A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-69 (DEE69) is caused by heterozygous mutation in the CACNA1E gene (601013) on chromosome 1q25.

Developmental and epileptic encephalopathy-69 (DEE69) 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 DEE, see 308350.

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 Variability

Royer-Bertrand et al. (2021) described 7 patients, aged 18 months to 31 years, with de novo mutations in the CACNA1E gene, only one of whom (patient 4) had seizures (infantile spasms), which began at 6.5 months of age and responded to topiramate. Of 3 other patients tested, 2 had an abnormal EEG and 1 was normal. All 7 patients had global developmental delay and/or intellectual disability. Four patients showed developmental regression and 3 showed motor stereotypies. Symptom onset/parental concern was shortly after birth to 24 months of age.

The heterozygous mutations in the CACNA1E gene identified in patients with DEE69 by Helbig et al. (2018) occurred de novo.

Five patients with DEE69 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.

In 30 unrelated patients with DEE69, 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.

Royer-Bertrand et al. (2021) described 7 patients, aged 18 months to 31 years, with de novo heterozygous mutations in the CACNA1E gene, including 6 missense and 1 splicing. None of the mutations were found in the gnomAD database. No functional evidence was provided for any of the mutations, but codon 702 appeared to be a hotspot. The only patient (patient 4) who had seizures (infantile spasms) had an ala702-to-ser substitution (601013.0006).