Early Infantile Epileptic Encephalopathy via the SLC25A22 Gene

Early infantile epileptic encephalopathy-3 (EIEE3) is an infantile onset seizure disorder defined by focal myoclonic seizures and burst suppression pattern on EEG. EIEE3 likely represents a spectrum of phenotypes, with two distinct phenotypes already having been attributed to SLC25A22 variants: early myoclonic encephalopathy (EME) and malignant migrating partial seizures of infancy (MMPSI) (Cohen et al. 2014; Poduri et al. 2013).

EIEE3 is characterized by seizure onset within the first weeks of life. Patients present with erratic myoclonus and focal seizures and may later develop tonic seizures. Seizures may manifest as: hemiconvulsions on one side of the body, myoclonus involving the hands, legs, and face, and/or eye deviation and lip smacking. Seizures are generally refractory to treatment with antieplileptic drugs. Other features commonly seen include hypotonia and microcephaly. EEG reveals a burst suppression pattern that is more pronounced during sleep (Cohen et al. 2014). Some patients may also experience a transient evolution to hypsarrhythmia on EEG, with an eventual return to a burst suppression pattern. MRI at early stages may appear normal, but as the disease progresses common findings include: thin corpus callosum, cerebellar hypoplasia, and general brain atrophy (Molinari et al. 2009). Prognosis is poor for EIEE3 patients; psychomotor development may be severely delayed or absent, resulting in a vegetative state and early death.

EIEE3 overlaps phenotypically with Ohtahara syndrome, another infantile onset epileptic encephalopathy. Two features that can help distinguish these disorders are: 1. EIEE3 patients typically present with erratic myoclonus rather than tonic spasms and 2. the burst suppression pattern of EIEE3 is more pronounced during sleep, whereas in OS patients there is no wake/sleep differential (Cohen et al. 2014). Interestingly, visual deficits and abnormal ERG readings indicating loss of macular and peripheral photoresponses were reported in a number of EIEE3 patients with SLC25A22 variants (Molinari et al. 2009). More studies will be needed to determine if retinal phenotypes are another hallmark of EIEE3.

One report described two patients with pathogenic SLC25A22 variants that were diagnosed with malignant migrating partial seizures of infancy (MMPSI); the patients had infantile onset partial seizures without myoclonus, and EEG revealed migrating seizures and no burst suppression pattern (Poduri et al. 2013).

EIEE3 is inherited in an autosomal recessive manner, and is caused by pathogenic variants in the SLC25A22 gene. All reported pathogenic SLC25A22 variants have been missense variants, which have been identified in the homozygous state in consanguineous families.

SLC25A22 encodes GC1, a mitochondrial carrier that catalyzes the transport of glutamate into the mitochondrial matrix (Fiermonte 2002). GC1 is highly expressed in astrocytes in areas of the brain controlling motor coordination (Berkich et al. 2007). Glutamate is an important neurotransmitter required for neuronal signaling. Glutamate is released by pre-synaptic neurons to signal post-synaptic neurons. Glutamate from the synapse is then taken up by astrocytes where it is converted to glutamine and recycled back to pre-synaptic neurons. It is hypothesized that loss of GC1 function leads to accumulation of glutamate in the cytosol of astrocytes and in the synaptic cleft. Dysregulation of extracellular glutamate could lead to inappropriate activation of post-synaptic glutamate receptors, impairing signaling in the brain and resulting in epilepsy (Cohen 2014).

EIEE3 is a rare disorder and clinical sensitivity cannot yet be estimated. Analytical sensitivity should be high because all pathogenic variants thus far reported are expected to be detected by sequencing methods.

This test provides full coverage of all coding exons of the SLC25A22 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.