Genetic Epileptic and Developmental Encephalopathies of the Early Age: From Symptoms Genetic Testing to Diagnosis

Abstract

Introduction. The problem of early diagnostics of orphan diseases is relevant for most countries of the world. The challenge for healthcare is to prevent new cases of orphan diseases by providing medical genetic testing and counseling at the stage of family planning. Department of psychoneurology of the State Intstitution "Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Medical Sciences of Ukraine" has been dealing with the problem of orphan diseases since 2012 and has significant experience in their diagnosis and treatment in children.The aim of paper: to develop an algorithm for the genetic diagnosis of epileptic and developmental encephalopathies in children with developmental delay and dimorphic features based on modern data on the application and interpretation of genetic methods. A case which demonstrate the complexity of interpreting the results and algorithms for early diagnosis of patients and the importance of medical and genetic counseling is presentedMaterial and methods: clinical and neurological examination, sleep video-EEG monitoring during night sleep, brain magnetic resonance imaging (3.0T), whole-exome sequencing (WES).Results. The article presents the algorithm of genetic diagnosis of orphan diseases in children with developmental and epileptic encephalopathies, developmental delay, and dimorphic features. A clinical case of a boy with general developmental delay and atonic epileptic seizures is presented. Sleep EEG-monitoring showed epileptiform activity in the stage of slow-wave sleep localized in the central-parietal and left temporal areas in the form of benign childhood epileptiform patterns.Whole-exome sequencing detected a variant of uncertain significance (VUS) c.5887C>T(p.Arg1963Cys) of SON gene in a heterozygous state, which leads to the replacement of arginine to cysteine. Mutations in the SON gene in the heterozygous state have been described in patients with Zhu-Tokita-Takenouchi-Kim syndrome (OMIM: 617140).Conclusions: It is important for pediatricians and neurologists to be aware of orphan diseases in children with developmental and epileptic encephalopaties and developmental delay. Genetic tests are wide available but they require competent interpretation by clinicists. After obtaining the results, it is important to compare the obtained result with the phenotype of patient. In case the phenotype of patient match and the results of genetic test, (detected VUS) this mutation could be etiological factor of the disease. In our case, the clinical signs coincided with those described in 2015 by the authors of the first description of Zhu-Tokita-Takenuchi-Kim syndrome, and therefore genetic testing helped to verify the final diagnosis. Therefore genetic counseling is extremely important for detection of etiology and prognosis of early developmental and epileptic encephalopathies/

Features of epileptic encephalopathy caused by SCN1A mutation

“…Проте, серед значної кількості отриманих відповідей в діагностиці та лікуванні захворювань нервової системи у дітей, перед фахівцями все ще стоїть значна кількість складних, невирішених запитань. Ми вже неодноразово наголошували у своїх публікаціях на тому, що окрім отримання результатів доступних методів генетичної діагностики, як-от NGS або WES, потрібно провести грамотну інтерпретацію результатів та підібрати максимально ефективний метод лікування [1]. У цій статті ми хотіли б розкрити ті проблеми, з якими може стикнутися дитячий невролог у діагностиці епілептичних енцефалопатій раннього дитячого віку, спричинених патологічними варіантами гена SCN1A.…”