criteria described by Coppola. Presented clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy for the

Synonyms of this epileptic syndrome in the world scientific literature are malignant migrating partial seizures of infancy, migrating partial seizures of infancy, malignant epilepsy of infancy with migrating multifocal seizures, Coppola-Dulac syndrome, and most genetic verified cases, which can be referred to early infantile

In most MMPSI cases, etiology remains unknown; familial cases are rare. In observation by Dulac, relatives in 3 of 24 patients had febrile convulsions, and 4 patients had family history of epilepsy [3]. Multiple tests for inherited metabolism

The first genetic sequencing for identification mutations specific for MMPSI was carried out by Coppola et al. [8]. Was performed automatic sequencing of genes of potassium (KCNQ2, KCNQ3) and sodium (SCN1A, SCN2A) ion channels in three children with MMPSI but no mutation have been found. Mutational screening of chloride (CLCN2) ion channel gene revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. But the same variation has been found in 38 out of 100 control alleles [8]. At present time a number of monogenic mutations were identified in patients with malignant migrating partial seizures of infancy. In catalog of human genes and genetic disorders – Online Mendelian Inheritance in Man (OMIM), we could find

2.1 Monogenic mutations with Mendelian type of inheritance

the following positions for MMPSI phenotype (Table 1):

Monogenic mutations as etiological factors of malignant migrating partial seizures of infancy
