Chromosomal syndromes associated with epilepsy

Introduction

The term syndrome is generally used for recurring and recognizable patterns of malformation. Many are due to chromosomal alterations. In a recent review, Singh et al. identified over 400 chromosomal imbalances associated with epilepsy or EEG abnormalities.[1] Recent advances in molecular cytogenetics have extended the number of detectable chromosomal syndromes.[2, 3]

Epilepsy in isolation is rarely associated with an under lying chromosomal abnormality. An exception may be an apparently balanced translocation interrupting a spe cific epilepsy gene. Patient features that may point towards a chromosome abnormality include coexisting psycho motor retardation, pre- and postnatal growth retardation, congenital malformations and facial dysmorphism.

Chromosomal deletions and rearrangements

Chromosomal deletions can arise within chromosomes interstitial deletions) or at the ends of chromosomes telomeric deletions). The telomeres of chromosomes are gene rich, and submicroscopic deletions may result in significant developmental abnormalities, including seizure disorders. Deletions can arise de novo or be familial, often with a variable phenotype in deletion carriers. Balanced translocations, which involve exchange of chromosomal segments between different chromosomes without apparent loss or gain of genetic material, or disruption of a functional gene, may lead to serious chromosomal imbalance among offspring.

Chromosome alterations larger than 2-3 Mb are usually detected microscopically using high-resolution banding. Fluorescent in situ hybridization (FISH), involving the hybridization (complementary base-pairing) of a fluo rescently labeled DNA probe to a targeted chromosomal area, has been revolutionary for the detection of submi croscopic chromosome abnormalities and microdeletion syndromes. Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is due to deletions of the short arm of chromosome 4(pter-pl5). Interestingly, the milder phenotype of Pitt-Rogers-Danks syndrome (PROS) is due to smaller distal 4p deletions. The seizure types reported in Wolf-Hirschhorn syndrome are summarized by Singh et al.,[4] and epilepsy also occurs in PRDS.[5] Additional features of Wolf-Hirschhorn syndrome include intrauterine growth retardation, cardiac and renal mal formations, characteristic 'Greek-helmet' facial appear ance, cleft palate, cerebral anomalies and variable, but often profound, mental retardation.

Investigations Karyotype, FISH of 4p.

Miller-Dieker syndrome

Miller-Dicker syndrome (MDS) is due to microscopic or submicroscopic deletions on the distal short arm of chro mosome 17(p13.3), involving the LIS1 gene. Hemizygosity involving LISI is responsible for 'classical lissencephaly[1], the most prominent feature of MDS. Seizures in MDS usually occur within the first 6 months of life, often presenting as infantile spasms. The EEG is very abnormal, simulating hypsarrythmia.[6] MDS, associated with loss of several genes contiguous with LAS/, represents the most severe LIS/-associated syndrome. Most patients with 'classical lissencephaly' do not have the additional dysmorphic facial features and occasional visceral malformations associated with MDS, and may only develop seizures in later childhood. About 40 per cent of cases, termed isolated lissencephaly sequence, have a submicroscopic deletion involving the LIS1 gene[7] Mutations within the LIS1 occur in a further 25 per cent of cases (see Chapter 4C).

Investigations: Karyotype, FISH of 17pl3.3.

1p36 deletion syndrome

Seizures are reported in three quarters of cases of del( 1) (p36.3), a microdeletion syndrome, that includes psy chomotor retardation, cerebral abnormalities on imaging, facial dysmorphism and visceral anomalies.[1, 8] Interestingly, a potassium channel (ß subunit gene, KCNAB2, is within the deleted region, raising the possibility that haploinsuf ficiency of this gene may be responsible for the occur rence of epilepsy in this condition.[9]

Investigations: Karyotype, FISH lpter.

