Chromosomal Abnormalities and Epilepsy: A Review for Clinicians and Gene Hunters

Authors

  • Rita Singh,

    1. Department of Medicine (Neurology), The University of Melbourne, Austin and Repatriation Medical Centre;
    2. Department of Neurology, Royal Children's Hospital;
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  • R. J. McKinlay Gardner,

    1. Murdoch Children's Research Institute, Royal Children's Hospital; and
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  • Kathryn M. Crossland,

    1. Department of Medicine (Neurology), The University of Melbourne, Austin and Repatriation Medical Centre;
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  • Ingrid E. Scheffer,

    1. Department of Medicine (Neurology), The University of Melbourne, Austin and Repatriation Medical Centre;
    2. Department of Neurology, Royal Children's Hospital;
    3. Department of Neurosciences, Monash Medical Centre, Melbourne, Australia
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  • Samuel F. Berkovic

    1. Department of Medicine (Neurology), The University of Melbourne, Austin and Repatriation Medical Centre;
    2. Department of Neurology, Royal Children's Hospital;
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Address correspondence and reprint requests to Dr. S. F. Berkovic at Department of Neurology, Austin and Repatriation Medical Centre, Heidelberg, Melbourne, Vic. 3084, Australia. E-mail: s.berkovic@unimelb.edu.au

Abstract

Summary:  Purpose: We analyzed databases on chromosomal anomalies and epilepsy to identify chromosomal regions where abnormalities are associated with clinically recognizable epilepsy syndromes. The expectation was that these regions could then be offered as targets in the search for epilepsy genes.

Methods: The cytogenetic program of the Oxford Medical Database, and the PubMed database were used to identify chromosomal aberrations associated with seizures and/or EEG abnormalities. The literature on selected small anomalies thus identified was reviewed from a clinical and electroencephalographic viewpoint, to classify the seizures and syndromes according to the current International League Against Epilepsy (ILAE) classification.

Results: There were 400 different chromosomal imbalances described with seizures or EEG abnormalities. Eight chromosomal disorders had a high association with epilepsy. These comprised: the Wolf–Hirschhorn (4p-) syndrome, Miller–Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20. Many other segments had a weaker association with seizures. The poor quality of description of the epileptology in many reports thwarted an attempt to make precise karyotype–phenotype correlations.

Conclusions: We identified certain chromosomal regions where aberrations had an evident association with seizures, and these regions may be useful targets for gene hunters. New correlations with specific epilepsy syndromes were not revealed. Clinicians should continue to search for small chromosomal abnormalities associated with specific epilepsy syndromes that could provide important clues for finding epilepsy genes, and the epileptology should be rigorously characterized.

Chromosomal abnormalities have provided important clues in the mapping of a number of genes, including some of particular interest to the neurologist. For example, a translocation with one breakpoint on the long arm of chromosome 17 in an individual with neurofibromatosis-1 provided an entrée to cloning the NF-1 gene (1). More commonly, “deletion mapping” has been applied to the task of gene identification. An important example was the gene for Duchenne muscular dystrophy, which was discovered through study of a patient with concomitant muscular dystrophy, McLeod syndrome, and chronic granulomatous disease due to an X chromosome deletion that had removed a set of contiguous genes (2). Riazi et al. (3) followed a case of duplication involving a region in chromosome 3 to identify a candidate epilepsy gene located within bands 3q26.3-q27, the gene KNMB3. However, despite the increasing interest in the genetics of epilepsy, little attention has been paid to cytogenetics as a resource to identify putative epilepsy genes. We attempted to redress the balance.

Chromosomal syndromes can be broadly grouped as follows: duplication syndromes, with an additional segment of chromosome material; deletion syndromes, in which a segment is lacking; and breakpoint disruption syndromes, in which only one or a few genes may be mutated. There are more recorded deletion than duplication syndromes. Both cause an abnormal phenotype due to a dosage effect resulting from the removal or addition of normal genetic sequences. The expression “haplo-insufficiency” refers to the functional effect of having only a single dosage of the genes in the remaining intact chromosome, corresponding to the deleted segment. “Triplo-excess” could be used to describe the opposite, a triple dose of genes due to a duplication.

