Epileptic Encephalopathy, Early Infantile, 1

A number sign (#) is used with this entry because early infantile epileptic encephalopathy-1 (EIEE1), also known as X-linked infantile spasm syndrome-1 (ISSX1), is caused by mutation in the aristaless-related homeobox gene (ARX; 300382) on chromosome Xp21.

Description

Early infantile epileptic encephalopathy is a severe form of epilepsy first reported by Ohtahara et al. (1976). It is characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of EIEE patients progress to 'West syndrome,' which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (Kato et al., 2007). Deprez et al. (2009) reviewed the genetics of epilepsy syndromes starting in the first year of life and included a diagnostic algorithm.

EIEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1) to syndromic (309510) and nonsyndromic (300419) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008).

Genetic Heterogeneity of Early Infantile Epileptic Encephalopathy

EIEE is a genetically heterogeneous disorder. Also see EIEE2 (300672), caused by mutation in the CDKL5 gene (300203); EIEE3 (609304), caused by mutation in the SLC25A22 gene (609302); EIEE4 (612164), caused by mutation in the STXBP1 gene (602926); EIEE5 (613477), caused by mutation in the SPTAN1 gene (182810); EIEE6 (607208), also known as Dravet syndrome, caused by mutation in the SCN1A gene (182389); EIEE7 (613720), caused by mutation in the KCNQ2 gene (602235); EIEE8 (300607), caused by mutation in the ARHGEF9 gene (300429); EIEE9 (300088), caused by mutation in the PCDH19 gene (300460); EIEE10 (613402), caused by mutation in the PNKP gene (605610); EIEE11 (613721), caused by mutation in the SCN2A gene (182390); EIEE12 (613722), caused by mutation in the PLCB1 gene (607120); EIEE13 (614558), caused by mutation in the SCN8A gene (600702); EIEE14 (614959), caused by mutation in the KCNT1 gene (608167); EIEE15 (615006), caused by mutation in the ST3GAL3 gene (606494); EIEE16 (615338), caused by mutation in the TBC1D24 gene (613577); EIEE17 (615473), caused by mutation in the GNAO1 gene (139311); EIEE18 (615476), caused by mutation in the SZT2 gene (615463); EIEE19 (615744), caused by mutation in the GABRA1 gene (137160); EIEE20 (300868), caused by mutation in the PIGA gene (311770); EIEE21 (615833), caused by mutation in the NECAP1 gene (611623); EIEE22 (300896), caused by mutation in the SLC35A2 gene (314375); EIEE23 (615859), caused by mutation in the DOCK7 gene (615730); EIEE24 (615871), caused by mutation in the HCN1 gene (602780); EIEE25 (615905), caused by mutation in the SLC13A5 gene (608305); EIEE26 (616056), caused by mutation in the KCNB1 gene (600397); EIEE27 (616139), caused by mutation in the GRIN2B gene (138252); EIEE28 (616211), caused by mutation in the WWOX gene (605131); EIEE29 (616339), caused by mutation in the AARS gene (601065); EIEE30 (616341), caused by mutation in the SIK1 gene (605705); EIEE31 (616346), caused by mutation in the DNM1 gene (602377); EIEE32 (616366), caused by mutation in the KCNA2 gene (176262); EIEE33 (616409), caused by mutation in the EEF1A2 gene (602959); EIEE34 (616645), caused by mutation in the SLC12A5 gene (606726); EIEE35 (616647), caused by mutation in the ITPA gene (147520); EIEE36 (300884), caused by mutation in the ALG13 gene (300776); EIEE37 (616981), caused by mutation in the FRRS1L gene (604574); EIEE38 (617020), caused by mutation in the ARV1 gene (611647); EIEE39 (612949), caused by mutation in the SLC25A12 gene (603667); EIEE40 (617065), caused by mutation in the GUF1 gene (617064); EIEE41 (617105), caused by mutation in the SLC1A2 gene (600300); EIEE42 (617106), caused by mutation in the CACNA1A gene (601011); EIEE43 (617113), caused by mutation in the GABRB3 gene (137192); EIEE44 (617132), caused by mutation in the UBA5 gene (610552); EIEE45 (617153), caused by mutation in the GABRB1 gene (137190); EIEE46 (617162), caused by mutation in the GRIN2D gene (602717); EIEE47 (617166), caused by mutation in the FGF12 gene (601513); EIEE48 (617276), caused by mutation in the AP3B2 gene (602166); EIEE49 (617281), caused by mutation in the DENND5A gene (617278); EIEE50 (616457) caused by mutation in the CAD gene (114010); EIEE51 (617339), caused by mutation in the MDH2 gene (154100); EIEE52 (617350), caused by mutation in the SCN1B gene (600235); EIEE53 (617389), caused by mutation in the SYNJ1 gene (604297); EIEE54 (617391), caused by mutation in the HNRNPU gene (602869); EIEE55 (617599), caused by mutation in the PIGP gene (605938); EIEE56 (617665), caused by mutation in the YWHAG gene (605356); EIEE57 (617771), caused by mutation in the KCNT2 gene (610044); EIEE58 (617830), caused by mutation in the NTRK2 gene (600456); EIEE59 (617904), caused by mutation in the GABBR2 gene (607340); EIEE60 (617929), caused by mutation in the CNPY3 gene (610774); EIEE61 (617933), caused by mutation in the ADAM22 gene (603709); EIEE62 (617938), caused by mutation in the SCN3A gene (182391); EIEE63 (617976), caused by mutation in the CPLX1 gene (605032); EIEE64 (618004), caused by mutation in the RHOBTB2 gene (607352); EIEE65 (618008), caused by mutation in the CYFIP2 gene (606323); EIEE66 (618067), caused by mutation in the PACS2 gene (610423); EIEE67 (618141), caused by mutation in the CUX2 gene (610648); EIEE68 (618201), caused by mutation in the TRAK1 gene (608112); EIEE69 (618285), caused by mutation in the CACNA1E gene (601013); EIEE70 (618298) caused by mutation in the PHACTR1 gene (608723); EIEE71 (618328), caused by mutation in the GLS gene (138280); EIEE72 (618374), caused by mutation in the NEUROD2 gene (601725); EIEE73 (618379), caused by mutation in the RNF13 gene (609247); EIEE74 (618396), caused by mutation in the GABRG2 gene (137164); EIEE75 (618437), caused by mutation in the PARS2 gene (612036); EIEE76 (618468), caused by mutation in the ACTL6B gene (612458); EIEE77 (618548), caused by mutation in the PIGQ gene (605754); EIEE78 (618557), caused by mutation in the GABRA2 gene (137140); EIEE79 (618559), caused by mutation in the GABRA5 gene (137142); and EIEE80 (618580), caused by mutation in the PIGB gene (604122).