Chromosomal duplications

Duplication (dup) of a chromosomal segment results in three, rather than two copies of the genes located within the replicated region. Direct duplications are oriented the same way as the original segment; in inverted duplication the orientation is reversed.[10]

Inverted duplication 15 (inv dup 15)

Inverted chromosomal 15 duplications may be interstitial or present as an extra, structurally abnormal chromosome (ESAC). Larger inv dup 15s contain two or more copies of the Prader-Willi svndrome/Angelman syndrome region. They are associated with an abnormal phenotype, includ ing autism, early onset seizures and ataxia, with a notable absence of dysmorphic features.[11]

Investigations: Karyotype, FISH with probes specific for Prader-Willi syndrome/Angelman syndrome.

Ring chromosomes

Ring chromosomes are uncommon and usually sporadic, although there are rare instances of parent-child transmission. The amount of genetic material lost in the formation of the ring determines the phenotype.[10] Two ring chromosomes are particularly associated with epilepsy.

Ring chromosome 14 (r14) Children with r14 have distinct facial features, psychomotor retardation, short stature, cutaneous dyspigmentation, retinal pigmentation, and neurological anomalies includ ing hypo- or hypertonia, tremor and athetosis. Epilepsy beginning in infancy is a fairly constant feature, including myoclonic and tonic-clonic seizures.[1]

Ring chromosome 20 (r20) The r20 syndrome includes epilepsy, mental retardation and microcephaly. Importantly, several patients have nor mal psychomotor development. Associated seizure and EEG patterns include prolonged complex partial seizures, and theta bursts on EEC[12] Notably , genes for benign familial neonatal convulsions, KCNQ2, and for autoso mal dominant nocturnal frontal lobe epilepsy, CHRXAl are located on chromosome 20.

Investigations: Karyotype, chromosome painting (confirms chromoso mal origin of the ring).

Trisomies

Seizures occur in 5-6 per cent of children with Down syndrome, due to the presence of an additional chromo some 21, also referred to as trisomy 21. Reflex epilepsies and infantile spasms may occur.[13] Seizures may also be a major clinical feature in the two other common viable trisomy syndromes: trisomy 13 (Patau syndrome) and trisomy 18 (Edward syndrome).

Mosaicism

As well as chromosomal abnormalities involving all body alls (constitutive anomalies), tissue-limited chromosomal abnormalities, or mosaicism, may present with a seizure disorder and other congenital anomalies.

Pallister-Killian syndrome

A distinctive dysmorphic syndrome associated with tetra somy 12p mosaicism, this may present with seizures.[11]

Hypomelanomosis of Ito

A condition with hypopigmented lesions that may follow (he lines of Blaschko, this is frequently associated with chromosomal mosaicism detectable in skin and blood. CXS malformations, seizures and mental retardation are common associations.

Investigations: Chromosomes from blood and from carefully positioned skin biopsy(ies). Inform cytogeneticist that mosaicism may he present.

Imprinted genes

A gene may have a subtle modification or 'imprint' when inherited maternally or paternally. These imprinted genes arc usually expressed only from the maternal or paternal allele. Absence of an expressed gene subject to imprinting cannot be compensated by its partner, because the inac-uvation arising from the imprinting process is irreversible. The resultant lack of gene product may result in a range of developmental anomalies, including the occurrence of epilepsy.

Angelman syndrome

Angelman syndrome is the best characterized of the imprinted disorders. Seizures occur in 80-90 per cent of uses. A deletion of 15q11-13 on the maternally derived chromosome is responsible for 70 per cent. Among the remainder, paternal uniparental disomy (2-3 per cent), imprinting center mutations within 15ql1-13 (3 percent) and mutations within the maternally derived UBE3A gene 7 per cent) result in critical lack of product from mater nallv expressed genes within this region of chromosome 15. The 1 1 (i often shows characteristic generalized high amplitude slowing, which is posteriorly dominant with spike and sharp waves, often facilitated by eye closure.[10] By contrast, seizures are uncommon in PWS, which arises from absence of a paternal derived 15ql1-13 region.

