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

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

analyzed consanguineous pedigree (parents are cousins) and obtained DNA from affected and unaffected family members, analyzed single nucleotide polymorphism (SNP) 500 K data to identify regions with evidence for linkage, performed wholeexome sequencing, analyzed homozygous variants in regions of linkage to identify a candidate gene, and performed functional studies of the candidate gene SLC25A22. In affected siblings, a homozygous c.328G-C transversion in the SLC25A22 gene was identified, resulting in a gly110-to-arg (G110R; 609302.0003) substitution at a highly conserved residue in the third transmembrane helix [9].

(p.Phe846Ser) was detected. He developed apnea seizures from the age of 2 months and further at 4 months demonstrated migrating hemiclonic convulsions increasing up to status epilepticus of multifocal migrating seizures. MRI has shown mild atrophy of the cerebellum and thin corpus callosum. High-dose combined antiepileptic therapy with phenobarbital, phenytoin, and lamotrigine, ketogenic diet, and vagus nerve stimulator (VNS) implantation are temporarily and partially effective [12]. Voltage-dependent sodium channels, such as SCN8A, are responsible for the initial membrane depolarization that occurs during generation of action potentials in most electrically excitable cells. Mutations in KCNT1 aside from EIEE13 also determine benign familial infantile seizures type 5 (OMIM 617080) and cognitive impairment with or without cerebellar ataxia (OMIM 614306) with autosomal

Barcia et al. in 2012 had identified four different de novo heterozygous mutations in the KCNT1 gene (608167.0001–608167.0004) in 6 of 12 unrelated pediatric patients (50%) with clinically manifestation as MMPSI. The gene KCNT1 encodes a sodium-activated potassium channel that is widely expressed at the nervous system. Its activity contributes to the slow hyperpolarization as the neuronal membrane potential that follows repetitive firing. The C-terminal cytoplasmic domain interacts with a protein network, including FMRP (fragile X mental retardation protein),

OMIM genetic classification for this type of MMPSI is early infantile epileptic encephalopathy type 14 (614959). At present time, the following allelic variants of

ARG428GLN (608167.0001 KCNT1). It was founded by Barcia et al. [13] in three unrelated patients of French origin and was identified as de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-togln substitution at a highly conserved residue in the cytoplasmic C-terminal

ALA934THR (608167.0002 KCNT1). In a child of French origin with MMPSI, Barcia et al. [13] identified a de novo heterozygous 2800G-A transition in exon 24 of the KCNT1 gene, resulting in an ala934-to-thr substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was shown to cause constitutive activation of the sodium-activated potassium channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C activation. ARG474HIS (608167.0003 KCNT1). It was identified in a patient of French origin with MMPSI by Barcia et al. [13] as de novo heterozygous 1421G-A transition in exon 15 of the KCNT1 gene, resulting in an arg474-to-his substitution at a highly

ILE760MET (608167.0004 KCNT1). It was also founded by Barcia et al. [13] in a

child of Ukrainian origin with early clinical manifestation of MMPSI and was identified as de novo heterozygous 2280C-G transversion in exon 20 of the KCNT1 gene, resulting in an ile760-to-met substitution at a highly conserved residue. All these mutations were identified by exome sequencing and also were confirmed by Sanger sequencing. Mutations were not found in 200 controls or in

PHE932ILE (608167.0009 KCNT1). Vanderver et al. [14] identified in an Australian boy the de novo heterozygous c.2794 T-A transversion in the KCNT1 gene, resulting in a phe932-to-ile substitution at a highly conserved residue in the cytoplasmic C-terminal domain. This mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and was not present in the 1000

2.1.4 Early infantile epileptic encephalopathy type 14 (EIEE14; 614959)

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

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

KCNT1 gene mutation in patients with MMPSI were identified:

dominant inheritance.

domain.

conserved residue.

111

several large control databases [13].

suggesting additional functions [13].

## 2.1.2 Early infantile epileptic encephalopathy type 6 (EIEE6; 607208)

It is a well-known fact that mutation in SCN1A is a leading etiological factor for severe myoclonic epilepsy of infancy (Dravet syndrome). OMIM genetic classification is early infantile epileptic encephalopathy type 6 (607208) with autosomal dominant inheritance. Nevertheless, Freilich et al. [10] have found a novel mutation in the SCN1A gene in the girl with MMPSI who died at the age of 9 months from recurrent status epilepticus (SE). This girl had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, SE of migrating multifocal seizures confirmed by EEG monitoring, progressive microcephaly, and profound psychomotor delay. By sequencing genomic DNA from blood, the heterozygous missense mutation c.C5006C > A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E; 182389.0023), which further was confirmed in brain DNA, was identified. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein [10].