The phenotype is also observed in other genetic disorders, including GLUT1 deficiency syndrome (606777); glycine encephalopathy (605899); Aicardi-Goutieres syndrome (225750); and in males with MECP2 mutations (300673), among others.

For associations pending confirmation, see MOLECULAR GENETICS.

Clinical Features

Feinberg and Leahy (1977) reported X-linked recessive inheritance of infantile seizures in a family in which 5 males in 4 sibships spanning 3 generations were affected. Although the proband was still living at the time of the report, the 4 other affected children died between 9 months and 6 years of age.

Pavone et al. (1980) reported the infantile spasm syndrome in male monozygotic twins. Onset was on the same day when they were 6 months old. Treatment with ACTH in 1 twin led to more rapid clinical and EEG improvement compared to treatment with clonazepam in the other. Both twins showed by computer tomography an area of low density in the right frontoparietal region; this had disappeared in both by 8 months later.

Rugtveit (1986) described infantile spasms in 2 brothers who, like 5 others, had nonspecific X-linked mental retardation. Claes et al. (1997) studied 2 families with X-linked infantile spasm syndrome. The disorder was characterized by infantile spasms, hypsarrhythmia on EEG, and developmental arrest leading to severe to profound mental retardation.

Bruyere et al. (1999) suggested that the disorder in 3 generations of a French family reported by Ronce et al. (1999) was the same as the disorder reported by Feinberg and Leahy (1977), Rugtveit (1986), and Claes et al. (1997).

Kato et al. (2007) noted that early infantile epileptic encephalopathy with suppression-burst pattern, one of the most severe and earliest forms of epilepsy, evolves into West syndrome in 75% of patients. They described 2 patients with EIEE defined by brief tonic seizures and a suppression-burst pattern of unknown etiology on EEG. EEG demonstrated transition to hypsarrhythmia, suggesting West syndrome, at age 1 and 7 months, respectively. ACTH therapy was not effective in either patient. Both patients had severe developmental delay; both had micropenis. These 2 patients were hemizygous for the same de novo 33-bp duplication in exon 2 of the ARX gene (300382.0017).

Wallerstein et al. (2008) reported a girl with EIEE1 due to a heterozygous truncating mutation in the ARX gene (300382.0021). She was the product of a twin pregnancy conceived by in vitro fertilization with a donor egg and the father's sperm. She developed severe intractable myoclonic seizures at age 4 months, consistent with epileptic encephalopathy. She had delayed development, with poor visual tracking and poor speech development. Mild dysmorphic features, including epicanthal folds, and mildly low-set ears were also noted. The other twin was apparently unaffected. The findings indicated that haploinsufficiency of the ARX gene can result in a severe phenotype in females.

Giordano et al. (2010) reported a family in which 2 boys, born of monozygotic twin sisters, had EIEE1 confirmed by genetic analysis (L535Q; 300382.0024). Both boys presented in early infancy with spasms associated with myoclonic jerks or clonic attacks. EEG showed a suppression burst pattern, which later evolved to hypsarrhythmia. The seizures were refractory to medication. One of the boys had poor overall growth, and both developed progressive microcephaly associated with intellectual impairment and spastic tetraparesis. Brain MRI at first was normal in both children, but showed diffuse brain atrophy around 2 years of age. Family history revealed a maternal uncle who died at age 2 years during status epilepticus.

Clinical Variability

Scheffer et al. (2002) reported a family in which 6 boys over 2 generations were affected with infantile-onset of seizures, including myoclonic seizures and tonic-clonic seizures, spasticity, hyperreflexia, and mental retardation, which they called XMESID. One had hypsarrhythmia. Three obligate female carriers had hyperreflexia and the matriarch developed progressive spastic ataxia at age 49 years. The authors suggested X-linked recessive inheritance. Scheffer et al. (2002) suggested that the disorder was somewhat distinct from the classic phenotype of X-linked infantile spasm syndrome, by the inclusion of spasticity, developmental delay from birth, and seizure pattern.

Guerrini et al. (2007) reported 6 boys, including 2 pairs of brothers, with a severe phenotype of infantile epileptic-dyskinetic encephalopathy, including chorea and dystonia. All 6 boys also had severe mental retardation. Seizure onset occurred earlier in life than dystonia, which was severe and progressed to quadriplegic dyskinesia. Three children had recurrent, life-threatening status dystonicus. Brain MRI showed basal ganglia abnormalities in 4 patients.

Inheritance

Feinberg and Leahy (1977) described an X-linked recessive form of the disorder, suggesting a specific genetic entity.

On the basis of a systematic study, Fleiszar et al. (1977) concluded that infantile spasms, although clinically distinct from other seizures, is etiologically heterogeneous. Their data supported a multifactorial model involving polygenic determination of susceptibility and requiring additional environmental factors such as anoxia, birth trauma, or immunization.

X-linked infantile spasm syndrome due to mutations in the ARX gene is an X-linked recessive disorder, occurring only in males (Stromme et al., 2002).