Duplications or deletions of large amounts of chromosome usually have such a drastic effect on prenatal development that the pregnancy aborts. A well-known exception is Down syndrome, in which duplication of an entire chromosome, albeit a small one (trisomy 21) causes a well-recognized phenotype. Smaller aberrations are more often compatible with postnatal survival. The majority of “classic” deletion syndromes have a phenotype of severe intellectual disability and physical malformation. With the development of finer cytogenetic methods, smaller deletions (“microdeletions”) associated with milder phenotypes are being discovered. Some may be recognizable clinically by those skilled in dysmorphology, but the majority are identified only after chromosomal analysis done as a screening investigation (4). To maintain a manageable perspective in terms of identifying candidate segments, we have chosen, for the most part, to list only smaller duplications and deletions, which we define as those no greater than ∼0.5% of the haploid autosomal length (HAL), or about three to five bands at the 850-band level of precision (5). One band can contain, on average, ∼60 genes, but there is wide variation, with gene-dense and gene-sparse chromosomal regions. By way of illustration, chromosome 21, which is gene-sparse, composes 1.9% of HAL, has 10 recognized bands in its long arm, and contains only 225 genes. Some larger regions also were noted, when a particular aggregation of cases with epilepsy was recorded. Deletions that remove only a single gene and that are not detectable by standard cytogenetic screening, such as pressure-sensitive neuropathy caused by deletion of the peripheral myelin protein gene on chromosome 17, are not reviewed here.

Few chromosomal syndromes specifically associated with epilepsy are widely recognized by neurologists. Pediatric neurologists order cytogenetic studies when faced with an intellectually disabled and dysmorphic child, usually without a particular syndrome in mind. Chromosomal studies are rarely part of the workup in adult epilepsy clinics. Indeed, in an otherwise physically and intellectually normal person, a chromosomal abnormality would be an unlikely finding. However, among patients with epilepsy and intellectual disability, ∼6% have chromosomal abnormalities, and this figure climbs to 50% in patients with seizures and multiple congenital abnormalities (6,7). Epilepsy syndromes including West syndrome and Lennox–Gastaut syndrome can be recognized in such populations.

Here we attempt to catalogue the epilepsies associated with chromosomal abnormalities and to classify the specific epilepsy syndromes. The aim of this survey has been to discover if there might be, in the literature, cytogenetic clues to the existence of specific epilepsy genes. Increasing numbers of genes with known or unknown functions are being identified and localized as part of the Human Genome Project, and if clinical epileptologists can associate specific epilepsy syndromes with particular chromosomal regions, candidate epilepsy genes could be pursued.

METHODS

The Cytogenetics program of the Oxford Medical Database published in 1994 (4) was examined by using selection criteria of seizures/epilepsy/abnormal EEG, and the PubMed database perused up to December 2000. Each chromosomal imbalance was then scrutinized, and only small aberrations, as defined earlier, were selected for detailed review. An exception was made for larger imbalances when there was an impressive association with seizures. Down syndrome and trisomy of 9p were included, but rarer trisomies were not. Complex chromosomal rearrangements were excluded, as we could not determine which chromosomal segment might have contributed to which component of the phenotype. Once selection had been made from the databases and the source literature reviewed, phenotypic features were analyzed.

Cytogenetic nomenclature

We have used the standard cytogenetic nomenclature (4). The important abbreviations are few. Del and dup refer to deletion and duplication, respectively. The short arm of the chromosome is denoted by p, and the long arm by q. The distal extremity of a chromosome arm is ter (terminal). The segment of a chromosome is indicated by its two- or three-digit band designation (Fig. 1). Thus an interstitial deletion extending from band 13.3 to band 22.3 on the short arm of chromosome 1 is written del(1)(p13.3->p22.3). A terminal deletion with the breakpoint at band 42 in the long arm of chromosome 1 is written as del(1)(q42->qter). A minus sign is a shorter designation of a deletion (e.g., 4p- means a deletion of the short arm of chromosome 4). Ring chromosomes form from an end-to-end fusion of the short and long arms of a chromosome, and there may or may not be loss of actual genetic material; they are denoted r, as in r(1) for a ring chromosome 1. If the parental origin of an abnormal chromosome must be indicated, mat (maternal) or pat (paternal) follows the description.

Figure 1.

Some chromosome regions associated with seizures. The eight most commonly identified lesions [Wolf–Hirschhorn (4p-) syndrome, Miller–Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20] are shown with some additional rarer abnormalities. The solid bars show regions involved; for chromosome 7q, many different overlapping deletions were described, as indicated by the dotted line.

Clinical analysis

The literature on the different seizure types associated with chromosomal disorders was reviewed critically with regard to the clinical and EEG details provided. An attempt was made to classify the seizures and syndromes best according to the current International League Against Epilepsy (ILAE) classification (8). However, many reports were brief to the point of being cryptic, and sometimes had only the one word “epilepsy.” Nevertheless, we have included all such cases. Most reports described associated neurologic, dysmorphic, and other clinical features. These are not listed in detail here unless the clinical findings are thought to be relatively specific. Intellectual disability and dysmorphic features were common to all chromosomal aberrations unless otherwise stated.

RESULTS

Search of the Oxford Medical Database and of the PubMed database to December 2000 revealed 424 chromosomal imbalances associated “significantly” with seizures and/or EEG abnormalities. Because the denominators were often not known, an assessment of the degree of association in many instances had to be made as a judgment, rather than a definite measurement. Of these, 385 were discarded as they were large or highly complex anomalies. The remaining 39 imbalances were distributed on 11 autosomes and the X chromosome. Figure 1 shows the regions of the more common imbalances listed.