In a scientific group of Epilepsy Research Centre, Department of Medicine, University of Melbourne, Australia, Carranza Rojo et al. [11] have investigated 15 unrelated children with MMPSI for mutations in genes associated with infantile epileptic encephalopathies (SCN1A, CDKL5, STXBP1, PCDH19, and POLG). One girl with seizure onset at 2 weeks had heterozygous missense mutation de novo 2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G; 182389.0024) that affects the sodium channel by substitution in the voltage sensor segment S4 of the second protein domain. She had epilepsy onset of alternative hemiclonic seizures (Dravet-like onset) at the age of 2 weeks with developing status epilepticus of multifocal migrating seizure. Also, the girl had acquired microcephaly, developmental regression, and severe intellectual disability with much more severe phenotype than children with Dravet syndrome. And, another girl who developed MMPSI at the age of 2 months had de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screenings of CDKL5, STXBP1, and PCDH19 and the three common European mutations of POLG were negative [11].

Along with Dravet and MMPSI syndromes, mutation in SCN1A gene has been also associated with generalized epilepsy with febrile seizures plus type 2 (604403), familial febrile seizures type 3A (604403), and familial hemiplegic migraine type 3 (609634). All the diseases have autosomal dominant inheritance.

### 2.1.3 Early infantile epileptic encephalopathy type 13 (EIEE13; 614558)

Ohba et al. [12] identified in seven unrelated patients with early-onset epileptic encephalopathies seven different de novo heterozygous missense mutations in the SCN8A gene, and one of them had MMPSI. In a 5-year-old bedridden severe delayed and profound intellectual disabled Japanese boy by whole-exome sequencing, de novo previously not described mutation in SCN8A gene c.2537 T > C

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

(p.Phe846Ser) was detected. He developed apnea seizures from the age of 2 months and further at 4 months demonstrated migrating hemiclonic convulsions increasing up to status epilepticus of multifocal migrating seizures. MRI has shown mild atrophy of the cerebellum and thin corpus callosum. High-dose combined antiepileptic therapy with phenobarbital, phenytoin, and lamotrigine, ketogenic diet, and vagus nerve stimulator (VNS) implantation are temporarily and partially effective [12].

Voltage-dependent sodium channels, such as SCN8A, are responsible for the initial membrane depolarization that occurs during generation of action potentials in most electrically excitable cells. Mutations in KCNT1 aside from EIEE13 also determine benign familial infantile seizures type 5 (OMIM 617080) and cognitive impairment with or without cerebellar ataxia (OMIM 614306) with autosomal dominant inheritance.

### 2.1.4 Early infantile epileptic encephalopathy type 14 (EIEE14; 614959)

Barcia et al. in 2012 had identified four different de novo heterozygous mutations in the KCNT1 gene (608167.0001–608167.0004) in 6 of 12 unrelated pediatric patients (50%) with clinically manifestation as MMPSI. The gene KCNT1 encodes a sodium-activated potassium channel that is widely expressed at the nervous system. Its activity contributes to the slow hyperpolarization as the neuronal membrane potential that follows repetitive firing. The C-terminal cytoplasmic domain interacts with a protein network, including FMRP (fragile X mental retardation protein), suggesting additional functions [13].

OMIM genetic classification for this type of MMPSI is early infantile epileptic encephalopathy type 14 (614959). At present time, the following allelic variants of KCNT1 gene mutation in patients with MMPSI were identified:

ARG428GLN (608167.0001 KCNT1). It was founded by Barcia et al. [13] in three unrelated patients of French origin and was identified as de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-togln substitution at a highly conserved residue in the cytoplasmic C-terminal domain.

ALA934THR (608167.0002 KCNT1). In a child of French origin with MMPSI, Barcia et al. [13] identified a de novo heterozygous 2800G-A transition in exon 24 of the KCNT1 gene, resulting in an ala934-to-thr substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was shown to cause constitutive activation of the sodium-activated potassium channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C activation.

ARG474HIS (608167.0003 KCNT1). It was identified in a patient of French origin with MMPSI by Barcia et al. [13] as de novo heterozygous 1421G-A transition in exon 15 of the KCNT1 gene, resulting in an arg474-to-his substitution at a highly conserved residue.

ILE760MET (608167.0004 KCNT1). It was also founded by Barcia et al. [13] in a child of Ukrainian origin with early clinical manifestation of MMPSI and was identified as de novo heterozygous 2280C-G transversion in exon 20 of the KCNT1 gene, resulting in an ile760-to-met substitution at a highly conserved residue.

All these mutations were identified by exome sequencing and also were confirmed by Sanger sequencing. Mutations were not found in 200 controls or in several large control databases [13].

