Epileptic Encephalopathy, Early Infantile, 69

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-69 (EIEE69) is caused by heterozygous mutation in the CACNA1E gene (601013) on chromosome 1q25.

Description

Infantile epileptic encephalopathy-69 (EIEE69) is an autosomal dominant severe neurodevelopmental encephalopathic disorder characterized by early-onset refractory seizures, hypotonia, and profoundly impaired development often associated with macrocephaly, hyperkinetic movements, and contractures. The disorder can sometimes result in early death. Some patients may have a favorable seizure response to topiramate medication (summary by Helbig et al., 2018).

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

Clinical Features

Helbig et al. (2018) reported 30 unrelated patients with a similar neurodevelopmental disorder characterized by early-onset intractable seizures, severe hypotonia, and severe or profound global developmental delay with absent or very poor speech and inability to sit or walk. Most of the patients were children in the first decade, although there were several teenagers and 1 patient who died at age 25 years. Six further patients died in the first years of life. Most patients presented with various types of seizures in the first months of life, although 2 patients had onset of seizures at 3 years of age and 2 had not had seizures by age 4 years. EEG in those with seizures showed multifocal discharges, polyspike slow-wave discharges, and sometimes hypsarrhythmia or burst-suppression patterns. Some patients showed developmental regression after onset of seizures. Additional common features included spastic quadriplegia, hyperreflexia, hyperkinetic movements, dystonia, myoclonus, clonus, poor or absent eye contact, nystagmus, cortical visual impairment, and loss of head control. Thirteen patients had congenital contractures and 13 had macrocephaly. Brain imaging was normal in many and showed nonspecific white matter volume loss, atrophy of the corpus callosum, or cortical atrophy in a few patients. Three patients (27, 28, and 29) had a slightly milder phenotype, including 2 who had not developed seizures by age 4 years and 1 who had been seizure-free and was off medication at age 6. These 3 patients were able to achieve walking and a few words.

Clinical Management

Five patients with EIEE69 reported by Helbig et al. (2018) showed a favorable seizure response to treatment with topiramate, which blocks R-type calcium channels. However, topiramate had no effect on seizure control in 10 of 18 (56%) patients.

Molecular Genetics

In 30 unrelated patients with EIEE69, Helbig et al. (2018) identified 14 different de novo heterozygous missense mutations in the CACNA1E gene (see, e.g., 601013.0001-601013.0005). The variants, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, occurred throughout the gene, although most clustered in the cytoplasmic ends of S6 segment transmembrane domains that line the inner pore of the channel and form the activation gate. All mutations were classified as pathogenic according to ACMG guidelines, and none were found in the ExAC or gnomAD databases. There were several recurrent mutations. In vitro functional expression studies of some of the mutations in human tsA201 transformed kidney cells showed that they resulted in consistent gain-of-function effects, including facilitated voltage-dependent channel activation, slowed inactivation, and increased current density compared to wildtype. The findings indicated that the mutations perturb the gating properties of the channel, resulting in increased inward calcium currents that may affect neuronal excitability and synaptic transmission. Three additional patients (31, 32, and 33) with a milder neurologic phenotype were found to carry heterozygous frameshift or nonsense mutations in the CACNA1E gene that were predicted to result in a loss of function and haploinsufficiency. Functional studies of these variants were not performed. One of these patients inherited the mutation from an apparently unaffected father, another was somatic mosaic for the mutation, and parental DNA from the third was unavailable. Thus, the significance of these loss-of-function mutations was unclear. The patients were ascertained though international collaboration between research and diagnostic sequencing laboratories.