<scp> <i>CHD2</i> </scp> ‐related developmental and epileptic encephalopathy: A phenotypic mimic of progressive myoclonic epilepsy

A 10-year-old male, second born to non-consanguineously married parents, presented with a history of unknown-onset seizures followed by tonic–clonic movements associated with up-rolling of eyes and frothing at the mouth, with progression to bilateral tonic–clonic seizures lasting approximately 4–5 min for the past three years. The seizure frequency was about one episode every two months. For the past year, he was noted to have frequently dropped objects from his hands, suggestive of myoclonic jerks, which limited his activities of daily living (ADL). He also developed episodes of aggression towards siblings, self-injurious behavior, excessive talking, often with inappropriate language and laughter, and a decline in scholastic performance. On examination, he had a normal head circumference (53 cm), no neurocutaneous markers, normal tone, power, and deep tendon reflexes. The differentials considered were progressive myoclonic epilepsy (PME)—Lafora disease and neuronal ceroid lipofuscinosis, Wilson disease, and genetic epilepsies. On investigations, hemogram, renal, and liver function tests were normal. Ophthalmologic evaluation, including fundus and slit lamp examination, was normal. Interictal electroencephalogram (EEG) revealed normal background activity, with frequent generalized spike and polyspike and wave with frontal predominance and fixation-off sensitivity. There was an appearance of generalized spike and polyspike epileptiform discharge complexes with eye closure and opening; however, hyperventilation and photic stimulation remained normal (Figure 1). Magnetic resonance imaging (MRI) of the brain was normal. Skin biopsy didn't reveal any abnormalities. Whole exome sequencing revealed a pathogenic, autosomal dominant, heterozygous nonsense variant c.5035C>T(p.Arg1679Ter) in exon-38 of the CHD2 gene (chr15:g.93020140C>T; Depth:111x), resulting in a stop codon and premature truncation of protein at codon 1679, suggestive of developmental and epileptic encephalopathy-94 (DEE94). He was started on valproate at 40 mg/kg/day and Clobazam 5 mg twice daily. At one-year follow-up, he has been seizure-free for the past five months; however, behavior issues still persist but are improving. The child has been able to do most of the ADL on his own and attends school without difficulty. Developmental and epileptic encephalopathy-94 (DEE94; MIM#615369) is due to pathogenic variations in the CHD2 (chromodomain helicase DNA-binding) gene (MIM*602119) in chromosome 15q26.1.1 CHD2 gene encodes chromodomain helicase DNA-binding protein-2, which are a family of ATP-dependent chromatin remodeling proteins. These proteins are essential for the regulation of gene expression by involvement on chromatin structure reorganization, and deposition of histone variants.2 DEE94 is an early-onset DEE characterized by multiple seizure types, a varied range of neurodevelopmental disorders, photosensitivity, and fever sensitivity.3-6 The onset of photosensitivity was usually at ages <3 years of life.4 Other variable features reported were facial dysmorphism, microcephaly, kyphoscoliosis, motor impairments, and severe constipation.4-6 The commonly reported seizure types are generalized tonic–clonic seizures (GTCS), myoclonic jerks, and absence seizures.3, 4, 7 West syndrome, eyelid myoclonia has been reported rarely in association with this entity.3, 8 The mean age at seizure onset was 3.3 ± 2.7 years. In the index child, the age at onset of seizures was 7 years, while as late as 22 years of life has been reported as the age at onset in the literature.3 Based on the literature review on CHD2-related epilepsy, the predominant patients were on anti-seizure medication (ASM) monotherapy (50%), while polytherapy was noted in about 28% of patients. Valproate was the most commonly used ASM (81%).3 About 63% patients reported ‘effective’ (>50% reduction of episodes) control of seizures, and drug-resistant epilepsy has been noted too.9 Among the reported epileptiform abnormalities in the EEG, generalized, focal/multifocal, and mixed are the common subtypes.3, 4 Normal EEG has been noted in about 8% of patients, and non-epileptiform abnormalities have been reported in 19% of patients.3 Among the reported neurodevelopmental disorders, 95% had developmental delay (DD)/intellectual disability (ID), 45% had autism spectrum disorder (ASD), and 28% had attention-deficit/hyperactivity disorder (ADHD). Neuroimaging has been reported to be predominantly normal (80%).3 The common neuroimaging abnormalities noted are hypoplasia of the inferior vermis, cerebellar subarachnoid space enlargement, incomplete hippocampal rotation, and periventricular white matter reduction.4 The index child had normal neuroimaging. The variant c.5035C>T noted in the index child has previously been reported by Luo et al.10 The lack of formal, age-appropriate neuropsychological testing before and after treatment limited the ability to quantify cognitive impairment and any potential treatment effect in the index child. CHD2-related DEE94 can phenotypically mimic a progressive myoclonic epilepsy. Study Design, Writing, Editing, Drafting, Critical Revision, and Final Approval: Ashwini Chityala, Megha Patel, Pradeep Kumar Gunasekaran, Sarbesh Tiwari, Lokesh Saini. All authors approved the final version of the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The Authors declare that they have no conflict of interest to disclose. Written informed consent was obtained from the parents. No datasets were generated during the study. Data S1: Data S2: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Which of the following epilepsy syndromes is commonly associated with fixation-off sensitivity? A 9-year-old male child with a history of myoclonic seizures and generalized tonic–clonic seizures for three years, currently on two anti-seizure medications, is found on genetic testing to have developmental and epileptic encephalopathy (DEE) due to a CHD2 variant. Which of the following is the most characteristic feature of this condition? Which of the following is the most commonly encountered seizure semiology in developmental and epileptic encephalopathy (DEE) due to CHD2 mutation? Answers may be found in the Supporting information.