MYOCLONIC ASTATIC EPILEPSY IN A PATIENT WITH A DE NOVO 4q21.22q21.23 MICRODUPLICATION.

Summary: Myoclonic astatic epilepsy in a patient with a de novo 4q21.22q21.23 microduplication: Myoclonicastatic epilepsy (MAE) is a rare form of symptomatic generalized epilepsy of uncertain etiology. To search the possible genetic basis of the disorder, here we investigate a 15 year-old patient with MAE, who is the only person presenting epilepsy in the family.High resolution array-CGH analysis was conducted on DNA extracted from peripheral blood of the patient and the parents. The copy number variant(s) (CNVs) identified were further confirmed by Fluorescent In Situ Hybridization (FISH). The array-CGH identified a de novo microduplication of about 778 Kb in the chromosome region 4q21.22-q21.23, involving 11 genes.This is the first report of a de novo CNV in MAE. The genes involved in the duplication are potential candidates that can be investigated in the future to determine their exact role in the etiopathogenesis of the disorder. However, we suggest performing microarray chromosomal analysis in patients with MAE, since rare de novo CNVs could be identified, and this is known to affect the diagnostic process and recurrence risk assessment.Key-words: Myoclonic-astatic epilepsy - Genetics - Duplication 4q22 - Lacosamide - De novo copy number variation. _INTRODUCTIONMyoclonic-astatic epilepsy (MAE) is also known as Doose syndrome, since it was first described as a separate nosological entity by Dr. Herman Doose in 1970 (3). Recently, the International League Against Epilepsy (ILAE) classified MAE as 1 of the 11 childhood-onset "electroclinical syndromes", together with other epileptic encephalopathies affecting cognition, such as Landau-Klefiher and Lennox-Gastaut (LGS) (1).The cause of this syndrome is unknown, but there is strong evidence suggesting the presence of a genetic background. In fact, twin studies have shown a higher concordance rate of 83-94% in monozygotic twin pairs compared to 65-71% in dizygotic twin pairs. Furthermore, a positive family history of seizures in first-, second-, or third-degree relatives has been reported in about one third of cases; this value is almost 200 times higher than in the general population (2). However, in spite of many studies being performed, the genetic architecture of MAE still remains elusive (5,6,10).Here we report on a patient with MAE carrier of a de novo microduplication on the chromosome region 4q21.22q21.23.METHODS AND RESULTSCLINICAL REPORTA male 15 year-old patient, the first child of healthy unrelated parents, was bom at 38 weeks of gestational age after an uncomplicated pregnancy. The psychomotor development of the child was normal until the 2.1 years of age when he suffered from a simple febrile seizure. A few months later, he had the first afebrile brief seizure of a generalized tonic-clonic type. After the onset of seizures, he began to display a mild cognitive impairment and growth retardation. Results from hematolog-ical, biochemical and metabolic examinations were normal, as well as a brain MRI. A few months following the first seizure, the child devel-oped daily brief, generalized myoclonic jerks of the body, isolated or in short series (two to three events). Proximal muscles were more involved, with a sudden flexion of the head ("head nodding") and trunk with loss of urine. Frequently, astatic seizures were preceded by myoclonus. He experienced atonic seizures characterized by a brief (2-4 seconds) generalized loss of postural tone that resulted in his falling, with immediate recovery. Moreover, the patient had atypical absences often associated with reduction of muscle tone. Over time, seizures occurred more frequently during night time sleep than during the day (Fig. 1 A). He had two episodes non-convulsive status epilepticus lasting 8 hours with impairment of consciousness together with stupor and apathy; in these occasions, EEG revealed continuous generalized epileptic activity (Fig. IB). …