Investigations: Karyotype. 15q 11 — 13 methylation studies, FISH, UBE3A mutation analysis (Angelman syndrome).

Fragile X syndrome

Fragile X syndrome, mostly arising from an expanded tri nucleotide repeat sequence within the FMRl gene located at Xq28, is an important cause of mental retardation and seizures, particularly in boys. Often associated with a maternal family history of intellectual disability, 25-40 per cent of cases have seizures, generally with characteristic focal spikes during sleep, which improve with age.[14]

Investigations: FMRl antibody analysis, methylation studies or direct sizing of CGG expansion. Karyotype.

Key points

• Over 400 chromosomal imbalances are associated with epilepsy
• Epilepsy is rarely an isolated feature of a chromosomal anomaly
• Coexisting mental retardation, pre- and postnatal growth retardation, congenital malformations and facial dysmorphism suggest the possibility of a chromosomal syndrome

References

1. Singh R, McKinlay Gardner RJ, Crossland KM, et al. Chromosomal abnormalities and epilepsy: a review for clinicians and gene hunters. Epilepsia 2002; 43: 127-140.
2. Schinzel A. Catalogue of Unbalanced Chromosome Aberrations in Man, 2nd edn. Berlin: de Gruyter, 2001.

3. Schinzel A, Niedrist D. Chromosome imbalances associated with epilepsy. American Journal of Medical Genetics 2001; 106: 119-124.

4. de Vries BBA, White AO, Knight SJL, et al. Clinical studies on submicroseopic subtelomeric rearrangements: a checklist. Journal of Medical Genetics 2001; 38: 145-150.

5. Kant SG, van Haeringen A, Bakker E, et al. Pitt-Rogers-Danks syndrome and Wolf-Hirschhom syndrome are caused by a deletion in the same region on chromosome 4p 16.3. Journal of Medical Genetics 1997; 34: 569-572.

6. Guerrini R, Carrozzo R. Epilepsy and genetic malformations of the cerebral cortex. American Journal of Medical Genetics 2001; 106: 160-173.

7. Pilz DT, Macha ME, Precht KS, et al. Fluorescence in situ hybridization analysis with LIS 1 specific probes reveals a high deletion mutation rate in isolated lissencephaiy sequence. Genetics in Medicine 1998; 1: 29-33.

8. Slavotinek A, Shaffer LG, Shapira SK. Monosomy 1 p36. Journal of Medical Genetics 1999; 36: 657-663.

9. Heilstedt HA, Burgess DL, Anderson AE, et al. Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome. Epilepsia 2001; 42: 1103-1111.

10. Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling, 2nd edn. New York: Oxford University Press, 1996.

11. Quarrell OWJ, Hamill MA, Hughes HE. Pallister-Killian mosaic syndrome with emphasis on the adult phenotype. American Journal of Medical Genetics 1988; 31: 841-844.

12. Canevini MP, Sgro V, Zuffardi O,et al. Chromosome 20 ring: a chromosomal disorder associated with a particular electroclinical pattern. Epilepsia 1998; 39: 942-951.

13. Stafstrom CE, Patxot OF, Gilmore HE, Wisniewski KE. Seizures in children with Down syndrome: etiology, characteristics and outcome. Developmental Medicine and Child Neurology 1991;33: 191-200.

14. Musemeci SA, Ferri R, Colognola RM , et al. Fragile-X syndrome: a particular epileptogenic EEG pattern. Epilepsia 1988;29:41-47.

15. Torrisi L, Sangiorgi E, Russo L, Gurrieri F. Rearrangements of chromosome 15 in epilepsy. American Journal of Medical Genetics 2001; 106: 125-128.

16. Nichols RD. The impact of genomic imprinting for neurobehavioral and developmental disorders. Journal of Clinical Investigation 2000; 105: 413-418.

17. Boyd SG, Harden A, Patton MA. The EEG in early diagnosis of the Angelman (happy puppet) syndrome. European Journal of Pediatrics 1988; 147: 508-513.

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