Epileptic Encephalopathy, Early Infantile, 3

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-3 (EIEE3) is caused by homozygous mutation in the SLC25A22 gene (609302) on chromosome 11p15.

Description

Early infantile epileptic encephalopathy is characterized by onset during the first months of life of erratic refractory seizures, usually myoclonic. The prognosis is poor, and most children with the condition either die within 1 to 2 years after birth or survive in a persistent vegetative state. The EEG pattern often shows a suppression-burst pattern with high-voltage bursts of slow waves mixed with multifocal spikes alternating with isoelectric suppression phases (Molinari et al., 2005).

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Molinari et al. (2005) investigated a sibship of 4 affected children (2 girls and 2 boys) and 4 healthy children born to Arab Muslim parents in Jerusalem who were first cousins. The proband was examined at age 2 days because of intractable seizures and neonatal hypotonia. At age 3 years, computerized tomography of the head revealed brain atrophy, and EEG showed myoclonic seizures and burst suppression. Nonketotic hyperglycinemia was ruled out. His eldest sister also had hypotonia and seizures a few hours after birth, and likewise showed brain atrophy at age 3 years. Electroretinogram (ERG) was normal, whereas visual evoked potential (VEP) showed a low amplitude signal and a slow response suggestive of abnormal visual nerve-conduction velocity.

Molinari et al. (2009) reported an Algerian male infant who developed refractory epileptic seizures with secondary generalization at 5 days of age. Interictal EEG showed suppression bursts. The disorder progressed, and he was given a diagnosis of West syndrome at age 6 months. The seizures progressively decreased without use of medication until age 5 years, but recurred at 7 years. Brain MRI showed cerebellar hypoplasia, dysmorphism of the corpus callosum, abnormal gyration in the temporoparietal regions, and abnormal myelination of the temporal poles, and ERG showed progressive changes with alteration and abolition of macular and peripheral responses. At age 10 years, he was microcephalic, hypotonic, and still had tonic seizures. There was no psychomotor acquisition and he was in a vegetative state.

Poduri et al. (2013) reported 2 sibs, born of consanguineous Saudi Arabian parents, with EIEE3 presenting as migrating partial clonic seizures within the first 2 weeks of life. EEG showed abnormal spikes in various brain regions. Other features included hypotonia and brisk tendon reflexes. Brain MRI was normal in 1 child, but showed delayed myelination and diffuse thinning of the corpus callosum in the other child. The seizures in both children were refractory to treatment, and psychomotor development was delayed and subsequently arrested. The children died at 14 months and 47 months of age.

Inheritance

The transmission pattern of EIEE3 in the family reported by Poduri et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

Molinari et al. (2005) mapped the locus for a form of early infantile epileptic encephalopathy in an Arab family to chromosome 11p15.5.

Molecular Genetics

In affected members of an Arab family with early infantile epileptic encephalopathy mapping to chromosome 11p15.5, Molinari et al. (2005) identified a homozygous missense mutation (P206L; 609302.0001) in a gene encoding a mitochondrial glutamate/H+ symporter, SLC25A22. Glutamate oxidation in cultured skin fibroblasts from patients was strongly defective. Expression studies showed that during human development, SLC25A22 is specifically expressed in the brain, within territories proposed to contribute to the genesis and control of myoclonic seizures. The findings provided the first direct molecular link between glutamate mitochondrial metabolism and myoclonic epilepsy and suggested potential insights into the pathophysiologic bases of severe neonatal epilepsies with suppression-burst pattern.

In an Algerian boy with severe epileptic encephalopathy and no psychomotor acquisition, Molinari et al. (2009) identified a homozygous mutation in the SLC25A22 gene (G236W; 609302.0002).

In 2 sibs, born of consanguineous Saudi Arabian parents, with EIEE3 presenting as migrating partial seizures in infancy, Poduri et al. (2013) identified a homozygous mutation in the SLC25A22 gene (G110R; 609302.0003). The mutation was found by homozygosity mapping followed by whole-exome sequencing. Expression of the mutation in E. coli showed that the mutant protein had decreased glutamate transport activity (less than 5%) compared to wildtype.