Incorporating epilepsy genetics into clinical practice: a 360°evaluation

Oates, Stephanie; Tang, Shan; Rosch, Richard; Lear, Rosalie; Hughes, Elaine; Williams, Ruth; Larsen, Line H.G.; Qin, Hao; Dahl, Hans Atli; Møller, Rikke S.; Pal, Deb K.

doi:10.1038/s41525-018-0052-9

Cited by 47 publications

(39 citation statements)

References 48 publications

(49 reference statements)

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“…However, it has also been seen in a patient with drug‐resistant focal epilepsy and mild ID . In contrast to the mild SCN8A ‐related epilepsies associated with Gly1483Lys and Asn1877Ser, the Ile1327Val variant has been reported in four unrelated patients with a devastating neonatal or even intrauterine onset DEE associated with severe to profound ID, hypotonia, and movement disorder …”

Section: Resultsmentioning

confidence: 99%

“…Pathogenic variants in SCN8A have originally been described in patients with developmental and epileptic encephalopathy (DEE), accounting for approximately 1% of DEEs . The number of SCN8A ‐related phenotypes is rapidly increasing, with the inclusion of SCN8A in gene panels and the expanded use of whole exome sequencing for diagnostic assessment of patients with epilepsy syndromes . Recently, it became obvious that SCN8A could cause more benign forms of epilepsy with normal cognition and treatable seizures .…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

2019

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Pathogenic variants in SCN8A have originally been described in patients with developmental and epileptic encephalopathy (DEE). However, recent studies have shown that SCN8A variants can be associated with a broader phenotypic spectrum, including the following: (1) Patients with early onset, severe DEE, developing severe cognitive and motor regression, pyramidal/extrapyramidal signs, and cortical blindness. Severe SCN8A-DEE is characterized by intractable seizures beginning in the first months of life. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms (apnea, cyanosis, mydriasis), evolving to clonic or bilateral tonic-clonic manifestations. Spasm-like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. Electroencephalograms (EEGs) show progressive background deterioration and multifocal abnormalities, predominant in the posterior regions. (2) Sporadic and familial patients with mild-tomoderate intellectual disability, discrete neurological signs, and treatable epilepsy. EEG is abnormal in half of the cases, showing multifocal or diffuse epileptiform abnormalities. (3) Familial cases with benign infantile seizures, sometimes associated with paroxysmal dyskinesia later in life, with no other neurological deficits, normal cognition, and usually normal interictal EEG. (4) Patients without epilepsy but with cognitive and/or behavioral disturbances, or with movement disorders. Extrapyramidal features, such as dyskinesia, ataxia, and choreoathetosis are common in all groups. Early death has been reported in about 5% of the patients, most often in the subgroup of severe DEE. Premature death occurs during early childhood and often for causes other than sudden unexpected death in epilepsy. All epilepsy subgroups exhibit better seizure control with sodium channel blockers, usually at supratherapeutic doses in the severe cases. In severe SCN8A-DEE, ketogenic diet often has a good effect, whereas levetiracetam has a negative effect, if any. The familial SCN8A-related epilepsies show an autosomal dominant pattern of inheritance, whereas the vast majority of SCN8A-DEEs occur de novo.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

2019

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“…Genetic Characteristics In Drug-resistant Epilepsy Of Published Studies Table 3 provides a summary of previous studies about genetic characteristics in DRE [12][13][14][15][16][17][18][19][20][21]. Regardless of varied molecular diagnostic tool used between studies, some gene mutations were found to appear repeatedly, such as SCN1A (5.6%, n = 74/1308), followed by SCN8A (1.37%, n = 18/1308), TSC2 (1.22%, n = 16/1308), SCN2A (1.07%, n = 14/1308) and KCNQ2 (0.99%, n = 13/1308) 3).…”

Section: Discussionmentioning

confidence: 99%

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Lin

Chou

Hong

2020

Preprint

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Background Drug-resistant epilepsy (DRE) affects 7–20% of children with epilepsy. Although some risk factors for DRE have been identified, the results have not been consistent. Moreover, data regarding the risk factors for epilepsy and its seizure outcome in the first 2 years of life are limited. Methods We analyzed data for children aged 0–2 years with epilepsy and neurodevelopmental disability (NDD) from January, 2013, through December, 2017. These patients were followed up to compared the risk of DRE in patients with genetic defect (genetic group) with that without genetic defect (nongenetic group). Additionally, we conducted a meta-analysis to identify the pooled prevalence of genetic factors in children with DRE Results A total of 96 patients were enrolled. A total of 68 patients were enrolled in the nongenetic group, whereas 28 patients were enrolled in the genetic group. The overall DRE risk in the genetic group was 6.5 times (95% confidence interval [CI], 2.15–19.6; p = 0.03) higher than that in the nongenetic group. Separately, a total of 1308 DRE patients were participated in the meta-analysis. The pooled prevalence of these patients with genetic factors was 22.8% (95% CI 17.4–29.3) Conclusions The genetic defect plays a crucial role in the development of DRE in younger children with epilepsy and NDD. The results can serve as a reference for further studies of epilepsy panel design and may also assist in the development of improved treatments and prevention strategies for DRE.

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“…Genetic insights have been particularly transformative in our understanding of some of the most severe disorders of neurodevelopment, known now as developmental and epileptic encephalopathies (DEEs) (Scheffer et al, 2016). DEEs usually occur as isolated cases in families, yet in a large proportion of cases, causative de novo mutations in single genes can now be identified from clinical genetic diagnostics (Epi et al, 2013;Oates et al, 2018). The most common genes and their functional effects are illustrated in Figure 1.…”

Section: Severe De Novo Mutations and Genomic Alterations In Neurodevmentioning

confidence: 99%

Functional Genomics of Epilepsy and Associated Neurodevelopmental Disorders Using Simple Animal Models: From Genes, Molecules to Brain Networks

Rosch

Burrows

Jones

et al. 2019

Front. Cell. Neurosci.

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The genetic diagnosis of patients with seizure disorders has been improved significantly by the development of affordable next-generation sequencing technologies. Indeed, in the last 20 years, dozens of causative genes and thousands of associated variants have been described and, for many patients, are now considered responsible for their disease. However, the functional consequences of these mutations are often not studied in vivo, despite such studies being central to understanding pathogenic mechanisms and identifying novel therapeutic avenues. One main roadblock to functionally characterizing pathogenic mutations is generating and characterizing in vivo mammalian models carrying clinically relevant variants in specific genes identified in patients. Although the emergence of new mutagenesis techniques facilitates the production of rodent mutants, the fact that early development occurs internally hampers the investigation of gene function during neurodevelopment. In this context, functional genomics studies using simple animal models such as flies or fish are advantageous since they open a dynamic window of investigation throughout embryonic development. In this review, we will summarize how the use of simple animal models can fill the gap between genetic diagnosis and functional and phenotypic correlates of gene function in vivo. In particular, we will discuss how these simple animals offer the possibility to study gene function at multiple scales, from molecular function (i.e., ion channel activity), to cellular circuit and brain network dynamics. As a result, simple model systems offer alternative avenues of investigation to model aspects of the disease phenotype not currently possible in rodents, which can help to unravel the pathogenic substratum in vivo.

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Incorporating epilepsy genetics into clinical practice: a 360°evaluation

Cited by 47 publications

References 48 publications

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Functional Genomics of Epilepsy and Associated Neurodevelopmental Disorders Using Simple Animal Models: From Genes, Molecules to Brain Networks

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