Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features

Morrison‐Levy, Nadine; Borlot, Felippe; Jain, Puneet; Whitney, Robyn

doi:10.1016/j.pediatrneurol.2020.12.001

Cited by 37 publications

(60 citation statements)

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“…More than 30 point mutations in GNAO1 have been described to underline different manifestations of pediatric encephalopathy: epileptic seizures, motor dysfunctions, or the combination of both, accompanied by a developmental delay [14][15][16]37]. These clinical features place GNAO1-encephalopathy into the bigger group of developmental and epileptic encephalopathies [38,39].…”

Section: Discussionmentioning

confidence: 99%

“…Advances in the next-generation whole-exome sequencing have identified multiple de novo missense mutations in GNAO1-the gene encoding Gαo-as the cause of rare yet severe neurological syndromes ranging from developmental delay with various movement disorders to early onset developmental and epileptic encephalopathy (DEE) [14][15][16]. As epilepsy affects nearly 0.7% of the population with about one-third lacking effective treatment [17,18], the number of cases with de novo GNAO1 mutations is expected to increase as sequencing of patients is further performed.…”

Section: Introductionmentioning

confidence: 99%

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Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Solis

Кожанова

Koval

et al. 2021

Cells

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Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Solis

Кожанова

Koval

et al. 2021

Cells

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“…DEEs are primarily attributed to genetic causes and while recessive and X-linked variants have been found, the majority of patients show de novo pathogenic variants [ 2 ]. Recently, an increasing number of DEE cases have been correlated with variants in ion channel genes [ 3 ].…”

Section: Main Textmentioning

confidence: 99%

De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

et al. 2021

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Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

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“…SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) is a rare and serious genetic epilepsy syndrome characterized by early-onset developmental delay and regression, cognitive impairment, and multiple intractable seizure types. [1][2][3] The SCN8A gene is highly expressed in the central nervous system and encodes the Nav1.6 voltage-gated sodium ion channel, which has a major role in regulating the excitatory neuronal networks in the brain. [1][2][3] The first human epileptogenetic SCN8A mutation to be identified was a missense gain-offunction mutation that altered the biophysical properties of the Nav1.6 sodium channel, as reported by Veeramah et al in 2012.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] The SCN8A gene is highly expressed in the central nervous system and encodes the Nav1.6 voltage-gated sodium ion channel, which has a major role in regulating the excitatory neuronal networks in the brain. [1][2][3] The first human epileptogenetic SCN8A mutation to be identified was a missense gain-offunction mutation that altered the biophysical properties of the Nav1.6 sodium channel, as reported by Veeramah et al in 2012. [4][5][6] Subsequent studies have confirmed the critical role of SCN8A in the initiation and propagation of action potentials and neuronal activity in the brain, and almost 400 individuals with SCN8A-related epilepsy have been described in the literature or documented in registries.…”

Section: Introductionmentioning

confidence: 99%

Clinical Characteristics and Treatment Experience of Individuals with SCN8A Developmental and Epileptic Encephalopathy (SCN8A-DEE): Findings from an Online Caregiver Survey

Cutts

Savoie

Hammer

et al. 2021

Preprint

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PurposeSCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. Variants in the SCN8A gene are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8A-related epilepsies.MethodsA 36-question online survey was developed to obtain de-identified data from caregivers of children with SCN8A-related epilepsy. The survey included questions on genetic diagnosis, disease manifestations/comorbidities, seizure severity/type, current/prior use of antiseizure medicines (ASMs), and best/worst treatments per caregiver perception.ResultsIn total, 116 survey responses (87 USA, 12 Canada, 12 UK, 5 Australia) were included in the quantitative analysis. Generalized tonic/clonic was the most common seizure type at onset and time of survey; absence and partial/focal seizures were also common. Most patients (77%) were currently taking ≥2 ASMs; 50% had previously tried and stopped ≥4 ASMs. Sodium channel blockers (oxcarbazepine, phenytoin, lamotrigine) provided the best subjective seizure control and quality of life.ConclusionThe SCN8A-DEE patient population is heterogeneous and difficult to treat, with high seizure burden and multiple comorbidities. The high proportion of patients who previously tried and stopped ASMs indicates a large unmet treatment need. Further collaboration between families, caregivers, patient advocates, clinicians, researchers, and industry can increase awareness and understanding of SCN8A-related epilepsies, improve clinical trial design, and potentially improve patient outcomes.HIGHLIGHTSThis is the first survey-based study of caregiver experiences in SCN8A-DEECaregivers report a broad range of seizure types and genetic variants in patientsPatients generally suffer from high seizure burden and multiple comorbiditiesResults suggest new treatments and standardized treatment protocols are neededPatient-centered research may improve awareness of SCN8A-DEE and patient outcomes

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Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features

Cited by 37 publications

References 101 publications

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

Clinical Characteristics and Treatment Experience of Individuals with SCN8A Developmental and Epileptic Encephalopathy (SCN8A-DEE): Findings from an Online Caregiver Survey

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