A genetic diagnostic approach to infantile epileptic encephalopathies

Kamien, Benjamin; Cardamone, Michael; Lawson, John A.; Sachdev, Rani

doi:10.1016/j.jocn.2012.01.017

Cited by 23 publications

(20 citation statements)

References 79 publications

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“…It is notable that the patient with deletion of only SPTAN1 had no epileptic encephalopathy. 36,40 In addition, one patient had complete SPTAN1 deletion with partial deletion of STXBP1 (exons [16][17][18][19][20], and this patient also showed only profound ID with normal brain MRI. 36 Collectively, these results suggest that SPTAN1 haploinsufficiency alone does not cause epileptic encephalopathy or brainstem and cerebellar lesions, and that only in-frame SPTAN1 mutations at specific positions can cause specific phenotypes (SPTAN1 encephalopathy) in a dominant negative manner.…”

Section: Role Of Spectrinsmentioning

confidence: 91%

“…However, at present, the genetic diagnosis of EOEEs remains challenging; therefore, more detailed studies of EOEEs are needed to establish efficient gene testing based on detailed clinical information of EOEEs. 2,16,17 In 2010, we found de novo in-frame mutations in SPTAN1 in two patients showing early-onset West syndrome with severe hypomyelination and developmental delay. 18 SPTAN1 at 9q34.11 consists of 53 exons and encodes α-ΙΙ spectrin, which is essential for proper myelination in zebrafish.…”

Section: Introductionmentioning

confidence: 99%

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SPTAN1 encephalopathy: distinct phenotypes and genotypes

et al. 2015

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Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.

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Section: Role Of Spectrinsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

SPTAN1 encephalopathy: distinct phenotypes and genotypes

et al. 2015

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“…1). The “known” gene group included genes in which mutations are known to cause one or more epileptic encephalopathy syndromes (n=19) 2, 21, 25, 27, 28, 32–34 . We also selected two sets of candidate genes for epileptic encephalopathies.…”

Section: Methodsmentioning

confidence: 99%

“…Epileptic encephalopathies are a devastating group of epilepsies characterized by refractory seizures and cognitive arrest or regression associated with ongoing epileptic activity, and typically carry a poor prognosis 1 . De novo mutations in several known genes are responsible for some epileptic encephalopathies 2 . Furthermore, we and others have shown that rare, de novo copy number variants (CNVs) account for up to ~8% of cases 3, 4 .…”

Section: Introductorymentioning

confidence: 99%

Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

et al. 2013

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“…In the past few years, several genes, such as ARX 4 , CDKL5 5 and SPTAN1 6 , have been implicated in West syndrome based on a candidate gene sequencing approach 7, 8 . Furthermore, several recent exome-sequencing studies have shown that West syndrome probands exhibit an excess of loss of function de novo mutations, which plays an important role in West syndrome 9 .…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies

Lin

Liu

et al. 2017

Sci Rep

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Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of de novo mutations to EE. In this study, we utilized WES for identifying causal de novo mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious de novo mutations in DYNC1H1 and RTP1 in two trios. Expression profile analysis showed that DYNC1H1 and RTP1 are expressed in almost all brain regions and developmental stages. Interestingly, co-expression and genetic interaction network analyses suggested that DYNC1H1 and RTP1 are tightly associated with known epilepsy genes. Furthermore, we observed that the de novo mutations of DYNC1H1 were identified in several different neuropsychiatric disorders including EE, autism spectrum disorders and intellectual disabilities by previous studies, and these mutations primarily occurred in the functional domain of the protein. Taken together, these results demonstrate DYNC1H1 as a strong candidate and RTP1 as a potential candidate on the onset of EE. In addition, this work also proves WES as a powerful tool for the molecular genetic dissection of children affected by sporadic EE.

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A genetic diagnostic approach to infantile epileptic encephalopathies

Cited by 23 publications

References 79 publications

SPTAN1 encephalopathy: distinct phenotypes and genotypes

SPTAN1 encephalopathy: distinct phenotypes and genotypes

Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies

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