Inherited Developmental and Epileptic Encephalopathies

Bartolini, Emanuele

doi:10.3390/neurolint13040055

Cited by 13 publications

(7 citation statements)

References 92 publications

(101 reference statements)

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“…Many genetic abnormalities were associated with the late onset of ES (beyond 1 year of age). Some genes like ALDH7A1, CDKL5, KCNQ2, KCNT1, NTRK2, STXBP1, UGP2 , and WWOX characteristically had an early infantile‐onset in the current cohort similar to that described previously, while genetic variations in NRROS and SYNGAP1 (2/3) had onset of ES beyond 1 year of life like that reported in most patients with these disorders 10,12–15,21,27 …”

Section: Discussionsupporting

confidence: 82%

“…Some genes like ALDH7A1, CDKL5, KCNQ2, KCNT1, NTRK2, STXBP1, UGP2, and WWOX characteristically had an early infantile-onset in the current cohort similar to that described previously, while genetic variations in NRROS and SYNGAP1 (2/3) had onset of ES beyond 1 year of life like that reported in most patients with these disorders. 10,[12][13][14][15]21,27 Microcephaly, facial dysmorphism, movement disorders, behavioral abnormalities, and non-specific neuroimaging findings were not uncommon in the current cohort, as reported previously with other developmental epileptic encephalopathies. [13][14][15] Therapeutic response to initial hormonal therapy was much higher than that reported in IESS from South Asia, suggesting a relatively better epilepsy outcome in genetic IESS.…”

Section: Phenotypic Features (N = 124) N (%)supporting

confidence: 84%

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Landscape of genetic infantile epileptic spasms syndrome—A multicenter cohort of 124 children from India

et al. 2023

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ObjectiveLiterature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce from developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children.MethodsBetween January 2021 and June 2022, this cross‐sectional, study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural‐genetic and structural‐metabolic etiology, were recruited and underwent detailed in‐person assessment for phenotypic characterisation. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analysed.ResultsOf 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant‐55.2%, recessive‐14.2%), while the rest had X‐linked inheritance. Underlying chromosomal disorders included trisomy 21 (n=14), Xq28 duplication (n=2), and others (n=3). Trisomy 21 (n=14), ALDH7A1(n=10), SCN2A (n=7), CDKL5 (n=6), ALG13 (n=5), KCNQ2 (n=4), STXBP1 (n=4), SCN1A (n=4), NTRK2 (n=4), and WWOX (n=4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre‐existing developmental delay (94.3%), early age at onset of ES (<6mo; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre‐existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy.SignificanceOur study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.

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Section: Discussionsupporting

confidence: 82%

Section: Phenotypic Features (N = 124) N (%)supporting

confidence: 84%

Landscape of genetic infantile epileptic spasms syndrome—A multicenter cohort of 124 children from India

et al. 2023

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“…Developmental encephalopathy is a condition of developmental impairment due to a nonprogressive brain condition without frequent epileptic activities. The term “developmental and epileptic encephalopathy (DEE)” used to be described as the coexistence of epileptic encephalopathy and developmental delay [ 3 ], but is now referred to as the condition of two comorbidities developing independently of each other, that is, developmental impairment related to both the underlying etiology and the epileptic encephalopathy, though they might share a common genetic etiology. The genetic etiologies responsible for DEE have been incrementally reported in recent decades, especially after the application of next generation sequencing (NGS) [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Tubulinopathy Presenting as Developmental and Epileptic Encephalopathy