Chromosome 1

Deletion of the long arm of chromosome 1, del(1)(qter->q42 or q43)

The most common chromosome 1 anomaly is at the distal end of the long arm (q42 or q43). Forty cases have been reported (9,10).

Epileptology. Seizures or possible seizures were reported in 21 of 40 cases. Seizures usually began in the first 3 years of life. Ten cases were described as generalized seizures (10–19); six as febrile seizures alone (10,14,20–22); three as febrile seizures before afebrile (9,10); four as complex partial seizures (9,10); and another three were not well defined (9,23,24). The seizures were often easily controlled, but the long-term outcome of epilepsy was not described. The only adult described had blackouts with fever from age 3 to 8 years and paroxysmal laughter, but the epileptic nature of these attacks was not established (14). EEG results were described in 16 cases with seizures (9,11,13,14,19–21,23). Three cases with febrile convulsions had a normal EEG (10,20,21), and one had focal discharges (14); four with complex partial epilepsy had multifocal and three had bilateral central epileptiform discharges, respectively (9,10). Vaughn (10) described two cases with partial seizures and centrotemporal spikes on EEG, which were age related and morphologically similar to rolandic spikes. One case with unclassified seizures after febrile seizures had a normal EEG (9). Two cases (11,13) with generalized epilepsy had generalized epileptiform abnormalities on EEG. Villa et al. (25) described a single case with 1q44 deletion and febrile seizures with EEG showing a slow background. This would perhaps narrow the area of cytogenetic interest.

Other features. Microcephaly, severe mental retardation, high-pitched shrill cry, abnormal posturing, and autonomic features were common (9,16). Eleven of 40 cases had agenesis of the corpus callosum (9,10,13,14,17,19,26–28).

Deletion of the short arm of chromosome 1, del(1)(p36->pter), del(1)(p36.3)

The recently delineated del(1)(p36) syndrome has seizures as a major component of the phenotype. In some, the deletion is interstitial, encompassing only band p36.3. Seizures are recorded in 17(74%) of 23 cases, including simple, complex partial, myoclonic, generalized tonic–clonic seizures, and infantile spasms (29–31).

Other chromosome 1 anomalies

Other deletions of the short arm of chromosome 1 such as del(1)(p22->p31) and del(1)(p13.3->p22.3) are rare (32). Seizures were reported in only two of eight cases of interstitial deletions (33,34), one with generalized seizures and a normal EEG (34), and in the other, seizures were described with a left temporal focus (33). Seizures and an abnormal EEG also have been described in four cases of complex rearrangements of chromosome 1 with other chromosomes including 13 (35), 15 (36), 11, 13, and 21 (37). Rasmussen et al. (38) did not describe seizures in a review of 48 cases of partial duplication of the distal portion of chromosome 1q.

Chromosome 2

Deletion of the short arm of chromosome 2, del(2)(p24->pter) and del(2)(p23->p25)

Epileptology. There are isolated reports of deletions on 2p, and most are interstitial deletions. A rare case of terminal deletion was reported to have febrile seizures with focal epileptiform discharges (39). There were three cases with interstitial deletions on chromosome 2p with seizures (40–42). Seizure onset varied from 6 months to 2 years, and in one case, seizures ceased at 12 years. One male infant had a therapy-responsive myoclonic epilepsy, with myoclonic jerks of the upper limbs and head beginning at age 6 months and a single generalized febrile seizure associated with generalized spike–wave discharges on EEG (42). Seizures were not further described in the remaining cases (40,41).

Other features. Microcephaly, severe developmental delay, and a superficial facial resemblance to Down syndrome were present (39).

Other chromosome 2 anomalies

There were isolated reports of deletions of the long arm of chromosome 2, which involved large segments. Seizures were not a prominent feature (43,44). Interstitial deletions of 2q31q33 were associated with seizures in six of nine cases (45–49); however, details were limited. On an adjacent segment of 2q, McMilin et al. (50) reported deletions encompassing q22.3q31, in which two of the four cases had seizures of heterogeneous types. The region in common, 2q31, thus suggests itself as a region of interest. Duplication syndromes often involved large segments, and seizures were infrequent.

Chromosome 3

Deletion of the Short Arm of Chromosome 3, del(3)(pter->p25)

Deletions of the short arm of chromosome 3 are rare, and three are associated with epilepsy (51). Only one, del(3)(pter->p25), is reviewed, as the other two were either too large or complex.

Epileptology. Seizures with fever were described in three of 20 cases (51–54). The EEG in one case showed diffuse background slowing with multifocal spikes (54).

Other features. Mental retardation was severe (55).