PHE932ILE (608167.0009 KCNT1). Vanderver et al. [14] identified in an Australian boy the de novo heterozygous c.2794 T-A transversion in the KCNT1 gene, resulting in a phe932-to-ile substitution at a highly conserved residue in the cytoplasmic C-terminal domain. This mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and was not present in the 1000

analyzed consanguineous pedigree (parents are cousins) and obtained DNA from affected and unaffected family members, analyzed single nucleotide polymorphism (SNP) 500 K data to identify regions with evidence for linkage, performed wholeexome sequencing, analyzed homozygous variants in regions of linkage to identify a candidate gene, and performed functional studies of the candidate gene SLC25A22. In affected siblings, a homozygous c.328G-C transversion in the SLC25A22 gene was identified, resulting in a gly110-to-arg (G110R; 609302.0003) substitution at a

It is a well-known fact that mutation in SCN1A is a leading etiological factor for severe myoclonic epilepsy of infancy (Dravet syndrome). OMIM genetic classification is early infantile epileptic encephalopathy type 6 (607208) with autosomal dominant inheritance. Nevertheless, Freilich et al. [10] have found a novel mutation in the SCN1A gene in the girl with MMPSI who died at the age of 9 months from recurrent status epilepticus (SE). This girl had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, SE of migrating multifocal seizures confirmed by EEG monitoring, progressive microcephaly, and profound psychomotor delay. By sequencing genomic DNA from blood, the heterozygous missense mutation c.C5006C > A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E; 182389.0023), which further was confirmed in brain DNA, was identified. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular

In a scientific group of Epilepsy Research Centre, Department of Medicine, University of Melbourne, Australia, Carranza Rojo et al. [11] have investigated 15 unrelated children with MMPSI for mutations in genes associated with infantile epileptic encephalopathies (SCN1A, CDKL5, STXBP1, PCDH19, and POLG). One girl with seizure onset at 2 weeks had heterozygous missense mutation de novo 2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G; 182389.0024) that affects the sodium channel by substitution in the voltage sensor segment S4 of the second protein domain. She had epilepsy onset of alternative hemiclonic seizures (Dravet-like onset) at the age of 2 weeks with developing status epilepticus of multifocal migrating seizure. Also, the girl had acquired microcephaly, developmental regression, and severe intellectual disability with much more severe phenotype than children with Dravet syndrome. And, another girl who developed MMPSI at the age of 2 months had de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screenings of CDKL5, STXBP1, and PCDH19 and the three com-

Along with Dravet and MMPSI syndromes, mutation in SCN1A gene has been also associated with generalized epilepsy with febrile seizures plus type 2 (604403), familial febrile seizures type 3A (604403), and familial hemiplegic migraine type 3

Ohba et al. [12] identified in seven unrelated patients with early-onset epileptic

encephalopathies seven different de novo heterozygous missense mutations in the SCN8A gene, and one of them had MMPSI. In a 5-year-old bedridden severe delayed and profound intellectual disabled Japanese boy by whole-exome sequencing, de novo previously not described mutation in SCN8A gene c.2537 T > C

highly conserved residue in the third transmembrane helix [9].

Epilepsy - Advances in Diagnosis and Therapy

linker of domain 4 of the SCN1A sodium channel protein [10].

mon European mutations of POLG were negative [11].

110

(609634). All the diseases have autosomal dominant inheritance.

2.1.3 Early infantile epileptic encephalopathy type 13 (EIEE13; 614558)

2.1.2 Early infantile epileptic encephalopathy type 6 (EIEE6; 607208)

Genomes Project or Exome Sequencing Project databases. Seizure onset was at age of 1 month with refractory myoclonic seizures that progressed to different polymorphic seizure types and status epilepticus. He also had microcephaly and severe developmental stagnation. Brain imaging showed serious delayed myelination, and EEG demonstrated background slowing with multifocal interictal discharges and occasional periods of burst suppression. The patient doesn't have classical MMPSI characteristics and survived (last observation at the age of 10) with a decrease of pharmacoresistant seizures at the age of 7 [14].

Mutation in TBC1D24 gene has been also associated to infantile familial myo-

Zhang et al. [19] in four patients from two unrelated families with progressive microcephaly, intractable seizures, and cerebral and cerebellar atrophy (MSCCA;

(603727.0001–603727.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. QARS (or GLnRS; 603,727) is a class I aminoacyl-tRNA synthetase. Aminoacyl-tRNA synthetases are enzymes that charge tRNAs with their cognate amino acids. The specificity of this reaction determines the fidelity of mRNA translation. At least one synthetase exists in the cytoplasm for each amino acid. QARS is essential for normal brain development. Studies in patient cells and expression of recombinant variants in E. coli showed that all four mutations caused a severe loss of QARS catalytic activity, consistent with a loss-offunction effect. Homozygous loss of QARS in zebrafish caused decreased brain and eye size and extensive cell death in the brain. Two sibs observed by Zhang et al. [19], born of unrelated French parents, had clinical and EEG signs of malignant migrating partial seizures of infancy and compound heterozygous mutations in the QARS gene, a c.169 T-C transition, resulting in a tyr57-to-his (603727.0003) substitution at a highly conserved residue in the N-terminal domain, and a c.1543C-T transition, resulting in an arg515-to-trp (603727.0004) substitution at a highly conserved residue in the catalytic domain. Patient cells showed decreased

aminoacylation activity of QARS compared to control. Expression of recombinant arg515trp (.0004) in E. coli resulted in no QARS catalytic activity, whereas tyr57his (.0003) decreased QARS activity to less than 10% that of controls. In addition, the arg515trp mutation appeared to cause protein misfolding and aggregation, resulting

