Alternative titles; symbolsEPILEPTIC ENCEPHALOPATHY, CHILDHOOD-ONSET; EEOC▼ TEXTA number sign (#) is used with this entry because of evidence that developmental ...
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-94 (DEE94) is caused by heterozygous mutation in the CHD2 gene (602119) on chromosome 15q26.
Developmental and epileptic encephalopathy-94 (DEE94) is a severe form of epilepsy characterized by onset of multiple seizure types in the first few years of life and associated with poor prognosis. Affected individuals have cognitive regression and impaired intellectual development (summary by Carvill et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
▼ Clinical Features
Rauch et al. (2012) reported a German girl (MS134) with childhood-onset epileptic encephalopathy. She had delayed psychomotor development with an IQ of 50-69 and onset of absence seizures at age 5 years.
Carvill et al. (2013) reported 6 unrelated patients with childhood-onset epileptic encephalopathy. The median age of seizure onset was 18 months (range, 1-3 years). All patients had myoclonic seizures in addition to variable seizure types, including absence, atonic, tonic, tonic-clonic, febrile, and status epilepticus. EEG studies showed multiple abnormalities. Four patients had developmental delay before the onset of seizures, 5 showed developmental regression after the onset of seizures, 3 had photosensitivity, and all had moderate to severe intellectual disability. One patient was diagnosed with autism spectrum disorder. The patients ranged in age from 2.5 to 29 years.
Suls et al. (2013) reported 3 unrelated patients with onset of seizures associated with fever between the ages of 14 months and 3.5 years. All subsequently developed multiple seizure types, including myoclonic, atypical absence, generalized tonic-clonic, and status epilepticus, that were mostly therapy-resistant. EEG studies showed generalized polyspike-wave discharges. Two patients had normal development before the onset of seizures, whereas 1 patient had mildly delayed development before seizure onset. All had mild but persistent intellectual and neurologic impairment, including autism spectrum disorder in 1 patient.
Petersen et al. (2018) reported a 5-year-old girl with global developmental delay, microcephaly, and seizures. Developmental delay was first noted at age 12 months, with delays in cognitive adaptive, clinical linguistic and auditory, and gross motor areas. Seizures began at age 13 months in the context of a febrile illness and developed into medical refractory cryptogenic generalized epilepsy by age 2 years. She also had a diagnosis of attention deficit-hyperactivity disorder (ADHD). Her mother had a history of infantile meningitis, bipolar disorder, ADHD, language delays, and dyslexia. She had seizures that started at age 5 years and were well controlled. Her development was reportedly normal, and she completed high school in mainstream classes without difficulty.
The heterozygous mutations in the CHD2 gene in the patients with DEE94 reported by Rauch et al. (2012), Carvill et al. (2013), and Suls et al. (2013) occurred de novo.
Petersen et al. (2018) identified a heterozygous mutation in the CHD2 gene in a proband with DEE94 who inherited the mutation from her mildly affected mother.
▼ Molecular Genetics
In a German girl (MS134) with DEE94, Rauch et al. (2012) identified a de novo heterozygous truncating mutation in the CHD2 gene (602119.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in either parent. The patient was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing. Rauch et al. (2012) postulated haploinsufficiency as the disease mechanism.
In 6 unrelated patients with developmental and epileptic encephalopathy, Carvill et al. (2013) identified 6 different de novo heterozygous mutations in the CHD2 gene (see, e.g., 602119.0002-602119.0006). Four of the mutations were truncating, and 2 were missense substitutions at highly conserved residues. The mutations were found by targeted sequencing of known or candidate genes in 500 individuals with epileptic encephalopathies and thus accounted for 1.2% of cases. Carvill et al. (2013) postulated haploinsufficiency as the disease mechanism. They noted that mutations in the related CHD7 gene (608892) cause developmental abnormalities.
In 3 unrelated patients with developmental and epileptic encephalopathy, Suls et al. (2013) identified 3 different de novo heterozygous mutations in the CHD2 gene (602119.0007-602119.0009). The mutations in the first 2 patients were found by whole-exome sequencing of 9 probands with a similar disorder. The third patient was identified by sequencing of the CHD2 gene in 150 probands with epileptic encephalopathy. Suls et al. (2013) postulated that haploinsufficiency for CHD2 was responsible for the phenotype, and suggested that helicase dysfunction in humans may result in neuronal hyperexcitability in the absence of dysmorphic features.
In a 5-year-old proband with DEE94 and her mildly affected mother, Petersen et al. (2018) identified a heterozygous nonsense mutation in the CHD2 gene (E210X; 602119.0010). The authors noted that this was the first known case of an inherited autosomal dominant pathogenic CHD2 variant in a clinically affected mother and daughter, and emphasized the importance of parental testing before providing recurrence risk estimates.
▼ Animal Model
Suls et al. (2013) found that morpholino knockdown of Chd2 in zebrafish resulted in multiple developmental abnormalities, including pericardial edema, microcephaly, body curvature, absent swim bladder, and stunted growth. Mutant zebrafish larvae also showed abnormal movement patterns, such as twitching and trembling, associated with epileptiform discharges.