Other chromosome 3 anomalies

Epilepsy was rare in deletions of the long arm of chromosome 3 (56), translocation, complex rearrangements, and duplication syndromes. Riazi et al. (3) described “grand mal” seizures in duplication of (3)(q26.3->q27) in two of three cousins, hypothesizing the molecular basis as a Ca-activated potassium channel gene.

Chromosome 4

Deletion of the Short Arm of Chromosome 4, del(4)(pter->p15&p16)

The 4p deletion syndrome (Wolf–Hirschhorn Syndrome, WHS) is well known and is strongly associated with epilepsy. Seizures (febrile and “grand mal”) are seen in cases with the deletion confined to band 4p16.3 (57,58), which may suggest a focus of interest. More than 120 cases of WHS have been reported (59). The clinical severity correlates with the extent of the deletion (60).

Epileptology. Most cases have refractory epilepsy that begins at ages between 6 and 24 months (61–65). The seizure types include generalized tonic–clonic seizures (GTCSs) (63–65), tonic spasms (63), myoclonic seizures, atypical absences associated with eyelid myoclonia, eye deviation and mouth jerks, partial motor seizures (59), and complex partial seizures (63). The EEG was described in detail by Sgro et al. (59), who found sequences of sharp-wave transients on a background of diffuse, high-voltage 3- to 4-Hz slow-wave discharges prominent over the biparietal and frontal regions and activated by eye closure.

Other features. The classic craniofacial anomalies are microcephaly, ocular hypertelorism with a “Greek helmet” appearance, epicanthic folds, and cleft lip or cleft palate (66). Mental retardation is severe, and most cases die in early childhood, with survival to adulthood being exceptional (67,68).

Deletion of the Long Arm of Chromosome 4, del(4)(q12->q22) and del(4)(q25->q27)

Two cases of del(4)(q25->q27) had neonatal seizures (69,70). Nitrazepam-responsive extensor spasms were described in a 9-month-old infant with del(4)(q13->q22) (71). Seizures have been described in two cases with del(4)(q12->q21) (72,73); in one case, seizures beginning at age 1 year were associated with right occipital sharp waves (72). The best-studied anomaly of 4q is a deletion of the terminal segment, in which seizures are rare (74).

Chromosome 5

There were no deletion or duplication syndromes associated with epilepsy on the short arm of chromosome 5. Seizures are not a feature of the well-known “cri du chat” (5p deletion) syndrome, nor with chromosome 5 rings (75,76) or duplications (77,78).

Chromosome 6

Deletion of the long arm of chromosome 6

Distal deletions including terminal deletions of the long arm of chromosome 6 are associated with seizures in ∼25% (five of 20) of cases (79–83). Interstitial deletions of the long arm of chromosome 6 were few, and seizures were mentioned in three cases (84–86).

Epileptology. Age at onset of seizures ranged from 4 months to 10 years. In five instances, generalized seizures were described (80–83). The EEG was reported as showing hypsarrhythmia in one case (81). Seizures were usually easily controlled.

Other chromosome 6 anomalies

Three 6q duplications were described, each too large to be of value in this review. In four terminal 6p duplications, seizures were not reported (87). No 6p deletions were recorded. Seizures occurred in four of 15 patients with ring chromosome 6, an uncommon anomaly (88–90). Details of the seizures and EEG were not given.

Chromosome 7

Deletion of the long arm of chromosome 7

There were >50 cases of 7q deletion described, of which 26 were terminal deletions. Seizures were described in 14 cases. No specific common region stood out; seizures were described in deletions of various sizes, extending from the pericentromeric region to the terminal region (91–99).

Epileptology. Seizure onset ranged from the neonatal period to 7 years (91,97). Febrile convulsions alone occurred in four cases (91,92,96,98), generalized seizures in three (94,95,97), myoclonic seizures in one (93), and a combination of afebrile and febrile seizures in one case (93). Two cases of Williams syndrome del(7)(q11.23), have been described with infantile spasms (100), but seizures are rare in this disorder. One case of benign rolandic epilepsy in association with del(7)(q11.23->q21.2) was reported (99). No seizure details were reported in two cases (98). EEG studies were mentioned in six cases with seizures; hypsarrhythmia was found in three (93,100), rolandic spikes in one (99), one with multifocal spikes (94), and one was normal (96).

Other features. Microcephaly was characteristic (5).

Other chromosome 7 anomalies

The 7p deletions described in the Oxford database were large, and the smallest of these (7p21.1->p11) did not have seizures. Four cases of duplicated regions of 7q were large, had complex rearrangements with other chromosomes, and seizures were not a feature (101,102). However, Löffler et al. (103) reported siblings with a pure duplication of 7q32-q34, each having a generalized seizure disorder. Seizures were not a feature of the reported cases of ring 7 syndrome (104,105).

Chromosome 8

Deletion of the long arm of chromosome 8, del(8)(q24.12->24.13)

This deletion syndrome also is known as Langer–Giedion syndrome, or tricho-rhino-phalangeal syndrome type II.