Clinical Management

Friling et al. (2003) found that 5 of 9 babies with infantile spasms being treated with systemic corticosteroids developed elevated intraocular pressure (IOP) and glaucomatous optic nerve cupping. Antiglaucoma treatment in all 5 and augmented trabeculectomy in 1 resulted in decreased mean IOP and improved mean cup-to-disc ratio. The authors advised early and intensive monitoring during steroid therapy to prevent ocular damage and visual impairment.

Mapping

In the 2 families with ISSX reported by Claes et al. (1997), linkage studies suggested localization to Xp in a region distal to DXS1068, with a maximum lod score of 2.36. In studies of a western Canadian family with X-linked infantile spasms, Bruyere et al. (1999) confirmed the mapping to Xp22.1-p21.3 and refined the interval containing the candidate gene to 7.0 cM.

Stromme et al. (1999) restudied the family described by Rugtveit (1986). Linkage studies defined a region bounded by DXS8012 proximally and DXS7593 in the cytogenetic area Xp22.11-p11.4, a candidate region of approximately 25 cM.

Molecular Genetics

Stromme et al. (2002) found that one of the genes in the mapping interval for infantile spasm syndrome was the aristaless-related homeobox gene ARX. They considered it a candidate gene underlying ISSX, primarily on the basis of its expression pattern in fetal, infant, and adult brain. They screened the ARX gene for mutations in 4 previously described families (Bruyere et al., 1999; Stromme et al., 1999; Claes et al., 1997) and in a previously undescribed Norwegian family. Mutations in the ARX gene (300382.0001-300382.0004) were detected in affected males of all 4 of these families.

In affected members of a family with X-linked myoclonic epilepsy with spasticity and mental retardation, Scheffer et al. (2002) and Stromme et al. (2002) identified a mutation in the ARX gene (300382.0003).

In 2 patients with EIEE evolving to West syndrome, Kato et al. (2007) found the same mutation in exon 2 of the ARX gene resulting in a 33-bp duplication in the first polyalanine tract (300382.0017).

Guerrini et al. (2007) identified the (GCG)10+7 expansion (300382.0001) in 6 boys, including 2 pairs of brothers, with a severe form of EIEE1, which they termed infantile epileptic-dyskinetic encephalopathy.

In 2 male first cousins with EIEE1, Giordano et al. (2010) identified a missense mutation in the ARX gene (L535Q; 300382.0024). Both unaffected mothers carried the mutation, as did the maternal grandmother. Giordano et al. (2010) noted that the mutation in this family did not involve an expanded polyalanine tract, indicating that missense mutations in the ARX gene can also lead to a severe phenotype.

Associations Pending Confirmation

See 614107.0001 for discussion of a possible association between variation in the KPNA7 gene and early infantile epileptic encephalopathy.

Possible association between EIEE and variation in other genes has also been reported: see CBL (165360.0010), CSNK1G1 (606274.0001), NAPB (611270.0001), and CAMK2G (602123.0002).

See 605410.0001 for discussion of a possible association between variation in the KCND2 gene and infantile-onset severe refractory epilepsy and autism (209850).

Genotype/Phenotype Correlations

Fullston et al. (2010) identified a truncating mutation in the ARX gene (Y27X; 300382.0023) in 2 male first cousins with EIEE1. Although the patients had a severe form of the disorder with early-onset refractory seizures and essentially no developmental progress, neither had evidence of pachygyria or lissencephaly on brain imaging and neither had ambiguous genitalia. Overexpression of the mutation in HEK293 cells showed the presence of an N-terminally truncated ARX protein that likely used a start codon at residue 41 (M41_C562), with no detection of the Y27X protein. As null ARX mutations are usually associated with lissencephaly and ambiguous genitalia (XLAG; 300215), Fullston et al. (2010) speculated that some partially functioning ARX protein was formed by reinitiation of mRNA translation in these patients.

History

West syndrome was first described by W. J. West, a 19th century neurologist who described the syndrome in his own son (Foldvary-Schaefer and Wyllie, 2003).