Portal de Periódicos da CAPES

Chromosome Abnormalities and Epilepsy

2001; Wiley; Volume: 42; Issue: s1 Linguagem: Inglês

10.1046/j.1528-1157.2001.00508.x

1528-1167

Maurizio Elia, S Musumeci, Raffaele Ferri, G.F. Ayala,

Genomic variations and chromosomal abnormalities

Chromosome abnormalities are often associated with central nervous system (CNS) malformations and with other neurologic dysfunctions. In particular, patients with chromosomal abnormalities can have mental retardation (MR) and have a higher risk for seizures than that found in the general population (1). Genetic tools such as karyotyping, high-resolution chromosome banding, fluorescent in situ hybridization (FISH), and other molecular genetics techniques have increased the number of chromosome abnormalities detected in subjects with MR or seizures. However, the majority of studies and reports published have usually considered sporadic cases or very small groups of patients with chromosome abnormalities. Furthermore, the characteristics of seizures and EEGs have been described in detail on very few occasions, to define the electroclinical phenotype, and eventually to classify the epilepsy. In recent years, a few identified chromosome abnormality syndromes seem to show a particular clinical and EEG picture; some of them are relatively common, such as Angelman's syndrome, the fragile-X (fra-X) syndrome, the Miller–Dieker syndrome; and others are more rare, such as trisomy 12p syndrome, the Wolf–Hirschhorn syndrome, and ring 20 syndrome. We review some clinical and neurophysiologic aspects of these syndromes that can support the neurologist in choosing the genetic analysis to be carried out, and help to identify specific genes influencing epileptogenesis. Angelman's syndrome (AS) is characterized by microcephaly, severe MR with absent speech, paroxysms of laughter, ataxic gait with jerky movements, and seizures. The estimated prevalence of AS is 1:62,000 (2). AS is a genetically heterogeneous condition. In ∼70% of cases, AS is caused by a de novo maternal deletion of chromosome 15q11-13; ∼2–3% of patients have a paternal uniparental disomy of chromosome 15; 2–5% of cases are caused by "imprinting mutations"(3). Recently, some de novo mutations in the E6-AP ubiquitin-protein ligase gene (UBE3A), mapped on the critical region for AS, have been found in some patients (mostly familial cases) with no other genetic changes (4). The UBE3A gene spans 120 kb and consists of 16 exons; most of the UBE3A mutations have been found in exon 9, which covers >50% of the coding region (5). Seizures occur mostly in infancy or early childhood and are polymorphous in AS, presenting as febrile convulsions, spasms, partial seizures, atypical absences, myoclonic absences, and recurrent episodes of "myoclonic status"(6,7). During wakefulness, the EEG is characterized by a slow background activity with focal or multifocal paroxysmal abnormalities predominant over the parietal–occipital regions. The ictal manifestations are characterized by brief bursts of diffuse slow spikes and waves, and by myoclonic jerks often rhythmic and bilateral, sometimes strictly related to the EEG discharges; in most cases, during drowsiness and sleep, paroxysmal discharges become more frequent (6). The deletion of the 15q11-13 region involves the GABRB3 gene, which codes for a γ-aminobutyric acid (GABA) subunit receptor. For this reason, cortical hyperexcitability might result from a reduction of the GABAergic inhibition. This seems to be suggested also by the murine model beta3−/−, which shows several behavioral and physiologic abnormalities typical of AS, such as hyperactivity, myoclonic body jerks, and generalized spike/waves in the EEG (8). Furthermore, it has been suggested that UBE3A gene mutations might play a specific role in the pathogenesis of AS, leading to premature stop codons in UBE3A mRNA, loss of function of the truncated protein, and then a failure in ubiquitination and degradation of some target proteins in the developing CNS (9). The fra-X syndrome, is the most common familial form of MR known, affecting an estimated 1:2,000 males. The demonstration of the fragile site at Xq27.3 region is dependent on the use of folate-deficient tissue-culture media. Many studies have identified the phenotype in fra-X syndrome including MR, macroorchidism, large and prominent ears, narrow face, and the signs related to a connective tissue dysplasia (10). More recently, molecular genetic studies demonstrated that fra-X syndrome results from a mutation in a (CGG)n repeat found in the coding sequence of the FMR-1 (fragile-X mental retardation) gene. Analysis of length variation in this region in normal individuals shows a range of allele sizes varying from a low of 6 to a high of 54 repeats. When ≥200 repeats are present, this phenomenon is associated with transcriptional silencing of the gene and is commonly referred to as the FMR-1 full mutation. The intermediate range of repeats (50–200) is referred to as the premutation. The risk of expansion during oogenesis to the full mutation with MR increases with the number of repeats (11). The FMR-1 gene codes for the FMR-1 protein, and its lack of expression in a functional form results in the fra-X syndrome (12). The majority of young fra-X patients have a characteristic EEG pattern of paroxysmal discharges resembling those usually observed in the benign childhood epilepsy with centrotemporal spikes. In a recent retrospective and prospective study on 193 patients with fra-X syndrome, this EEG pattern was found in 43.5 and 48%, at all ages, and between 50.3 and 52% in patients younger than 12 years. Spikes tended to disappear in adulthood, and if present, they were usually nonspecific, rare, and localized over one scalp location. The prevalence of seizures in the two groups of fra-X subjects was between 17 and 29.2%, depending on the referral bias of specific clinics. The age at onset of seizures was between 2 and 9 years. Complex partial seizures predominated (>85%), in respect to other types of seizures, such as generalized tonic–clonic seizures and partial motor seizures. Seizures involving the frontal and temporal lobes were commonly seen, and they were usually well controlled by anticonvulsants (13). Cortical hyperexcitability in fra-X syndrome seems to be demonstrated by the presence of spikes in the EEGs of subjects