Epileptology. Seizures occur in a minority of cases (106–113). Seizures usually began in infancy (range, 7 days–13 years). One case had absences with a “disorganized EEG”(112), and one had febrile convulsions with focal epileptiform abnormalities on EEG (109). A 7-day-old boy had left-sided partial seizures, and his EEG showed frontocentral epileptiform discharges (107). His seizures were attributed to hypoparathyroidism. In two cases, seizure details were not given (110,113). Two other cases described by Fennel et al. (114) with deletion (8q24.1->qter) were reported to have a phenotype distinct from Langer–Giedion syndrome and generalized seizures with a nonspecific EEG pattern.

Other features. As its name indicates, this syndrome involves abnormalities of hair, nose, and phalanges, and other features include microcephaly, mental retardation, and multiple exostoses (115).

Other chromosome 8 anomalies

In one family, five of nine individuals with dup(8)(q21.2->q22) due to a familial insertional translocation had tonic–clonic seizures (116).

Chromosome 9

Deletion of the short arm of chromosome 9, del(9)(p22/23->pter)

Seizures occur in <10% of cases of this relatively common deletion, which frequently occurs in combination with other chromosomal aberrations (117). In 80 cases of 9p deletion, 39 had a pure 9p deletion, and 41 occurred with another unbalanced chromosome segment. Most of the pure 9p deletion cases occurred de novo, the break point usually being at p22.

Deletion of the long arm of Chromosome 9

Seizures occurred in three of 10 cases with interstitial deletions, but clinical details were not provided (118).

Other chromosome 9 anomalies

Duplication of the entire short arm of chromosome 9 involves 1.6% of HAL, and has a clear association with epilepsy (119).

Epileptology. In one carefully studied case, complex partial seizures suggestive of left hemisphere origin were described with multifocal, bilateral, epileptiform discharges on interictal EEG.

Other features. Mental retardation, microcephaly, short stature, and kyphosis are characteristic. A variety of diffuse developmental abnormalities are described neuropathologically and on MRI in partial and complete trisomy 9 cases (119).

Chromosomes 10 to 13

There were only isolated case reports or large aberrations described with epilepsy on chromosomes 10 (120–126), 11 (37,127), 12 (128), and 13 (129–131). Trisomy 12p was associated with myoclonic absences and generalized spike–waves in three patients (132,133).

Chromosome 14

Ring Chromosome 14

Ring chromosome 14 is the only anomaly of chromosome 14 with a striking association with epilepsy. Seizures are universal in this condition (134). At least 35 cases were reported (135–137), some of which are familial (138–140). Any potential epilepsy genes would most likely be sited in the terminal long arm region, because the terminal short arm contains no single-copy genes. Less likely is the possibility of seizures being a consequence of the “general ring syndrome”: during successive cell divisions, the ring tends to be lost, resulting in cellular monosomy (141).

Epileptology. Seizures begin in infancy and are intractable. A variety of seizure types have been described including GTCS (134,136,137,140,142–147), myoclonic (138,142,147), “minor motor seizures”(148), complex partial seizures, and secondarily generalized attacks (137,146). Of the 17 EEG reports identified, nine were normal or showed only nonepileptiform abnormalites (134,136,138,145,149–152), and eight had epileptiform discharges predominantly of multifocal type (134,137,142,143,146,147,153).

Other features. Retinal changes were mentioned in 12 of 22 cases (137) involving retinal pigmentation and macular abnormalities, particularly associated with a breakpoint at 14q32 or proximal to 14q24 (136). Other common features were cerebral atrophy, ventricular dilatation, generalized hypotonia, and ataxia (137).

Other chromosome 14 anomalies

The duplication syndromes of chromosome 14 involved large segments, and seizures were not prominent (154).

Chromosome 15

Deletion of the long arm of chromosome 15, del(15)(q11->q13)mat

Angelman syndrome (AS) is due to a deletion of the segment 15q11-q13 on the maternally derived chromosome in 70% of cases. About a fourth are presumed due to a mutation in a specific gene (155), and 2–3% are due to paternal uniparental disomy (that is, both homologs of segment 15q11->q13 are derived from the father), leading to nonfunctioning of this segment (156). Patients with a chromosomal deletion have a more severe phenotype than the single gene form or those with paternal uniparental disomy (157).

Candidate Angelman genes include a cluster of γ-aminobutyric acid (GABA)A receptor genes (α5, β3, γ3), which inhibit excitatory mechanisms in the central nervous system (CNS) and whose absence produces epilepsy and hyperactivity in a mutant mouse model. A role for these in AS is yet to be proven (158,159). Mutations in the ubiquitin-protein ligase (UBE3A) gene were identified in some cases without chromosomal deletions (155,160). It remains open to question whether the nonfunction of this gene has a direct or an epigenetic role in causing seizures and whether the GABA-receptor genes have a role in some cases. Analysis of phenotype–genotype correlations suggested that cases with deletions involving GABA-receptor genes had more severe epilepsy (161).

