Epileptic Encephalopathy in Childhood: A Stepwise Approach for Identification of Underlying Genetic Causes

Abstract

Epilepsy is one of the most common neurological disorders in childhood. Epilepsy associated with global developmental delay and cognitive dysfunction is defined as epileptic encephalopathy. Certain inherited metabolic disorders presenting with epileptic encephalopathy can be treated with disease specific diet, vitamin, amino acid or cofactor supplementations. In those disorders, disease specific therapy is successful to achieve good seizure control and improve long-term neurodevelopmental outcome. For this reason, intractable epilepsy with global developmental delay or history of developmental regression warrants detailed metabolic investigations for the possibility of an underlying treatable inherited metabolic disorder, which should be undertaken as first line investigations. An underlying genetic etiology in epileptic encephalopathy has been supported by recent studies such as array comparative genomic hybridization, targeted next generation sequencing panels, whole exome and whole genome sequencing. These studies report a diagnostic yield up to 70%, depending on the applied genetic testing as well as number of patients enrolled. In patients with epileptic encephalopathy, a stepwise approach for diagnostic work-up will help to diagnose treatable inherited metabolic disorders quickly. Application of detailed genetic investigations such as targeted next generation sequencing as second line and whole exome sequencing as third line testing will diagnose underlying genetic disease which will help for genetic counseling as well as guide for prenatal diagnosis. Knowledge of underlying genetic cause will provide novel insights into the pathogenesis of epileptic encephalopathy and pave the ground towards the development of targeted neuroprotective treatment strategies to improve the health outcome of children with epileptic encephalopathy.

Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches

“…Seizure types include; infantile spasms (in one-third), tonic–clonic seizures, tonic seizures, atonic seizures, gelastic seizures, and myoclonic seizures. Other clinical features variably present include cataracts, spastic quadriparesis, megaloblastic anemia, and irritability [ 34 ]. The brain MRI may show delayed myelination followed by cerebral atrophy.…”

“…Neu–Laxova syndrome has recently been shown to be a serine biosynthesis defect caused by PHGDH or PSAT1 deficiency [ 34 ]. This syndrome is characterized by dysmorphic facies, microcephaly, intrauterine growth restriction, skin abnormalities (ichthyosis and hyperkeratosis), and flexion deformities of the limbs.…”

Diagnostic Testing in Epilepsy Genetics Clinical Practice

“…Conventional etiological evaluation of epilepsy patients was complex and traditionally included karyotype, molecular karyotyping, and individually tailored serial metabolic and molecular genetic tests [5]. Secondary invasive tests such as biopsies and cerebrospinal fluid examination, aid in diagnosis in a small percentage of additional cases [15]. The main performance characteristic of any genetic testing modality is a diagnostic yield [16].…”

A clinical case of epilepsy in a female patient with double mutations in the SCN2A and PCDH19 genes

“…По данным J. Patel и S. Mercimek-Mahmutoglu [5], среди 110 пациентов с резистентной эпилепсией, задержкой моторного и психического развития генетические причины выявлены в 28% случаев. Болезни обмена (дефицит пиридоксина, болезнь Менкеса, GLUT-1 и др.)…”