Ring Chromosome 20 Epilepsy Syndrome

Ring chromosome 20 epilepsy syndrome [r(20)], has a striking association with seizures, whereas in other aberrations of chromosome 20 seizures are infrequent. This syndrome is characterised by medically intractable complex partial epilepsy, nocturnal subtle seizures, behavioural problems and mild mental impairment. Chromosomal abnormalities are rarely considered in patients with severe, young onset epilepsy with no dysmorphism or intellectual impairment, but this is the usual phenotype of ring chromosome 20. Chromosomal analysis, relatively simple and cheap, may save complex and unnecessary evaluation at a later stage. This syndrome is undoubtedly an underdiagnosed condition as chromosomal testing is not routine in epilepsy patients. Diagnosis is often delayed for many years after onset of seizures.

Borgaonkar and colleagues at Johns Hopkins University catalogued ring chromosome 20 syndrome as a genetic syndrome in 1976. Since then, over 60 cases of r(20) have been reported in the literature. To date there is still no published data on the incidence and prevalence of this syndrome. This disorder appears to be pan-ethnic and non-gender specific. Cases of this syndrome have been reported from many different parts of the world involving different ethnicities. Almost all cases reported are sporadic except a few with known family history. With more widespread cytogenetic chromosomal karyotyping in non-aetiological cases of epilepsy, more cases of r(20) will undoubtedly be recognised [1].

Phenotypic characteristics

Epileptology

Epilepsy is a constant feature of this syndrome and typically starts in early childhood and in many cases is intractable and drug resistant. Seizure onset has been reported between 1 and 17 years of age. Seizures are often complex partial in type and reported as episodes of altered consciousness with staring, oral automatisms, unspecified automatic behaviour, focal motor symptoms and/or head turning. Periods of intense fear and sometimes prolonged confused states lasting for several minutes to hours are described (non-convulsive status epilepticus). Subtle nocturnal behavioural changes such as stretching, rubbing and turning have been observed which resemble normal arousal behaviour. Generalised tonic-clonic seizures are rarely reported. In addition, subtle nocturnal seizures (SNS) and nocturnal frontal lobe seizures (SNFLS) are also reported. Seizures can be easily mistaken for non-epileptic events. Features of frontal lobe epilepsy are often recognised. Seizures are difficult to control with antiepileptic medications and if the diagnosis of r(20) has not been made patients are subjected to epilepsy surgery workup and unnecessary investigations [2,3,4,5].

Cognition & Behaviour

Cognition is usually normal before the onset of epilepsy; however, there is the possibility of mental impairment if seizures are frequent and persistent. Individuals may have normal cognition despite periods of poorly controlled epilepsy and others may have profound learning disabilities and require help with all aspects of daily life. Behavioural problems can vary from minor concentration and attention difficulties with high levels of activity to profound problems. Several of the children reported in the medical literature have been described to have periods of very diffi- cult behaviour, often associated with poor seizure control. The behaviour and cognitive difficulties do vary with time and may worsen with increasing seizures. However, the child may regain these lost skills with improved seizure control [6].

Physical Features

Abnormal physical features are often lacking. Major and minor malformations including facial dysmorphism are subtle or absent. This lack of dysmorphic features and often omission of chromosomal testing in patients with refractory epilepsy leads to delayed diagnosis. Rare cases of r(20) syndrome with dysmorphic features published in the literature consist of microcephaly, plagiocephaly, dental malocclusions, micrognathia, cauliflower-shaped ears, and coarse facial features with slanting eyelids (obliquely downward and outward) [7]. Occasional renal and cardiac abnormalities are also reported in the syndrome.

Neurophysiology

Electroencephalography (EEG)

No characteristic electroencephalographic (EEG) features distinguish r(20) syndrome from other refractory epilepsies, therefore diagnosis alone cannot be suspected by EEG. A wide spectrum of EEG abnormalities has been described. Interictal EEG (Figure 1) may be normal to mildly slow, and in some cases bifrontal spikes and sharp waves may be seen. Burst of sharply contoured theta activity has also been described. Interictal patterns are often more pronounced in sleep and may share similarities with other epileptic encephalopathies such as Lennox-Gastuat syndrome (LGS) and Landau-Kleffner syndrome (LKS).

Ictal EEGs (Figure 2) may show prolonged runs of diffuse slowing with frontal dominance inter- mixed with bifrontal sharp wave discharges. Ictal patterns often raise the possibility of a frontal lobe focus. In patients with non-convulsive status epilepticus the above described patterns may be combined with large portions of normal appearing EEG activity [8,9]

Magnetoencephalography

Ictal magnetoencephalography (MEG) has been performed on one patient with r(20) syndrome. MEG and EEG were simultaneously recorded and the equivalent current dipoles (ECD) of ictal discharges on MEG were localised to the medial frontal lobe. The authors suggested that the mechanism of underlying epilepsy in r(20) syndrome may be similar to medial frontal lobe epilepsy [10].

