Two novel PCDH19 mutations in Russian patients with epilepsy with intellectual disability limited to females: a case rep

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Two novel PCDH19 mutations in Russian patients with epilepsy with intellectual disability limited to females: a case report Anastasiya Aleksandrovna Kozina1,2, Elena Grigorievna Okuneva3, Natalia Vladimirovna Baryshnikova2,3, Inessa Dmitrievna Fedonyuk4, Alexey Aleksandrovich Kholin2,4, Elena Stepanovna Il’ina4, Anna Yurievna Krasnenko3, Ivan Fedorovich Stetsenko3, Nikolay Alekseevich Plotnikov3, Olesia Igorevna Klimchuk3, Ekaterina Ivanovna Surkova3* and Valery Vladimirovich Ilinsky1,2,3,5

Abstract Background: Epilepsy with intellectual disability limited to females (Epileptic encephalopathy, early infantile, 9; EIEE9) is a rare early infantile epileptic encephalopathy characterized by an unusual X-linked inheritance: females with heterozygous mutations are affected, while hemizygous males are not. Case presentation: We describe the clinical and molecular characteristics of 2 Russian patients with EIEE9 (females, ages 3 years and 7 years). In these patients seizures developed at the age of 3 years. Additionally, for our patients and for cases described in the literature we searched for a possible relationship between the type and localization of the mutation and the EIEE9 clinical phenotype. Conclusions: We identified two novel PCDH19 mutations in EIEE9 patients: a missense mutation in exon 1 (c.1236C > A, p.Asp412Glu) and a frameshift in exon 3 (c.2386_2387insGTCT, p.Thr796fs). We conclude that the age of seizure onset and the presence of intellectual disability may depend not on the type and localization of PCDH19 mutations, but on the X-inactivation status. The study also highlights the need to screen for EIEE9 among young female epilepsy patients. Keywords: Epilepsy with intellectual disability limited to females, EIEE9, PCDH19, Protocadherin 19, Case report

Background Epilepsy with intellectual disability limited to females (early infantile epileptic encephalopathy type 9, OMIM 300088, EIEE9) is a rare X-linked disease affecting heterozygous females and sparing hemizygous males. EIEE9 was first described by [1]. The main characteristic of EIEE9 is early infantile (6–36 months) onset of seizures of various types (tonic, clonic, tonic-clonic, partial seizures) and severity [2]. Seizures usually are provoked by fever and are resistant to anti* Correspondence: [email protected] 3 Genotek Ltd., Nastavnicheskii pereulok 17/1, 105120 Moscow, Russia Full list of author information is available at the end of the article

epileptic drugs [3]. Additionally, patients often have cognitive impairment up to severe intellectual disability [4]. EIEE9 is caused by mutations in the PCDH19 (protocadherin 19) gene [5]. This gene is located on the X-chromosome, thus EIEE9 has an X-linked pattern of inheritance. Disorders with the same type of inheritance are typically characterized by affected males and unaffected carrier females. However, core clinical symptoms of EIEE9 manifest only in females, while carrier males may have several neuropsychiatric features such as obsessional tendencies [3]. Males w