Generalized Epilepsy and Myoclonic Seizures in 22q11.2 Deletion Syndrome

Abstract

Prompted by the observations of juvenile myoclonic epilepsy (JME) in 22q11.2 deletion syndrome (22q11DS) and recurrent copy number variants in genetic generalized epilepsy (GGE), we searched for further evidence supporting a possible correlation of 22q11DS with GGE and with myoclonic seizures. Through routine diagnostics, we identified 3 novel individuals with the seemingly uncommon combination of 22q11DS and JME. We subsequently screened the literature for reports focussing on the epilepsy phenotype in 22q11DS. We additionally screened a database of 173 22q11DS patients and identified a fourth individual with JME as well as 2 additional cases with GGE. We describe 6 novel and 22 published cases with co-occurrence of 22q11DS and GGE. In many patients, GGE was associated with myoclonic seizures allowing for a diagnosis of JME in at least 6 individuals. Seventeen of the 173 22q11DS cases (10%) had a diagnosis of either focal or generalized epilepsy. In these cases, focal epilepsy could often be attributed to syndrome-associated hypocalcaemia, cerebral bleeds, or structural brain anomalies. However, the cause of GGE remained unclear. In this study, we describe and review 28 individuals with 22q11DS and GGE (especially JME), showing that both disorders frequently co-occur. Compared to the reported prevalence of 15-21%, in our case series only 10% of 22q11DS individuals were found to have epilepsy, often GGE. Since 22q11.2 does not contain convincing GGE candidate genes, we discuss the possibility of an aetiological correlation through a possibly disturbed interaction with the GABA_B receptor.

<b><i>TOP3B</i></b>: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy?

“…Frequently, both gain and loss variations are found and associated with severe phenotypes including neurological conditions such as seizures, intellectual disability, and cerebral malformations. 22q11.2 microdeletion/duplication syndrome is strongly associated with neurological and psychiatric disorders such as autism, bipolar disorder, schizophrenia, intellectual disability, and epilepsy [Kao et al, 2004;Robin et al, 2006;Lemke et al, 2009;Karayiorgou et al, 2010;Stoll et al, 2013;Kim et al, 2016;Strehlow et al, 2016;Wenger et al, 2016]. The TOP3B gene encodes a topoisomerase DNA (III) β protein.…”

Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders

“…The deletion increases the risk of acute symptomatic and unprovoked epileptic seizures, although the reported rates are wide‐ranging. Between 1% and 14.5% of patients have hypocalcemia‐induced seizures . In adulthood, 17.6% of patients with 22q11.2DS exposed to psychotropic drugs have epileptic seizures, suggesting a reduced seizure threshold .…”

“…In adulthood, 17.6% of patients with 22q11.2DS exposed to psychotropic drugs have epileptic seizures, suggesting a reduced seizure threshold . Between 4.4% and 36.8% have repeated unprovoked seizures (ie, epilepsy) . Structural brain abnormalities in these individuals can include diffuse cerebral atrophy (18.8%), polymicrogyria (13.9%), hippocampal malrotation (10.9%), gray and white matter heterotopia (5.9%), and focal cortical dysplasia (2%) .…”

“…Structural brain abnormalities in these individuals can include diffuse cerebral atrophy (18.8%), polymicrogyria (13.9%), hippocampal malrotation (10.9%), gray and white matter heterotopia (5.9%), and focal cortical dysplasia (2%) . Between 1% and 6.9% of patients have genetic generalized epilepsy (GGE), and the deletion prevalence is elevated in GGE cohorts …”

A Case of 22q11 Deletion Syndrome (22q11DS) with a Panayiotopoulos Epileptic Pattern: Are Additional Copy-Number Variations a Possible Second Hit in Modulating the 22q11DS Phenotype?

“…In the literature, the epileptic seizure incidence is estimated from about 10% (5) to 21% (6). In a recent article, the incidence of epilepsy in a cohort of 145 22q11DS children was reported to be 15.2%; excluding patients with “structural epilepsy” (CNS abnormalities), the prevalence of “genetic epilepsy” is 8.3% (2).…”