The landscape of early infantile epileptic encephalopathy in a consanguineous population

Abstract

Epileptic encephalopathies (EE), are a group of age-related disorders characterized by intractable seizures and electroencephalogram (EEG) abnormalities that may result in cognitive and motor delay. Early infantile epileptic encephalopathies (EIEE) manifest in the first year of life. EIEE are highly heterogeneous genetically but a genetic etiology is only identified in half of the cases, typically in the form of de novo dominant mutations. Method: This is a descriptive retrospective study of a consecutive series of patients diagnosed with EIEE from the participating hospitals. A chart review was performed for all patients. The diagnosis of epileptic encephalopathy was confirmed by molecular investigations in commercial labs. In silico study was done for all novel mutations. A systematic search was done for all the types of EIEE and their correlated genes in the literature using the Online Mendelian Inheritance In Man and PubMed databases. Results: In this case series, we report 72 molecularly characterized EIEE from a highly consanguineous population, and review their clinical course. We identified 50 variants, 26 of which are novel, causing 26 different types of EIEE. Unlike outbred populations, autosomal recessive EIEE accounted for half the cases. The phenotypes ranged from self-limiting and drug-responsive to severe refractory seizures or even death. Conclusions: We reported the largest EIEE case series in the region with confirmed molecular testing and detailed clinical phenotyping. The number autosomal recessive predominance could be explained by the society's high consanguinity. We reviewed all the EIEE registered causative genes in the literature and proposed a functional classification. IntroductionEpileptic encephalopathies (EE), are disorders of the developing brain characterized by intractable seizures and electroencephalogram (EEG) abnormalities, that typically result in cognitive and motor delay, regression, and sometimes death. [1,2] Forty percent of seizures in children aged three years or less can be classified as EE [3]. Early infantile epileptic encephalopathy (EIEE) have their onset during infancy and are highly variable in etiology and natural history. While seizure is the core symptom for all EIEE syndromes often accompanied by

Spectrum of Movement Disorders in GNAO1 Encephalopathy: in-depth Phenotyping and Literature Review

“…Patient 3 with the novel variant p.Aal301del showed severe developmental delay and progressive spasticity without any obvious paroxysmal movements. Patient 4, who carried the variant p.Ala227Val, presented with infantile hypotonia without early-onset epilepsy, unlike a previous report of infantile spasm and early-onset epileptic encephalopathy as a main presentation in patients with the same variant [7,17]. It is obvious that a genotype-phenotype correlation exists, at least in certain loci.…”

A de novo SCN8A heterozygous mutation in a child with epileptic encephalopathy: a case report

“…MRI studies are typically normal [15]. There is no clear correlation between phenotypic severity and genetic mutations so far [1, 4]. SCN8A mutations lead to premature channel opening, impaired inactivation and increased persistent current.…”

“…One third of them shows pharmacoresistance, and 40% of patients who are younger than 3 years are related to the epileptic encephalopathy [1]. Epileptic encephalopathy (EE) refers to a heterogenous group of epileptic disorders, characterized by intractable seizure, impairment and regression of cognitive and behavioral functions [1, 2]. The causes of EE include structure anomalies, inborn errors of metabolism and genetic insults.…”

Modeling Genetic Epileptic Encephalopathies using Brain Organoids

“…Epilepsy affects around 50 million people worldwide and is considered the most frequent chronic neurologic condition in children (Aaberg et al ., 2017; Blumcke et al ., 2017). Approximately 40% of seizures in the early years of life are accounted for by early infantile epileptic encephalopathies (EIEEs), which are pathologies of the developing brain, characterized by intractable epileptiform activity and impaired cerebral and cognitive functions (Lado et al ., 2013; Shao and Stafstrom, 2016; Nashabat et al ., 2019). Several genes have been implicated in causing EIEEs (McTague et al ., 2016).…”