Developmental and epileptic encephalopathies

Current analyses of monogenic epilepsy genes implicate >900 genes in DEEs out of >1000 established monogenic genes.

“Current analyses of monogenic epilepsy genes implicates >900 genes in DEEs (Gene4Epilepsy; http://github.com/bahlolab/genes4epilepsy),out of >1000 established monogenic genes 26 .”

• cites [26] Oliver, K. L. et al. Genes4Epilepsy: an epilepsy gene resource. Epilepsia 64, 1368–1375 (2023). This study identified 926 known monogenic epilepsy genes in 2023 and showed that 825 genes were associated with DEEs; since publication, >1,000 genes have been listed on the publicly accessible database. sourceDisputed

  The Results section reports 825 genes associated with a DEE phenotype out of 926 curated monogenic epilepsy genes, not more than 900 out of more than 1,000. It says 1,128 genes were reviewed, but 202 were excluded for insufficient or disputed evidence. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

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The primary cause of death in patients with DEEs is sudden unexpected death in epilepsy (SUDEP).

“The primary cause of death is sudden unexpected death in epilepsy (SUDEP) 17 ; other causes include cerebral oedema following status epilepticus 18 , chest infections and accidental causes 19 .”

• cites [17] Nashef, L., So, E. L., Ryvlin, P. & Tomson, T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 53, 227–233 (2012). sourcePartly supported

  The Summary identifies SUDEP as a category of death in people with epilepsy, and Box 3 defines which deaths qualify. The paper does not establish that SUDEP is the primary cause of death in patients with developmental and epileptic encephalopathies (DEEs); searches for DEEs and comparative causes of death found no such finding. (LLM, conf=0.83)

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75% of patients with SCN3A GOF variants have a malformation of cortical development (MCD), such as polymicrogyria.

“Intriguingly, 75% of patients with SCN3A GOF variants have a malformation of cortical development (MCD), such as polymicrogyria 36,37 .”

• cites [36] Zaman, T. et al. Mutations in SCN3A cause early infantile epileptic encephalopathy. Ann. Neurol. 83, 703–717 (2018). sourcePartly supported

  The Discussion reports polymicrogyria in two patients with the p.Ile875Thr variant and says it was not a consistent feature of the cohort. The paper links the severe epilepsy variants to gain of function, but does not support the claimed 75% rate of cortical malformations; one of the four patients with de novo variants did not have an MRI. (LLM, conf=0.88)

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• cites [37] Zaman, T. et al. SCN3A-related neurodevelopmental disorder: a spectrum of epilepsy and brain malformation. Ann. Neurol. 88, 348–362 (2020). sourcePartly supported

  The Discussion (Genotype-phenotype correlations) reports cortical malformations in 13 of 16 patients (81%) with gain-of-function variants, not 75%; its 75% figure refers to developmental and epileptic encephalopathy. The Results (Clinical characteristics) identify polymicrogyria as a common cortical malformation, so the association and example are supported, but the stated percentage is not. (LLM, conf=0.90)

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GOF KCNQ2 DEEs include IESS associated with a recurrent GOF variant with severe outcome.

“Conversely, GOF KCNQ2 DEEs include IESS associated with a recurrent GOF variant with severe outcome 48 .”

• cites [48] Millichap, J. J. et al. Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant. Epilepsia 58, e10–e15 (2017). sourceSupported

Heterozygous de novo pathogenic variants in KCNT1 cause a spectrum of DEEs from Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) to sleep-related hypermotor epilepsy (SHE).

“Heterozygous de novo pathogenic variants in KCNT1, encoding a sodium-activated potassium channel, cause a spectrum of DEEs from Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) to sleep-related hypermotor epilepsy (SHE) 56,57 .”

• cites [56] Barcia, G. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44, 1255–1259 (2012). sourcePartly supported

  The indexed passage describing the sequencing results (labeled Abstract; page unavailable) reports heterozygous de novo KCNT1 variants in patients with malignant migrating partial seizures of infancy (MMPSI), an early-onset epileptic encephalopathy. The paper does not report sleep-related hypermotor epilepsy or establish the claimed spectrum extending to it. (LLM, conf=0.88)

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• cites [57] Heron, S. E. et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 44, 1188–1190 (2012). sourceNot checked — no full text of the source

In resource-restricted regions, the incidence of acquired antenatal, perinatal and early infantile structural brain injury is increased.

“In resource-restricted regions, the incidence of acquired antenatal, perinatal and early infantile structural brain injury is increased 15,16 .”

• cites [15] Surana, P. et al. Infantile spasms: etiology, lead time and treatment response in a resource limited setting. Epilepsy Behav. Rep. 14, 100397 (2020). sourcePartly supported

  The Discussion (page unavailable) reports a higher proportion of acquired causes among this North Indian infantile-spasms cohort than in studies from better-equipped healthcare settings. The Results identify neonatal hypoglycemic and asphyxiation brain injuries as common causes. The paper does not establish an increased population incidence of acquired antenatal, perinatal, and early-infantile structural brain injury across resource-restricted regions; it notes that the study was not population-based. (LLM, conf=0.84)

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• cites [16] Raga, S. V., Essajee, F., Solomons, R., Van Toorn, R. & Wilmshurst, J. M. Epileptic spasms: a South African overview of aetiologies, interventions, and outcomes. Dev. Med. Child. Neurol. 65, 526–533 (2023). sourceNot checked — no full text of the source

Patients with DEEs with seizure onset in early infancy have an even higher mortality rate with 50% dying by age 2 years.

