Epileptic Encephalopathy, Early Infantile, 37

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-37 (EIEE37) is caused by homozygous mutation in the FRRS1L gene (604574) on chromosome 9q31.

Description

Early infantile epileptic encephalopathy-37 is an autosomal recessive severe epileptic-dyskinetic disorder characterized by onset of intractable seizures or abnormal movements in the first years of life. Affected individuals show global developmental delay and/or developmental regression after onset of seizures. Patients also show a hyperkinetic movement disorder with choreoathetosis, spasticity, and rigidity. The individuals are severely affected, with mental retardation, absent speech, and impaired volitional movements (summary by Madeo et al., 2016).

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

Clinical Features

Madeo et al. (2016) reported 8 children from 4 families with an epileptic-dyskinetic encephalopathy. The age at onset ranged from 6 to 24 months. Patients presented with either choreoathetotic movement or intractable severe seizures, including hemiclonic and generalized tonic-clonic with multifocal origin. Most patients showed severe developmental regression after onset of seizures. All had severe intellectual impairment with absent speech and decreased volitional movements. Variable features included opisthotonic posturing, tremor, hypotonia, hyperreflexia, and nystagmus. Five sibs in 1 consanguineous family became less responsive over time and the hyperkinetic movement disorder gradually gave way to a rigid, akinetic state. Brain imaging in this family showed diffuse cortical and cerebellar volume loss and flattening of the caudate heads.

Shaheen et al. (2016) reported a large consanguineous Arab family in which 5 individuals, ranging in age from 6 to 28 years, had epileptic encephalopathy with onset of seizures between 6 months and 2.5 years of age. All had developmental delay since infancy and showed further regression after onset of seizures. Brain MRI was normal, but EEG showed slow wave background activity and continuous spike-and-wave discharges during sleep. Two of the sibs in this family had previously been reported by Saadeldin and Al-Tala (2011) and were noted to have myoclonus.

Inheritance

The transmission pattern of EIEE37 in the families reported by Madeo et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 4 unrelated families with EIEE37, Madeo et al. (2016) identified 4 different homozygous mutations in the FRRS1L gene (604574.0001-604574.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Three of the mutations resulted in a truncated protein. Fibroblasts from patients in 2 families showed markedly reduced FRRS1L protein levels. Additional studies of the variants and of patient cells were not performed. However, knockdown of the FRRS1L gene in neuronal cells attenuated calcium influx and diminished AMPA-induced inward currents, suggesting that it functions normally as an important modulator of glutamate signaling. Madeo et al. (2016) concluded that abnormalities of glutamatergic neurotransmission resulted in the clinical features of this disorder.

In 6 affected members of a large consanguineous family with EIEE37, Shaheen et al. (2016) identified a homozygous truncating mutation in the FRRS1L gene (604574.0001). The mutation was found by a combination of linkage analysis and exome sequencing. Functional studies of the variant and studies of patient cells were not performed.