Epileptology. Seizures occur in 80–90% of cases (158,162–164). Onset is usually before age 3 years, and seizures are often refractory. Infantile spasms have been described, but the more common presentation is with myoclonic seizures, atonic seizures, atypical absences, and febrile and afebrile GTCSs. Episodes of nonconvulsive status epilepticus and partial seizures also are reported (158,162–164). Guerrini et al. (148) emphasized that the marionette-like gait and hand-flapping may be due to rhythmic, fast bursting cortical myoclonus. The EEG often shows characteristic generalized high-amplitude slowing, which is posteriorly dominant with spike and sharp waves, often facilitated by eye closure (165). In those with prominent cortical myoclonus, the EEG shows 5- to 10-Hz sinusoidal or sharp activity (158). EEG abnormalities and epilepsy fade in the second decade (165).

Other features. The phenotypic features are subtle in infancy and include brachycephaly, midfacial hypoplasia, deep-set eyes, macrostomia, and prominent mandible (165). Head circumference is usually below the 25th centile, and often below the 2nd centile. Expressive speech, if any, is limited to a few words. Paroxysms of inappropriate laughter and a happy disposition are characteristic. Children with AS often have a limited sleep requirement.

Inversion duplication of chromosome 15, inv dup(15)

This supernumerary chromosome can produce an effective tetrasomy (quadruple dose) of the segment 15(q11→q13), and is a relatively common chromosome syndrome (166–169). More than 80 cases have been recorded (166). Duplication of the 15(q11→q13) region has been reported with autism, epilepsy, and ataxia (170).

Epileptology

Seizures are a hallmark of this condition. In 10 cases in which description of the epilepsy was given, the onset occurred in early infancy, sometimes as early as 6 weeks (166,168,170–172). The seizures were described as generalized in five of 10 cases, and no description was available in the others. The EEG was variably described as multifocal, hypsarrhythmic, or spike–wave discharges in five cases.

Other features

The lack of dysmorphic features is notable.

Chromosome 16

Seizures were not associated with aberrations of chromosome 16.

Chromosome 17

Deletion of the Short Arm of Chromosome 17

Two important chromosomal aberrations associated with seizures are located on the short arm of chromosome 17: Smith–Magenis syndrome (SMS) with del(17)(p11.2), and Miller–Dieker syndrome (MDS) with terminal and subterminal deletion del(17)(p13).

del(17)(p11.2)

Epileptology

“Seizures” were reported in eight of 31 SMS patients (173–176). Four of these were definite seizures: two had febrile convulsions, and another two had generalized seizures. Four others had paroxysmal attacks of abnormal behavior including rage, suspected to be “seizures.” EEG studies were described in 12 cases and were normal in five and epileptiform in two, whereas the remaining five were nonepileptiform.

Other features

Self-mutilation is a notable feature. Hyperactivity, speech delay, and growth failure are typical (173–174).

del(17)(p13.3)

The MDS deletion may be submicroscopic and detectable only with DNA probes (177–179). The important brain gene involved in the deleted sequence has been cloned and named LIS-1 (lissencephaly-1) (180). All MDS cases have severe cortical developmental abnormalities ranging from agyria (grade 1) to widespread agyria with restricted areas of pachygyria primarily involving the frontal and temporal regions (grade 2).

Epileptology

All MDS cases have seizures that usually begin in the first year of life, although rarely in the neonatal period. Infantile spasms occur in 50% cases (181,182), and other forms of generalized epilepsy such as myoclonic, tonic, and tonic–clonic seizures are common. Partial seizures also are described (7). The EEG is very abnormal with high-amplitude alpha or beta activity alternating with high-amplitude slow rhythms and simulates slow spike–wave complexes or hypsarrhythmia (182).

Other features

The most consistent features are profound intellectual disability, with atonic diplegia and microcephaly. Characteristic facies comprise a prominent forehead, bitemporal hollowing, short nose with upturned nares, and a small jaw. The disease follows a grim course, with only some patients surviving into adult life.

Ring chromosome 17

Fewer than 10 cases are described in the literature (183–187). They share some phenotypic features with MDS, including seizure types and EEG findings, and in some, lissencephaly, which may reflect deletion of (or influence on) LIS-1 (184).

Other chromosome 17 anomalies

There were only isolated case reports of other chromosome 17 aberrations. Two of five cases of deletion of 17q, in the region of q21.3 to q24.3, had seizures (188).

Chromosomes 18 and 19

Anomalies of chromosomes 18 and 19 are not generally associated with epilepsy, apart from some cases of distal 18q deletion and q21.1→q22.3. Seizures have not been well described in 18q syndrome, with the exception of one report of complex partial seizures with prominent autonomic manifestations that could be confused with syncope (189).

