Clinical Report: CNVs (Deletions of 3p24.1, 6p12.2; 12q24.22) Detected by Array CGH in Patient with Microcephaly and Early Epileptic Encephalopathy with Infantile Spasms
Authors: Belousova Elena D. , Iourov Ivan I. , Shulyakova Irina V. , Tsyshkova Oxana N. 
Published: January 2023

Introduction: Infantile spasms (ISs) are an age-dependent epileptic seizures that are associated with mental retardation, autism, and cerebral palsy. They are part of epileptic encephalopathies such as West and Ohtahara syndromes and early myoclonic encephalopathy. There is growing evidence that ISs result from disturbances in important genetic pathways of brain development. Recent studies show that patients with ISs may have mutations in several genes including ARX, CDKL5, FOXG1, etc. as well as other candidate genes identified from pathogenic copy number variants (CNVs). Case study: The male child was born at term by normal delivery after non-complicated pregnancy. At 3 months of age infantile spasms (ISs) started alongside with deterioration of psychomotor development, affecting head control, reaching for objects and eye tracking. At time of hospitalization ISs were numerous (hundreds per day), they were combined with myoclonic seizures and episodes of motor arrest with staring. Child had axial hypotonia, lack of hand grasping and eye contact. An electodecremental event during spasms, generalized discharges of polyspykes during myoclonias and focal spikes during motor arrest were recorded. Brain MRI showed non-specific brain atrophy. Metabolic screening, including urine and serum amino acids, organic acids, lactate, pyruvate and liver function tests, was normal. Treatment with vigabatrin with doses up to 192 mg/kg/ day was ineffective and injections of synthetic analog of ACTH were started. But the child deteriorated progressively, the burst-suppresion pattern was recorded on EEG and an epileptic status developed. IV benzodiazepine and valproic acid were only partly efficacious. Refractory epileptic status was stopped by general anaesthesia. The child survived but his developmental prognosis is poor. Since the child lacked features specific for any aetiological diagnosis an array comparative genome hybridization (array CGH) was performed. It’s revealed several copy number variants (CNVs): deletion of 3p24.1 with involvement of gene EOMES that encodes the protein-regulator of neurogenesis; deletion of 6p12.2 with involvement of gene TMEM14A (inhibitor of apoptosis) and deletion of DNA of gene FBXO21, which is highly expressed in prefrontal cerebral cortex. Discussion: Epileptic encephalopathies (EE) are severe brain disorders in which the epileptic electrical discharges may contribute to progressive psychomotor dysfunction. There are single gene disorders among them (with well described phenotype) but majority of cases remained unexplained, sometimes because of the fact that clinical and EEG features of different EE are overlapping. Molecular karyotyping can help us in defining their etiology. In our patient with EE with ISs the rare combination of copy number variations (CNVs) was found. We speculate that these CNVs (including genes playing important role in brain development) may be responsible for severe epileptic encephalopathy with ISs.