Epileptic Encephalopathy, Early Infantile, 41

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-41 (EIEE41) is caused by heterozygous mutation in the SLC1A2 gene (600300) on chromosome 11p13.

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

Clinical Features

The EPI4K Consortium (2016) reported 2 unrelated girls with EIEE41. They had an extremely severe phenotype, with onset of multiple seizure types in the first week of life followed by profound developmental impairment without detectable regression. One of the patients was a 17-year-old girl with quadriparesis, nephrocalcinosis, delayed dentition, severe growth failure with microcephaly, hirsutism, kyphoscoliosis, joint contractures, and tapering fingers. Brain imaging showed extreme supratentorial atrophy with absence of myelination of the cerebrum and thin corpus callosum; the cerebellum was unaffected. The other patient was a 6-year-old girl with hypotonia and profound intellectual disability. Brain imaging showed delayed myelination, thin corpus callosum, and frontal atrophy. EEG in both patients showed multifocal abnormal activity.

The EPI4K Consortium (2016) noted that the EPI4K Consortium and Epilepsy Phenome/Genome Project (2013) had reported a patient with EIEE41. The EPI4K Consortium (2016) summarized the clinical features of this patient, an 8-year-old girl. She had onset of mainly myoclonic seizures at age 1 month. There was some developmental regression after onset of seizures, and she had severe intellectual disability. Other features included blindness, hypotonia with head lag, and mild spasticity. EEG showed disorganized background activity, frequent discharges, and hypsarrhythmia; brain imaging was normal.

Guella et al. (2017) reported 2 unrelated boys with EIEE41. Both presented with focal motor seizures and twitching in the first weeks of life, followed by severely delayed psychomotor development. Each had episodes of developmental regression. One had cortical visual impairment, feeding difficulties with G-tube placement, a hyperkinetic movement disorder, lack of speech, and inability to sit unsupported. The other had refractory seizures, hypotonia, inability to fix or follow, no head control, G-tube, and tracheostomy. Brain imaging in both patients showed cerebral atrophy and delayed myelination.

Molecular Genetics

In 2 unrelated patients with EIEE41, the Epi4K Consortium (2016) identified 2 different de novo heterozygous missense mutations in the SLC1A2 gene (G82R, 600300.0001 and L85P, 600300.0002). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. The same de novo heterozygous G82R mutation had previously been identified in another patient with EIEE by the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013), which included 264 probands with epileptic encephalopathy who underwent exome sequencing.

In 2 unrelated patients with EIEE41, Guella et al. (2017) identified de novo heterozygous missense mutations in the SLC1A2 gene (600300.0003 and 600300.0004). The first patient was identified from a cohort of 42 individuals with epileptic encephalopathy who underwent sequencing of candidate genes; the second patient was identified through collaboration with clinical and research databases. In vitro functional studies of the variants and studies of patient cells were not performed, but Guella et al. (2017) postulated a toxic gain-of-function effect, perhaps related to glutamate toxicity.