Rearrangements of chromosome 15 in epilepsy

Abstract

A number of observations point to chromosome 15 as a good candidate to harbor genes involved in epilepsy. This hypothesis is supported by at least two lines of evidence: one is the finding that haploinsufficiency of the 15q11-q13 region, of maternal origin, is responsible for Angelman syndrome, one of the cardinal manifestations of which is epilepsy; the second is the observation that extra copies of this same genomic region, in the form of inv-dup(15) or intrachromosomal duplications, again of maternal origin, are usually associated with a severe neurological phenotype characterized by developmental delay and untreatable seizures. Therefore, both reduced and increased dosage of genes from the 15q11-q13 region, possibly subjected to maternal imprinting, appear to be causally involved in severe forms of epilepsy. We tested the hypothesis that submicroscopic rearrangements of this genomic region might be responsible for nonsyndromic epilepsy in both familial and sporadic forms. To this purpose, we genotyped 118 epileptic patients and their parents with closely spaced microsatellite markers mapped within the 15q11-q13 region. We report on the results of these studies and review the relevant literature.

A survey of seizures and current treatments in 15q duplication syndrome

“…This seizure rate is similar to that reported in the autistic spectrum population in general, 37 and much lower than seizure rates reported in those with idic(15). 6,8,31,32 This, however, may be artificially inflated by response bias, since parents of children with seizures may be more likely to respond to a seizure survey than parents of children with no seizures. It is also possible that families of children with more severe epilepsy might have been more likely to respond.…”

“…4 Maternal duplications of this region are the most commonly identified genetic cause of autism, 5 with prevalence estimates in autism ranging from 0.5% to 3%. 3 Multiple genes from this region are implicated in the pathogenesis of autism spectrum disorders, epilepsy, and schizophrenia, 2,[6][7][8] and numerous studies implicate UBE3A as the causative gene resulting in impaired cognitive function in AS. 9 These results suggest that altered function of UBE3A through underexpression (AS) or overexpression (idic (15) or int dup (15)) impairs neurocognitive development.…”

“…18,19 Studies of the PWACR in idic(15) suggest an effect of both dose-dependent gene expression of the GABA A -receptor subunits and the size of the duplication. 6,[20][21][22][23] The X-linked gene, MeCP2, encodes the methyl CpG binding protein 2 (MeCP2), which binds to sites in the imprinting control region (PWACR) as well as intermittent binding along the 15q11.2-q13 region, perhaps isolating functional domains of imprinted regions for expression. 24 Some studies showed that MeCP2 deficiency is associated with impaired expression of both UBE3A and GAB-RB3, 15,16,25 thus linking Rett, Angelman, and Dup15q syndromes at the molecular level.…”

“…6,8,31,32 Infantile spasms are associated with maternally inherited duplications of 15q11-q13, suggesting a role for GABAergic synapses and postsynaptic density in the etiology of Dup15q seizure semiology. 33 Idic (15) is characterized by developmental delay, severe epilepsy, moderate-to-severe intellectual disability, early central hypotonia, autistic behavior, absent or poor language (e.g., marked echolalia), and minor dysmorphic features (e.g., down-slanting palpebral fissures, epicanthal folds, low-set ears, "coarse" facial features, and hypopigmented areas of the skin).…”

Management of Prader-Willi Syndrome

“…104,133,170 On the other hand, epilepsy is a well-characterized feature of Angelman syndrome 79 and is also associated with other chromosome 15q11-q13 defects, including interstitial duplications of maternal origin within the imprinted region. 46,205,208,233 A recent study of children referred from general pediatrics and neurology clinics reported a history of febrile seizures in 18 of 40 individuals (45%) with PWS and deletion, as compared with 1 of 14 patients (7%) with maternal uniparental disomy. 219 The same group reported seizures in 42 of 47 patients (89%) with Angelman syndrome and deletion, as compared with 4 of 9 patients (44%) with paternal uniparental disomy.…”