Hung

et al. 2022

Children

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Tubulin proteins play a role in the cortical development. Mutations in the tubulin genes affect patients with brain malformations. The present report describes two cases of developmental and epileptic encephalopathy (DEE) due to tubulinopathy. Case 1, a 23-year-old boy, was found to have a brain malformation with moderate ventriculomegaly prenatally. Hypotonia was noted at birth. Seizures were noted on the 1st day with multifocal discharges on the EEGs, which became intractable to many anticonvulsants. Brain MRI showed marked dilated ventricles and pachy/polymicrogyri. He became a victim of DEE. A de novo mutation in TUBB2B was proven through next-generation sequencing (NGS). Case 2, a mature male baby, began to have myoclonic jerks of his limbs 4 h after birth. EEG showed focal sharp waves from central and temporal regions. Brain MRI showed lissencephaly, type I. The seizures were refractory initially. A de novo mutation in TUBA1A was proven at the 6th week through NGS. He showed the picture of DEE at 1 year and 2 months of age. The clinical features of the tubulinopathies include motor delay, intellectual disabilities, epilepsy, and other deficits. Our cases demonstrated the severe form of tubulinopathy due to major tubulin gene mutations. NGS makes the early identification of genetic etiology possible for clinical evaluation.

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“…27,32 Additionally, taking into account patient 5 and her family history (asymptomatic father; sister with neurological disability and autistic features; and patient 5 with seizures in the neonatal period but normal outcome so far) suggests the hypothesis that other factors, such as the presence of modifier genes that encode channels with direct interactions or that are part of the same pathway, may modulate the penetrance or clinical expression associated with KCNQ2-related disorders. 33 Therefore, gaining a comprehensive understanding of the pathogenic molecular mechanisms underlying KCNQ2 variants and their correlation with clinical phenotypes holds significant implications for the clinical management of patients. It not only aids in accurate diagnosis and prognosis but also paves the way for targeted therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Previous functional studies have shown that DEE-causing substitutions often induce strong loss-of-function, dominant-negative, or gain-of-function effects, in contrast to SLNE-causing variants associated with haploinsufficiency [ 27 32]. Additionally, taking into account patient 5 and his family history(asymptomatic father; sister with neurological disability and autism features; and patient 5 with seizures in the neonatal period but normal outcome so far), suggests the hypothesis that other factors, such as the presence of modifier genes that encode channels with direct interactions or that are part of the same pathway, may modulate the penetrance or clinical expression associated with KCNQ2-related disorders [33].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series

Vilan,

Grangeia,

Ribeiro

et al. 2023

Neuropediatrics

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Background: Carbamazepine (CBZ) is effective in treating KCNQ2/3 related seizures, which may present with a distinctive aEEG pattern. Objective: To assess how improved recognition of the distinctive aEEG ictal pattern associated with KCNQ2/3 variants has enabled early and effective targeted therapy with CBZ. Methods: Retrospective descriptive study of 5 neonates with KCNQ2/3 pathogenic gene variants admitted at a level three neonatal intensive care unit (NICU) over an eight-year period. Results: The distinctive ictal aEEG pattern was recognized in 4 neonates after an average of 61.5 hours (minimum 12 h, maximum 120h) from the first electroclinical seizure and prompted the use of CBZ that was effective in all. The two most recently diagnosed patients could avoid polytherapy as they received CBZ as the 1st and 2nd antiseizure medication (ASM) respectively. Three out of five patients with continuous normal voltage (CNV), sleep wake cycling (SWC) and shorter post-ictal suppression had normal neurodevelopmental outcome. Regarding the remaining two infants, one was not trialled with CBZ and had a high seizure burden, both presented with a prolonged post-ictal suppression, no SWC and had moderate-to-severe developmental delay. Genetic results became available after the neonatal period in all but one of the infants, who had a prenatal diagnosis. Conclusions: Recognition of the distinctive ictal aEEG pattern in the NICU allowed early and effective targeted therapy with CBZ in four neonates, well before genetic results became available. Furthermore, a CNV background pattern with SWC and short post-ictal suppression were associated with normal developmental outcomes.

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Inherited Developmental and Epileptic Encephalopathies

Cited by 13 publications

References 92 publications

Landscape of genetic infantile epileptic spasms syndrome—A multicenter cohort of 124 children from India

Landscape of genetic infantile epileptic spasms syndrome—A multicenter cohort of 124 children from India

Tubulinopathy Presenting as Developmental and Epileptic Encephalopathy

Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series

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