Chromosome 20

Ring chromosome 20 has a striking association with epilepsy, whereas in the other aberrations of chromosome 20, there were only isolated cases with epilepsy (190–193). More than 30 cases of epilepsy associated with ring chromosome 20 have been reported (194–207). The locus of fusion between the deleted long and short arms in ring chromosome 20 in 12 cases was one of p13q13, p13q13.3, or p13q13.33.

Epileptology

Seizures occur in virtually all cases. Age at onset of seizures varies from infancy to 14 years and is characteristically resistant to treatment (196,198). Although a variety of seizure types were initially reported in single cases, a report by Inoue et al. (196) of six cases studied with video-EEG monitoring crystallized a characteristic seizure pattern of repeated nonconvulsive status. The nonconvulsive episodes consisted of prolonged periods of confusion, with speech difficulties and complex automatisms. Such attacks often occurred daily. Tonic motor seizures also were common. Interictal EEG often shows focal epileptiform transients from frontal or temporal regions. The characteristic finding is of long runs of bilateral high-amplitude slow wave with or without a spike component, with a bifrontal predominance (195,196,199,200,202,206–209).

Other features

Microcephaly was reported in a few cases. Otherwise, a lack of phenotypic features makes early diagnosis difficult (195,204). Unlike that in most chromosomal syndromes, intellect is usually within the normal range or mildly deficient.

Chromosome 21

Epilepsy occurs in 5–6% of individuals with trisomy 21 (Down syndrome), which is less common than in most mental retardation syndromes (7). Of those with epilepsy, reflex epilepsies (210) and infantile spasms (211,212) are most common. In recent times, a second increase in the prevalence of epilepsy (9–10%) has been reported after age 50 years, associated with dementia (213,215). Generalized tonic–clonic seizures were the most common; myoclonic, atonic, and absences with tonic–clonic seizures have been reported. Isolated cases of epilepsy associated with deletions of the long arm of chromosome 21 are reported (216,217).

Chromosome 22

Only isolated case reports exist for aberrations of chromosome 22 associated with epilepsy.

Chromosome X

Deletion on the short arm of chromosome X

Seizures have been recently reported in association with distal deletions in the pseudoautosomal region of the short arm, involving band Xp22.3 (218,219). These were apparently generalized convulsive seizures and myoclonic seizures. Ichthyosis was a feature in one report (219).

Genetic defect on the long arm of chromosome X

The fragile X syndrome is an important cause of epilepsy and intellectual disability, particularly in male patients and where there is a family history of intellectual disability. It was originally described as a cytogenetic abnormality. Subsequently, the responsible gene (FMR1 gene at Xq28) was the first to be shown with a trinucleotide repeat sequence (CGG) subject to amplification, with clinical expression correlated with the size of the CGG expansion (220).

Epileptology

Various authors reported a 25–40% incidence of seizures (221,222). Generalized tonic–clonic seizures are the most common seizure type. However, partial seizures and West syndrome leading to the Lennox–Gastaut syndrome have occasionally been reported (223). The EEG studies show characteristic focal spikes during sleep (223) similar to those seen in benign rolandic epilepsy. Both the epilepsy and EEG improve with age.

Other features

Mental retardation of varying degrees and macroorchidism are hallmarks of this syndrome. Generalized hypotonia in infancy may be seen. Macrocephaly and other dysmorphic features including a prominent jaw, thickening of nasal bridge, and large ears may occur.

DISCUSSION

The aim of this study was to seek associations between epilepsy syndromes and small chromosomal aberrations. Such chromosomal regions are likely to contain genes coding for neuronal function that, when faulty, lead to epilepsy. We surveyed >400 publications on chromosomal abnormalities and seizures. Most of these articles had only limited descriptions of the epileptology, in terms of the ILAE classification (8). Few included details on the clinical, EEG, or video-EEG monitoring results of seizure semiology. A number provided no information other than the mere statement “epilepsy” or “seizures.” Nevertheless, not wishing to discard potentially useful information, we accepted the briefest statements as to the presence of epilepsy.

We identified an association with seizures in relation to particular regions of chromosome 1, 2, 4, 6, 7, 8, 9, 15, 17, X, and to ring chromosomes 14, 17, and 20. These regions are shown in Fig. 1. In some of these aberrations [for example, the Wolf–Hirschhorn syndrome (4p deletion) and Angelman syndrome], characteristic features of the epileptology have already been identified, but in general, the range of seizure types and EEG patterns in the relatively well defined abnormalities remains quite broad.