Neuroimaging

A wide spectrum of structural and functional neuroimaging studies has been performed in patients with r(20) syndrome. In the majority of the patients structural abnormalities are not seen. In a few patients minor structural abnormalities have been reported. A recent [18F] fluoro-L- DOPA PET study in patients with r(20) showed decreased uptake in the basal ganglia bilaterally. The authors discussed the possible role of subcortical structural abnormalities in epileptic mechanisms [11].

Differential diagnosis

Both clinical and electroencephalographic findings in patients with r(20) syndrome can be confused with other refractory epilepsy syndromes. This syndrome can be misdiagnosed as Lennox-Gastaut syndrome (LGS) which is characterised by medically refractory mixed intractable seizures. Tonic and atonic seizures characteristic of LGS are rarely seen in r(20) syndrome. Non-aetiologic frontal lobe epilepsy is another frequent consideration and has phenotypic and EEG similarities with r(20) syndrome. Identifying r(20) syndrome in patients suspected of intractable frontal lobe epilepsy is critical to avoid unnecessary investigations and treatments. Unlike r(20) syndrome, the seizures in autosomal dominant nocturnal frontal lobe epilepsy (ADNFE) are predominantly nocturnal and rarely refractory. The nocturnal EEG pattern in r(20) may also have overlapping features of continuous spike and wave discharges in slow wave sleep (CSWS) and electrical status epilepticus in sleep (ESES). Early chromosomal testing to look for ring 20 mosaicism may avoid misdiagnosis [12].

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Diagnosis and genetics

Diagnosis of ring chromosome 20 syndrome can be made by recognition of certain characteristic clinical features, however definitive diagnosis requires chromosomal testing. This is most easily done by looking at the chromosome pattern (karyotype) in blood cells but any other tissue including skin could be examined (Figure 3).

At least 50-100 cells should be cytogenetically analysed to diagnose mosaic ring 20. Analyses of fewer than 50 cells may not reveal ring mosaicism. Cytogenetic testing is most easily done by looking at the chromosome pattern (karyotype) in blood cells but any other tissue including skin could be examined. Since chromosomal analysis is not a routine investigation when epilepsy first presents, the diagnosis of r(20) syndrome may be delayed or go unrecognised. Almost all parents of individuals with r(20) syndrome have no evidence of r(20) syndrome in their own blood chromosome analysis (personal communication – Spinner laboratory – Children’s Hospital of Philadelphia). A few individuals, typically relatives of affected children, have been found to have a ring chromosome 20 without any evidence of symptoms.

Most individuals with r(20) syndrome have some cells which have two normal chromosome 20s and others which have a normal and a ring chromosome. Studies have shown that a higher degree of mosaicism is associated with earlier age of seizure onset and malformations. However, the degree of mosaicism does not determine response to drug treatment. The range in age of onset of seizures and IQ for a given mosaic ratio is relatively wide. Therefore the prediction of phenotype from the mosaicism ratio should be done with caution with regards to genetic counseling [13].

Ring chromosome 20 results from a chromosomal break on each arm resulting in ring formation (Figure 4).

Deletion of the short arms (p) of chromosome 20 does not appear to result in epilepsy however terminal deletion of the long arm (q) is associated with epilepsy. In r(20) syndrome the breakpoint in most patients is in the p13q13.33 region of chromosome 20. The genes involved in this region (q13.33 region of chromosome 20) have yet to be identified, however this telomeric region includes two genes that are related to other distinct epilepsy syndromes; these are autosomal dominant nocturnal frontal lobe epilepsy (ADNFE) and benign familial neonatal convulsions (BFNC).

The genes identified in ADNFE and BNFC are the nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) and potassium voltage-gated channel subfamily KQT member 2 (KCNQ2) respectively (Figure 5).

Mutations in these genes are responsible for the clinical manifestations in these disorders. Haploinsufficiency of these candidate genes may account for clinical symptoms of r(20) syndrome. Previous studies have not reported deletion in these candidate genes. However, Spinner and colleagues utilising newer array based techniques (personal communication) have identified deletion in both candidate genes associated with a worse phenotype [14,15]. The recurrent risk for r(20) syndrome is very low, as the chromosomal ring formation is usually a ‘de novo’ event.

Treatment and outcome

Management of children with r(20) is symptomatic. Seizures are typically difficult to treat. No comparative studies have been done between the older and newer antiepileptic drugs (AEDs). From the review of published literature, no one drug seems to be better than any other drug and patients are frequently exposed to multiple AEDs. Unfortunately seizures are difficult to control with antiepileptic medication and may require consideration of alternative treatments. Epilepsy in r(20) syndrome is not amenable to resective surgery. Few patients have undergone epilepsy surgery without any benefit. Vagus nerve stimulation (VNS) treatment has been reported to have a good outcome in a few cases. There are no published reports on use of ketogenic diet in patients with r(20) syndrome, however its efficacy and safety is well established in other intractable epilepsies like Lennox-Gastaut syndrome. The role of other unconventional treatments of epilepsy is not established for the treatment of r(20) syndrome [16].