“Patients with DEEs with seizure onset in early infancy have an even higher mortality rate with 50% dying by age 2 years 7, 8 .”

• cites [7] Specchio, N. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1398–1442 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in childhood and includes DEEs. sourceCould not verify

  The passages on mortality in §5.4 (Febrile infection-related epilepsy syndrome) and §5.4.3 (Course of illness; page unavailable) concern FIRES, which the paper says occurs predominantly in older children, and report approximately 10% mortality in its acute phase. Searches for early-infancy DEEs, death by age 2, and 50% mortality found no passage addressing the claimed population and rate. (LLM, conf=0.78)

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• cites [8] Howell, K. B. et al. The severe epilepsy syndromes of infancy: a population-based study. Epilepsia 62, 358–370 (2021). sourceNot checked — no full text of the source

Functional studies show a range of GOFs due to increased potassium current amplitude, correlating with phenotypic severity in KCNT1 DEEs.

“Functional studies show a range of GOFs due to increased potassium current amplitude, correlating with phenotypic severity 56,58 .”

• cites [56] Barcia, G. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44, 1255–1259 (2012). sourcePartly supported

  The indexed paper’s functional-results passage (labeled Abstract; page unavailable) reports that two KCNT1 mutations produced currents 2–3 times greater than wild type, supporting gain of function through increased current amplitude. It does not establish a range of gain-of-function effects correlated with phenotypic severity in KCNT1 developmental and epileptic encephalopathies. (LLM, conf=0.87)

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• cites [58] Quraishi, I. H. et al. An epilepsy-associated KCNT1 mutation enhances excitability of human iPSC-derived neurons by increasing slack KNa currents. J. Neurosci. 39, 7438–7449 (2019). sourcePartly supported

  The Introduction (page unavailable) reports increased Slack potassium currents and gain of function across many epilepsy-associated KCNT1 mutations. The Discussion (page unavailable) describes a spectrum of epilepsy phenotypes, but does not say that the magnitude of current increase correlates with phenotypic severity. (LLM, conf=0.87)

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A new type of Early Infantile DEE (EIDEE) was identified that is caused by gain of function (GOF) SCN1A pathogenic variants with onset by three months.

“Recently, a new type of Early Infantile DEE (EIDEE) was identified that is caused by gain of function (GOF) SCN1A pathogenic variants with onset by three months 32,33 .”

• cites [32] Sadleir, L. G. et al. Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound Thr226Met phenotype. Neurology 89, 1035–1042 (2017). sourcePartly supported

  The Abstract Conclusions identify a distinct early infantile SCN1A encephalopathy, and the Results report seizure onset at 6–12 weeks. The Discussion says gain of function is only a possibility and that functional studies are required to establish the mechanism; it does not show that GOF variants cause the disorder. (LLM, conf=0.90)

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• cites [33] Brunklaus, A. et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain 145, 3816–3831 (2022). This study expands the spectrum of SCN1A DEEs associated with GOF pathogenic variants, highlighting the therapeutic implications for the GOF SCN1A diseases. sourceSupported

Around one-third of patients cannot be classified as having a specific DEE syndrome.

“Incidence estimates have been reported for many DEE syndromes; however, around one-third of patients cannot be classified as having a specific syndrome 3,9 .”

• cites [3] Poke, G., Stanley, J., Scheffer, I. E. & Sadleir, L. G. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023). This is the key epidemiology study of all DEEs with onset prior to 16 years of age, highlighting that DEEs have a cumulative incidence of 1 in 590 children and providing the cumulative incidence for several DEE syndromes. sourceSupported
• cites [9] Symonds, J. D. et al. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain 144, 2879–2891 (2021). sourceSupported

The association of SCN3A pathogenic variants with MCD reflects a key role for sodium conductance in cortical progenitors, which affects cortical gyration during early brain development.

“The association of SCN3A pathogenic variants with MCD 37 , therefore, reflects a key role for sodium conductance in cortical progenitors, which affects cortical gyration during early brain development 39 .”

• cites [37] Zaman, T. et al. SCN3A-related neurodevelopmental disorder: a spectrum of epilepsy and brain malformation. Ann. Neurol. 88, 348–362 (2020). sourceSupported
• cites [39] Smith, R. S. et al. Sodium channel SCN3A (Na(V)1.3) regulation of human cerebral cortical folding and oral motor development. Neuron 99, 905–913.e7 (2018). sourcePartly supported

  The Results and Discussion report that pathogenic SCN3A variants alter sodium-channel currents and that expression of a mutant channel disrupts gyrification in developing ferrets. The Abstract also reports high fetal SCN3A expression in cortical progenitor cells. But the paper says altered sodium conductance *might* underlie polymicrogyria; it does not establish that sodium conductance specifically in progenitors causes the gyration changes. (LLM, conf=0.83)

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Recessive causes occur more frequently in populations with high rates of consanguinity.

