Mosaic ring chromosome 6 and clinical significance in resistant epilepsy
Abstract
To the Editor Epilepsy is a neurologic disease occuring as a result of sudden abnormal and synchronized discharges of a group of neurons in the central nervous system CNS characterized with convulsions 1 Genetic diseases with monogenic chormosomal and multi factorial inheritance are involved in the etiology in 40 of the patients with epilepsy 2 Very significant dysmorphic characteristics are present in most chromosamal disorders associated with epilepsy 3 We presented a 7 year old male patient who was referred to our clinic because of resistant epilepsy and whose chromosomal analysis on peripheral blood revealed mos 47 XY r 6 [3] 46 XY r 6 [40] 45 XY 6[7] Based on this case we aimed to discuss the significance of use of cytogenetic techniques and multidiciplinary study in understanding clinical and basic mechanisms of epilepsy Familial history of our patient who had mental retardation revealed no consanginuous marriage or recurrent abortus He was born from healthy parents from the second pregnancy and his perinatal history was normal On physical examination his body weight was found to be 20 kg 10 25th percentile his height was found to be 104 cm lt;3rd percentile and his head circumference was found to be 36 cm lt;3rd percentile The patient had dysmorphic characteristics including bilateral wide and borderline low set ears brachycephaly low frontal hair line wide and prominent nose micrognatia and microcephaly In addition he had high arched palate and irregular and overcrowded teeth Picture 1 Our patient had retardation in neuromotor development It was reported that he started to walk without support in the last one year with physiotherapy education The patient was receiving speech therapy In spite of this he could not make a long sentence composed of 3 4 words and talked indeterminedly Abdominal ultrasonography USG brain magnetic resonance imaging MRI and metabolic screening tests were found to be normal The intelligence quotient was measured to be 43 by WISC R Sleep electroencephalography EEG revealed diffuse epileptic changes The mother stated that the patient was diagnosed as epilepsy when he was 6 months old but he had generalized seizures 2 times a week despite all antiepileptic drugs used with different combinations Chromosomal analysis on peripheral blood was planned because of the dysmorphic characteristics epilepsy and mental retardation For karyotype analysis peripheral blood lymphocytes stimulated by phytohemaglutinine FHE were cultured for 72 hours Metaphase preparations obtained from the culture were stained using trypsin giemsa banding method GTG Cytogenetic examination of prometaphases revealed a chromosomal organization of mos 47 XY r 6 [3] 46 XY r 6 [40] 45 XY 6[7] Picture 2 Ring chromosome was observed to have a single centromer in CBG banding The karyotypes of the mother and the father were found to be 46 XX and 46 XY respectively Ring chromosome is defined as a structural chromosomal change occuring by adherence of the two ends of a normal chromosome forming a ring Ring chromosomes are observed rarely and are generally de novo 3 More than 90 of the patients with ring chromosome have been observed to be rare Phenotype and genotype may show difference since the amount of substance deleted at the ends varies from patient to patient 3 4 Ring chromosome 6 was defined by Moore et la 4 for the first time in a child with growth retardation Afterwards cases from different areas have been reported occasionally These diseases reported have generally been diagnosed postnatally but there are also patients who have been diagnosed prenatally 3 4 5 6 Chilren with ring chromosome 6 who have been reported until the present time in the literature have been observed to display a wide clinical spectrum ranging from normal intelligence level to neurologic and dysmorphic findings including epilepsy hydrocephaly microcephaly and mental retardation 5 6 Similarly our patient had dysmorphic characteristics including microcephaly and low set ears However the main significant findings in our patient included epilepsy and mental retardation Jajal et al 7 reported that the phenotypic properties caused by chromosome 6p deletion may be similar to the phenotype