The long term outcome of the syndrome is not known. It is not lethal; however, r(20) patients, like other refractory epilepsies, are at risk of other complications of epilepsy including status epilepticus and sudden unexpected death in epilepsy (SUDEP). The best predictor of outcome is likely to be the degree of seizure control.

References

1. Borgaonkar DS, Lacassie YE, Stoll C. Usefulness of chromosome catalog in delineating new syndromes. Birth Defects Orig Artic Ser. 1976;12(5):87-95.

2. Augustijn PB, Parra J, Wouters CH, Joosten P, Lindhout D, van Emde Boas W. Ring chromosome 20 epilepsy syndrome in children: electroclinical features. Neurology. 2001 Sep 25;57(6):1108-11.

3. Inoue Y, Fujiwara T, Matsuda K, Kubota H, Tanaka M, Yagi K, Yamamori K, Takahashi Y. Ring chromosome 20 and nonconvulsive status epilepticus. A new epileptic syndrome. Brain. 1997 Jun;120 ( Pt 6):939-53.

4. Canevini MP, Sgro V, Zuffardi O, Canger R, Carrozzo R, Rossi E, Ledbetter D, Minicucci F, Vignoli A, Piazzini A, Guidolin L, Saltarelli A, dalla Bernardina B. Chromosome 20 ring: a chromosomal disorder associated with a particular electroclinical pattern. Epilepsia. 1997 Sep;39(9):942-51.

5. Ville D, Kaminska A, Bahi-Buisson N, Biraben A, Plouin P, Telvi L, Dulac O, Chiron C. Early pattern of epilepsy in the ring chromosome 20 syndrome. Epilepsia. 2006 Mar;47(3):543-9

6. Herrgard E, Mononen T, Mervaala E, Kuusela L, Aikia M, Stenback U, Paakkonen L,
Airaksinen  RL, Kalviainen R. More severe epilepsy and cognitive impairment in the offspring of a mother with mosaicism for the ring 20 chromosome. Epilepsy Res. 2007 Jan;73(1):122-8.

7. Garcia DM, Ortiz R, Gomez A, Barriuso E. Ring 20 chromosome syndrome with epilepsy and dysmorphic features: a case report. Epilepsia. 2001 Dec;42(12):1607-10.

8. Kobayashi K, Ingaki M, Sasaki M, Sugai K, Ohta S, Hashimoto T. Characterstic EEG findings in ring 20 syndrome as a diagnosis. Electroencephalography Clin Neurophysiol 1998 Oct:107;258-262.

9. Petit J, Roubertie A, Inoue Y, Genton P. Non-convulsive status in the ring chromosome 20 syndrome: a video illustration of 3 cases. Epileptic Disord. 1999 Dec;1(4):237-41.

10. Tanaka N, Kamada K, Takeuchi F. Ictal magnetoencephalographic study in a patient with ring 20 syndrome. Journal of neurology, neurosurgery and Psychiatry. 2004;75:488-90.

11. Biraben A, Semah F, Ribero JM, Douaud P, Remy P, Depaulis A. PET evidence for a role of the basal ganglia in patients with ring chromosome 20 epilepsy. Neurology 2004;63:73-77.

12. Combi R, Dalpra L, Tenchini ML, Ferini-Strambi L. Autosomal dominant nocturnal frontal lobe epilepsy. A critical overview. J Neurol 2004 Aug; 251(8):923-34.

13. Nishiwaki T, Hirano M, Kumazawa M, Ueno S. Mosaicism and phenotype in ring chromosome 20 syndrome. Acta Neurol Scand. 2005 Mar;111(3):205-8.

14. Garcia-Cruz D, Vasquez AI, Perez-Rulfo D, Davalos NO, Penaloza J, Garcia-Ortiz JE, Patino-Garcia B, Sanchez-Corona J. Ring-20-syndrome and loss of telomeric regions. Ann Genet. 2000 43(3-4):113-6.

15. Elghezal H, Hannachi H, Mougou S, Kammoun H, Triki C, Saad A. Ring chromosome 20 syndrome without deletions of subtelomeric and CHRNA-KCNQ2 genes loci. European Journal of Medical Genetics.2007;50(6):441-5.

16. Parr JR, Pang K, Mollett A, Zaiwalla Z, Selway R, McCormick D, Jayawant S. Epilepsy responds to vagus nerve stimulation in ring chromosome 20 syndrome. Dev Med Child Neurol. 2006 Jan;48(1):80.