Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

Abstract

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

Presenting Patterns of Genetically Determined Developmental Encephalopathies With Epilepsy and Movement Disorders: A Single Tertiary Center Retrospective Cohort Study

“…The literature provides few epidemiological data about the distribution of molecular genetic diagnosis of developmental encephalopathies with epilepsy and movement disorders in the pediatric populations while several recent studies reported detailed and updated genotype-phenotype correlations for about 60 single-gene related disorders other than historically wellknown patterns such as the ones of Rett or Angelman syndrome (1,(13)(14)(15)(16)(17)(18). The studies including epidemiological data were often hardly comparable because of several methodological differences in terms of analyzed cohorts, inclusion and exclusion criteria, and modalities of data collection (1,2). Most of these data were not statistically significant because of the rare or ultrarare prevalence of the analyzed diseases.…”

“…The spectrum of genetic developmental encephalopathies presenting with epilepsy and movement disorders has significantly expanded in the last decade with the characterization of more than 100 monogenic disorders, and several genotype-phenotype correlation studies prominently focusing on single genes, specific pathogenic copy number variants, or non-mendelian conditions ( 1 , 2 ).…”

Neonatal Seizures: An Overview of Genetic Causes and Treatment Options

“…Therefore, pathogenic variants of these genes may further perturb the susceptible immature brain, making it more prone to developing epileptic attacks, which, in their turn, may be responsible for poor neurodevelopmental outcomes. Usually, seizures are very heterogenous in this period of life, though the prevalent types in the neonatal age are tonic, myoclonic or spasms [10]. Clinical semiology is essential since it may reflect the aetiology.…”

“…In addition, it is noteworthy mentioning that an increasing number of genes not traditionally considered as causative of neonatal-onset epilepsies or DEEs has been described. In this regard, a recent review shed light on the several genetic aetiologies of phenotypes with neonatal-onset epilepsies or DEEs and movement disorders, which often include genes typically considered as causative of later-onset disorders [10].…”

“…It is possible to taxonomize epilepsies in more than one category (genetic, metabolic, structural, immune and unknown) which are no longer considered mutually exclusive. Since genetic, metabolic and structural causes explain the 10-15% of all neonatal seizures, this approach is useful in providing an appropriate diagnostic assessment, allowing an adequate and early treatment initiation and preventing poor outcomes [1,2,4,7,8,10].…”