caused by ring chromosome 6 7 8 However Kara et al 3 showed that de novo mosaic ring chromosome 6 and deletions occuring at the end of chromosome 6q caused different clinical pictures This was thought to be related to the unstable state of ring chromosome in mitosis mosaicism of cells and variance of the regions where deletion occurs In the literature a relation has been shown between some chromosome regions and epilepsy by ldquo;linkage rdquo; analyses 6p22 32 and 6q23 25 which are among these regions were deleted in our patient explaining epilepsy Proteins coded by EPM2A EPM2B NHLRC1 genes defined in these regions have been shown to remove polysaccharides from the cell by tyrosine phosphatase activity 9 10 In patients in whome these genes are not functioning understanding complex genetic mechanisms is important in terms of defining neurotransmitters and ion channels determining the course of treatment Understanding genetic base in patients diagnosed with epileptic syndromes is the most significant step in determining treatment In addition to genetic counselling for the family understanding the physiopathology of the disease and development of new therapeutic methods will be only possible by displaying the profile of the genetics of epilepsy Development of more specific treatments with studies directed to determine known genes and chromosome anomalies and potential prevention of the etiopathogenetic process will pioneer applicable treatment methods in the future Zeynep Ocak1 Sevil Bilir Göksügür2 Ertuğrul Mevlüt Kocaman1 1Abant Izzet Baysal University Medical Faculty Medical Genetics Bolu Turkey 2Abant Izzet Baysal University Medical Faculty Department of Pediatrics Bolu Turkey References 1 Dulac O Berkovic S Shields WD Gene searching in the epilepsies: Clinical requirements prior to molecular genetic study ILAE commission on the search for epilepsy genes Subcomission on phenotype characterization Epilepsia 2002; 43: 1262 1267 2 Gardiner MR Impact of our understanding of the genetic aetiology of epilepsies J Neurol 2000; 247: 327 334 3 Kara N Okten G Gunes S Saglam Y Tasdemir H Pinarli F An epileptic case with mosaic ring chromosome 6 and 6q terminal deletion Epilepsy Research 2008; 80: 219 223 4 Moore CM Heller RH Thomas GH Developmental abnormalities associated with a ring chromosome 6 J Med Genet 1973; 10: 299 303 5 Urban M Bommer C Tennstedt C Lehmann K Thiel G Wegner RD Bollmann R Becker R Schulzke I Körner H Ring chromosome 6 in three fetuses: case reports literature review and implications for prenatal diagnosis Am J Med Genet 2002; 108: 97 104 6 Bertini V De Vito G Costa C Simi P Valetto A Isolated 6q terminal deletions: an emerging new syndrome Am J Med Genet 2006; 140: 74 81 7 Jalal SM Macias VR Roop H Morgan F King P Two rare cases of 6p partial deletion Clin Genet 1989; 36: 196 199 8 Ahza H Ramlı S Loong T Salahshourıfar I Zılfalıl B Yusoff N De novo ring chromosome 6 in a child with multiple congenital anomalies Kobe J Med Sci 2010; 56: 79 84 9 Ianzano L Young EJ Zhao XC Chan EM Rodriguez MT Torrado MV Scherer SW Minassian BA Loss of function of the cytoplasmic isoform of the protein laforin EPM2A causes Lafora progressive myoclonus epilepsy Hum Mutat 2004; 23: 170 176 10 Ianzano L Zhang J Chan EM Zhao XC Lohi H Scherer SW Minassian BA Lafora progressive myoclonus epilepsy mutation database EPM2A and NHLRC1 EMP2B genes Hum Mutat 2005; 26: 397
Keywords
Dirençli epilepsi olgusunda mozaik ring kromozom 6 ve klinik önemi
Abstract
Epilepsi, merkezi sinir sisteminde (MSS) bir grup nöronun ani, anormal, aşırı ve senkronize deşarjları sonucu ortaya çıkan nöbetlerle seyreden nörolojik bir hastalıktır (1). Epilepsili hastaların yaklaşık %40’ının etiolojisinde monojenik, kromozomal ve çok etmenli kalıtımlı genetik hastalıklar bulunmaktadır (2). Epilepsi ile birliktelik gösteren kromozomal bozuklukların çoğunda çok önemli dismorfik özellikler bulunmaktadır (3). Biz tedaviye dirençli epilepsi ile kliniğimize yönlendirilen periferik kandan kromozom analizi sonucu mos 47,XY,+r(6)[3]/ 46,XY, r(6)[40]/ 45,XY,-6[7] olarak bulunan yedi yaşındaki erkek hastayı sunduk. Bu olgu üzerinden epilepside klinik ve temel mekanizmaların anlaşılmasında sitogenetik tekniklerin kullanımı ve çok disiplinli çalışmanın önemini tartışmayı amaçladık.
Keywords
