Ring chromosome 20 syndrome (ORPHA:1444)
A rare chromosomal disorder, characterized by childhood onset drug resistant epilepsy with typical electroencephalographic findings (EEG), mild to severe intellectual disability and behavioral problems.
Epidemiology
The overall birth prevalence of ring chromosomes is 1/30-60,000 and ring 20 (r20) is one of the most common and is probably underdiagnosed.
Clinical description
Initial psychomotor development is usually unaffected. Age of seizure onset varies between 1-24 years (frequently 4-10 years) and are typically recurrent focal motor seizures during sleep or whilst awake with alteration of consciousness, staring, automatisms, ictal visual, affective behavior and periods of intense fear. Seizures can progress to generalized tonic or tonic-clonic seizures. Non-convulsive status epilepticus (NCSE) is common, recognizable by an altered state of vigilance, staring, reduced motor activity and speech. R20 syndrome is considered a developmental epileptic encephalopathy since epilepsy onset is followed by an early cognitive-behavioral decline which seems to be focused on frontal lobe dysfunction. Language and learning disabilities, attention problems, aggressive and obsessive behavior, and apathy are frequently reported. The electroencephalogram (EEG) shows frontal spikes within runs of bilateral slow high voltage activity. Age-related patterns of sleep deterioration, ranging from normal to destructured non-rapid eye movement/rapid eye movement, is also typical. There are no distinct dysmorphisms although microcephaly, strabismus, micrognathia, down-slanting palpebral fissures, ear abnormalities and poor somatic growth can be present. Associated brain, cardiac and renal malformations are rare.
Etiology
A ring chromosome is an aberrant chromosome whose ends have fused together. Ring chromosomes are unstable: during mitosis, the ring may be lost or duplicated. Patients carrying a ring chromosome often have mosaic karyotypes with normal cells, cells with a ring chromosome, cells with monosomy and/or cells with reorganized/duplicated rings. Some patients with r20 lose the terminal part of 20q. The epileptogenic mechanism remains unknown. Currently there is no evidence to support a correlation between the level of mosaicism and the severity of the phenotype, although non-mosaic cases present with the most severe symptoms/comorbidities.
Diagnostic methods
Diagnosis is suspected in patients with childhood onset recurrent seizures with a cognitive deterioration, behavioral changes and typical EEG findings. As mosaicism is frequent, r20 chromosome should be confirmed by karyotyping with at least 100 metaphases on blood lymphocytes. Diagnosis may be missed using other genetic techniques including aCGH.
Differential diagnosis
Differential diagnosis includes primarily Lennox Gastaut syndrome. Moreover, frontal lobe epilepsy, continuous spike and wave during slow wave sleep and NCSE of other etiologies should be considered.
Genetic counseling
R20 mosaicism could be sporadic or inherited: parent-to child transmission has been reported in a few exceptional families. Genetic counseling is recommended.
Management and treatment
Seizures associated with r20 are often refractory to medications and there is no specific treatment regimen for the disorder. A more favorable outcome has been reported with the combination of valproate and lamotrigine. Ketogenic diet can be helpful, with better results if introduced at seizure onset. Resective brain surgery is not a therapeutic option. Mild improvement with vagus nerve stimulation is reported.
Prognosis
Prognosis is generally poor since epilepsy is drug resistant, remaining into adulthood. Cognitive performance can remain locked at the time of epilepsy onset or worsen over time.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Dr Valentina DE GIORGIS | EpiCARE* - Pr Rima NABBOUT | EpiCARE* -  Allison WATSON | EpiCARE*


                                * European Reference Network