without seizures, the presence of spikes evoked by finger tapping (14), the presence of giant somatosensory evoked potentials (15), and the increased susceptibility to audiogenic seizures present in fra-X knock-out mice at different ages (16). The gross anatomy and histology of the fra-X brain appears almost normal, and the most notable neuropathologic findings are abnormally long and thin cortical dendrites and abnormal dendrite spine morphology (17). In addition, magnetic resonance imaging (MRI) structural abnormalities such as abnormally enlarged hippocampal volumes have been found in FMR-1 full-mutated patients by Reiss et al. (18). Increase in dendritic branching has been detected in the knock-out fra-X mice (19). FMR1 protein might play a key role in determining cortical hyperexcitability and seizures in fra-X syndrome, and future genetic and biochemical studies will certainly cast new light on this topic. The Miller-Dieker syndrome (MDS) is characterized by a type I or classic lissencephaly resulting from a migrational arrest between weeks 12 and 16 of gestation; the cortex has four instead of six layers (i.e., marginal, superficial cellular, cell sparse, and deep cellular layers). The prevalence of type I lissencephaly has been estimated at 11.7 per million births. Patients with MDS have profound MR, mixed hypotonia and spasticity, epilepsy, facial abnormalities such as prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border of the upper lip, and small jaw. In isolated lissencephaly sequence (ILS), neuropathology is more variable, and the clinical picture is similar to that of MDS, although the dysmorphic facial appearance is uncommon (20). In lissencephaly, before age 1 year, the EEG is characterized by unusual high-amplitude fast rhythms, which may alternate with high-amplitude theta and delta rhythms resembling hypsarrhythmia. Seizures occur commonly in the first months of life, and they are in form of partial, myoclonic, and tonic seizures, or spasms (21). FISH shows deletions of chromosome 17p13.3 in 92% of patients with MDS, and in 44% of subjects with ILS (22). The LIS1 (lissencephaly 1) gene, mapping to 17p13.3 and encoding the beta subunit of platelet-activating factor acetylhydrolase (PAFAH) isoform Ib, an inactivating enzyme for platelet-activating factor (PAF), is considered to cause MDS and ILS (23). Recently it was shown that PAFAH-Ib interacts with tubulin; this factor seems indirectly to influence neuronal activity and might have implications in the impairment of neuronal migration observed in lissencephaly (24). An animal model of lissencephaly is now available, the LIS± mouse, which has many neuropathologic, neurophysiologic, and behavioral features similar to those observed in humans (25). Trisomy 12p can be caused by a malsegregation of a maternal translocation or by a de novo occurrence; 32 cases have been reported (1). In most cases of trisomy 12p, EEG and clinical characteristics of seizures have not been described in detail, but in three patients, the EEG showed 3-Hz generalized spike-and-wave discharges (26). One of these subjects and another described later had childhood myoclonic absences, which were of short duration and apparently well controlled by antiepileptic drugs (AEDs). Abnormal expression of genes codifying for the subfamily of K+ channels, located on chromosome 12p, could be responsible for seizures and the EEG abnormalities (27). The Wolf–Hirschhorn syndrome (WHS) or 4p- results usually from a de novo deletion and only rarely from a translocation. More than 120 cases have been described. The phenotype is characterized by facial dysmorphic features, microcephaly, hypertelorism, epicanthic folds, cleft lip or cleft palate, severe MR, and marked growth retardation. Seizures are frequent, mostly beginning between ages 6 months and 1 year; they are myoclonic seizures, simple partial seizures, atypical absences with eyelid myoclonias, eye deviation or mouth jerks, and status epilepticus. On the EEG, central–parietal sharp waves, atypical high-voltage spike-and-wave complexes enhanced by eye closure, spike-and-wave discharges, and frequent segmental myoclonic jerks are evident (28). Defects in GABAA-receptor function may play a role, in fact the GABAA alpha2 and beta subunit genes are located on the 4p12-13 region; recently, a novel gene, WHSC2, mapping in this region, has been identified and characterized (29). The ring 20 syndrome has been reported in 33 mostly sporadic, or mosaic cases. Patients with ring 20 syndrome have MR of variable degree, absence of gross dysmorphic features, and rare heart or urogenital anomalies. Seizures are present in 90% of cases (30). They begin between ages 1 month and 21 years and are mostly complex partial seizures or partial seizures with secondary generalization. A peculiar nonconvulsive status epilepticus, often at the onset of seizures, occurs in many cases, with a daily or weekly frequency, and lasting 10–50 min. Interictal EEG shows slow waves, spikes, sharp waves, or spike-and-wave complexes over the frontal regions; the ictal EEG is characterized by long runs of slow waves intermixed with high-voltage spikes, which are diffuse, are prominent over the frontal regions, changing in frequency during the discharges (31,32). Bursts of 5-Hz theta waves, occurring over both temporal regions, without apparent clinical manifestations, have been reported in ring 20 syndrome (33). Evidence of frontal lobe dysplasias has been reported. The physiopathology of epilepsy in the ring 20 syndrome is not clearly understood, although it is known that the gene of the autosomal dominant nocturnal frontal epilepsy (CHRNA4) maps to the 20q13.2-q13.3 region (31). The number of chromosome abnormalities associated with a particular electroclinical pattern is still limited. Our brief review shows that the EEG features can strongly support the diagnostic workup in chromosome disorders. In the near future, a detailed study of many additional syndromes due to chromosome abnormalities is needed to identify additional EEG and clinical patterns. This might provide information on the role of already known or still unknown genes involved in the susceptibility to develop seizures, but also might help us to increase our knowledge of the outcome of epilepsy associated with a specific chromosome abnormality, and then to improve care.