On personal observation of MMPSI patients, one Russian boy with clinical and

electroencephalographic pattern of mixed form (MMPSI and early myoclonic encephalopathy) had rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222,765) from the group of peroxisomal metabolic diseases [20]. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) is caused by homozygous or compound heterozygous mutation in the DHAPAT gene (GNPAT; 602,744), which encodes acyl-CoA:dihydroxyacetonephosphate acyltransferase, on chromosome 1q42. This peroxisomal disorder is characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, micrognathia, dysplastic external ears, eye abnormalities‑cataract and coloboma, congenital contractures, dwarfism, hypotonia, and severe mental retardation. Biochemically, plasmalogen

in decreased expression of the soluble mutant protein [19].

synthesis and phytanic acid alpha-oxidation are defective.

113

2.1.7 Rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222765)

clonic epilepsy (OMIM 605021, autosomal recessive inheritance), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome – OMIM 220500) with autosomal recessive inheritance, and also autosomal recessive deafness type 86 (614617), and autosomal dominant deafness

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

2.1.6 Progressive microcephaly with seizures and cerebral and cerebellar atrophy

615,760) identified compound heterozygous mutations in the QARS gene

type 65 (616044).

(MSCCA; 615760)

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

GLY288SER (608167.0010 KCNT1). Ishii et al. in two unrelated Japanese girls with MMPSI identified a de novo heterozygous c.862G-A transition in the KCNT1 gene, resulting in a gly288-to-ser substitution at a highly conserved residue in the pore region of the channel [15].

Kawasaki et al. described three infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure [16].

Madaan with colleagues from Child Neurology Division, Department of Pediatrics, All India Institutes of Medical Sciences (New Delhi, India), in 2018 identified a child with MMPSI who had a novel heterozygous missense mutation in exon 10 of the KCNT1 gene (chr9:138650308; c.808C > C/G (p.Q270E)). Neither quinidine nor ketogenic diet could control his seizures, and the child succumbed to his illness at 9 months of age [17].

My personal observation consists of two Russian girls with MMPSI having KCNT1 mutations: one with gly288ser (608167.0010 KCNT1) and the other with previously not described mutations c.1066C > T (arg356trp) in exome 12 (chr9:138656907C > T, rs752514808). So, it seems that KCNT1 is a major diseaseassociated gene for the MMPSI phenotype.

It is interesting that mutations in KCNT1 also determine another form of epilepsy – nocturnal frontal lobe epilepsy type 5. But the mutation is different from the cases of MMPSI and is marked .0005–.0008 (ARG928CYS, TYR796HIS, ARG398GLN, and MET896ILE).

### 2.1.5 Early infantile epileptic encephalopathy type 16 (EIEE14; 615338)

Milh et al. [18] identified compound heterozygosity for two mutations in exon 2 of the TBC1D24 gene (686 T-C transition, resulting in a phe229-to-ser, 613577.0005, and 468C-A transversion, resulting in a cys156-to-ter, 613577.0006) in two sisters with malignant migrating partial seizures of infancy. These girls early developed clonic seizures in the second month of life and subsequently demonstrated prolonged, almost continuous migrating seizures of different types with severe neurologic deterioration and lack of psychomotor development [18].

OMIM genetic classification for this type of MMPSI – early infantile epileptic encephalopathy type 16 (615338). The screening of TBC1D24 in an additional set of eight MMPSI patients observed by Milh and colleagues was negative. The TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RABspecific GTPase-activating proteins, which coordinates peripheral membrane Rab proteins and other GTPases for the proper transport of intracellular vesicles. Coimmunoprecipitation studies showed that the phe229ser mutation impaired the interaction of TBC1D24 with adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6, 600,464), and overexpression of the mutant protein in primary cortical neurons abolished the ability of TBC1D24 to increase neurite length and arborization, consistent with a loss of function [18].

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

Mutation in TBC1D24 gene has been also associated to infantile familial myoclonic epilepsy (OMIM 605021, autosomal recessive inheritance), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome – OMIM 220500) with autosomal recessive inheritance, and also autosomal recessive deafness type 86 (614617), and autosomal dominant deafness type 65 (616044).