This review serves also to emphasize an aspect of clinical practice. A karyotype analysis should be performed in a child or adult with seizures and dysmorphic features or intellectual disability. Certain clinical features may provide particular clues (Table 1). The “Greek helmet” appearance in an infant with seizures may signal Wolf–Hirschhorn syndrome. Miller–Dieker syndrome should be suspected in an infant with lissencephaly, refractory epilepsy, and severe developmental delay. Funduscopy revealing retinal abnormalities could suggest ring chromosome 14 (138–140). Characteristic facial features, gait, and absence of speech with a predominance of myoclonic, atonic, and atypical absence seizures and a classic age-related EEG pattern are the hallmarks of Angelman syndrome. Agenesis of the corpus callosum can occur in many chromosomal syndromes with or without epilepsy, and terminal deletion of the long arm of chromosome 1 should be added to this list. Whereas dysmorphic features and intellectual disability are usual in autosomal chromosomal aberrations, an important exception is ring 20, in which the physical phenotype is normal, and intellectual impairment may be mild or absent. Refractory seizures with recurrent nonconvulsive status should lead to consideration of this particular chromosomal abnormality (192,195,196).

Table 1.  Possible clinical clues to commoner chromosomal abnormalities associated with epilepsy
Chromosomal abnormalitiesSeizure phenotypeFindings of possible diagnostic value
del(1)q42-qterNo characteristic phenotypeAgenesis of corpus callosum
del(4)pterHeterogeneous generalized and partial seizures “Greek-helmet” shaped head, cleft lip and palate
r14Heterogeneous generalized and partial seizuresRetinal pigmentation and macular abnormalities
del(15)q11-q13Myoclonic, atonic, atypical absence, tonic–clonic seizures “Happy puppet,” characteristic EEG
del(17)p11.2No characteristic phenotypeSelf-mutilation, hyperactivity
del(17)p13.3Infantile spasms, other generalized seizure typesCharacteristic facies, lissencephaly, characteristic EEG
r20Nonconvulsive status, tonic seizuresLack of dysmorphic features or intellectual disability
21 trisomyHeterogeneous generalized and partial seizuresDown syndrome
Fragile XHeterogeneous generalized and partial seizuresMacroorchidism, macrocephaly

The mechanisms of the enlarging number of chromosomal imbalances associated with epilepsy are of considerable neurobiologic interest. These dosage imbalances might, for some neuronal genes, lay the basis for the observed epilepsy phenotypes. The segments reviewed earlier, although cytogenetically short, are long at a molecular level, and presumably contain many genes (dozens or perhaps hundreds). Nevertheless, having offered a focus on these regions, a start could be made in looking at those genes known to be located here, and which have, or may plausibly have, a functional neuronal role. An example is the Smith–Magenis deletion: this segment of chromosome 17 contains a number of identified genes, including one known “neuronal gene,” a brain finger protein gene, ZNF179 (224). Potentially this gene, or other candidate neuronal genes that come to be identified, could have roles in determining neuronal function such that, when faulty, epilepsy could result.

In these chromosomal syndromes, the mechanism is one of an imbalance, with either one or three copies of a normal gene. The associated phenotypes, including epilepsy, may reflect a “general” effect in which neuronal development, migration, differentiation, and functioning have progressed less than optimally, because of haplo insufficiency or “triplo-excess” of a collection of genes, and fairly nonspecific neurologic abnormalities, including a lowered seizure threshold, are the result. There may have been a more particular dosage (or position) effect on a gene having a specific role in cortical excitability, perhaps a gene coding for an ion channel, with the seizures being a more direct consequence. Because gene dosage might not necessarily cause seizures, it should be noted that chromosomal syndromes that do not have epilepsy as a feature are by no means excluded as containing epilepsy genes.

Comparing the “epileptogenic” chromosomal regions with the relatively small current list of known chromosomal linkages for idiopathic epilepsy syndromes (2q, 6p, 8q, 10q, 15q, 16p, 19p, 19q, 20q, 22q, Xp) (225), there is little overlap. We note that the genes for benign familial neonatal convulsions (BFNCs) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) are located at the terminal end of the long arm of chromosome 20 (20q13), and that epilepsy is recorded in the ring chromosome 20 syndrome (226–228). However, the clinical patterns of the epilepsy in this syndrome are not those of BFNC and ADNFLE. We are, of course, at a very early stage in our understanding of epilepsy genes, and with so few known, it is not surprising that there was little overlap with the cytogenetic segments to which we have drawn attention.

Despite these caveats, we believe that the approach we have taken has the potential to provide signposts to epilepsy genes. An improved quality of clinical assessment and the increasing precision of cytogenetic analysis may sharpen the tool of chromosomal searching. It is to be hoped that future case reports of patients with epilepsy and a chromosome abnormality will include diligent classification of epilepsy and epileptic syndromes, according to the ILAE classification systems. The identification of specific epilepsy syndromes associated with particular chromosomal aberrations will increase the list of “epileptogenic” regions on chromosomes, providing clues that gene hunters need.

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