“whereas, recessive causes occur more frequently in populations with high rates of consanguinity 14 .”

• cites [14] Elkhateeb, N. et al. The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children. Clin. Genet. 105, 510–522 (2024). sourceSupported

The incidence of syndromes associated with de novo genetic variants is likely to be similar around the world.

“The incidence of syndromes associated with de novo genetic variants is likely to be similar around the world 13 ; whereas, recessive causes occur more frequently in populations with high rates of consanguinity 14 .”

• cites [13] Symonds, J. D. et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain 142, 2303–2318 (2019). This Scottish epidemiological study provides the incidence and phenotypes of seizure disorders with onset under 3 years of age. sourceSupported

GOF variants in CACNA1A cause DEEs with status epilepticus, alternating focal seizures, paroxysmal hemiplegia, neonatal jitteriness, ataxia and movement disorder.

“GOF variants cause DEEs with status epilepticus, alternating focal seizures, paroxysmal hemiplegia, neonatal jitteriness, ataxia and movement disorder 62, 63 .”

• cites [62] Le Roux, M. et al. CACNA1A-associated epilepsy: electroclinical findings and treatment response on seizures in 18 patients. Eur. J. Paediatr. Neurol. 33, 75–85 (2021). sourcePartly supported

  The Discussion (page unavailable) links the GOF-associated phenotype to recurrent status epilepticus, focal or generalized seizures, hemiplegic episodes, neonatal jitteriness, and cerebellar and movement abnormalities. It does not establish alternating focal seizures in this cohort; the Discussion says no patient had the early phenotype with migrating focal seizures. It also says classifying the cohort as having developmental and epileptic encephalopathy (DEE) is debatable. (LLM, conf=0.87)

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• cites [63] Hamdan, F. F. et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am. J. Hum. Genet. 101, 664–685 (2017). sourcePartly supported

  The Results table lists two CACNA1A missense mutations among de novo mutations in genes established as causes of DEE and/or intellectual disability. Our copy does not identify those variants as gain-of-function or link CACNA1A to the specific symptoms listed; the passages describing status epilepticus, jitteriness, and movement disorders concern other genes. (LLM, conf=0.82)

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A recent study of methylation profiles in 582 patients identified the etiology in 2% of individuals.

“A recent study of methylation profiles in 582 patients identified the etiology in 2% of individuals 142 (a similar yield to that observed when performing genome sequencing after exome sequencing).”

• cites [142] LaFlamme, C. W. et al. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement. Nat. Commun. 15, 6524 (2024). sourceSupported

An antisense oligonucleotide which down-regulates SCN8A ameliorates seizures and survival in mice with Scn1a or Kcnq2 LOF, or Scn8a GOF variants.

“For example, an antisense oligonucleotide which down-regulates SCN8A ameliorates seizures and survival in mice with Scn1a or Kcnq2 LOF, or Scn8a GOF variants 97 .”

• cites [97] Hill, S. F., Ziobro, J., Jafar-Nejad, P., Rigo, F. & Meisler, M. H. Genetic interaction between Scn8a and potassium channel genes Kcna1 and Kcnq2. Epilepsia 63, e125–e131 (2022). sourcePartly supported

  The Results (Kcnq2 mutant mice; page unavailable) report that an Scn8a antisense oligonucleotide prolonged survival and prevented observed seizures in Kcnq2-deficient mice. This paper does not report those treatment outcomes in mice with Scn1a loss-of-function or Scn8a gain-of-function variants; its Discussion mentions Dravet syndrome and Scn8a gain-of-function in other contexts. (LLM, conf=0.90)

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CHD2 causes photosensitive myoclonic DEEs including epilepsy with eyelid myoclonia and epilepsy with myoclonic-atonic seizures.

“CHD2, encoding a chromodomain helicase binding protein 108 , causes photosensitive myoclonic DEEs including epilepsy with eyelid myoclonia and epilepsy with myoclonic-atonic seizures 137 .”

• cites [137] Thomas, R. H. et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology 84, 951–958 (2015). sourcePartly supported

  The Abstract and Results describe CHD2-associated myoclonic encephalopathy with marked photosensitivity and absence seizures with eyelid myoclonia. They do not identify those seizures as the syndrome epilepsy with eyelid myoclonia. The Discussion (section labeled Molecular results; page unavailable) explicitly distinguishes CHD2 encephalopathy from epilepsy with myoclonic-atonic seizures, noting that the CHD2 cases lacked that syndrome’s defining seizure type. (LLM, conf=0.90)

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Recessive variants in WWOX cause a spectrum of phenotypes including DEE with microcephaly and profound delay and spinocerebellar ataxia.

“Recessive variants cause a spectrum of phenotypes including DEE with microcephaly and profound delay and spinocerebellar ataxia 146 .”

• cites [146] Oliver, K. L. et al. WWOX developmental and epileptic encephalopathy: understanding the epileptology and the mortality risk. Epilepsia 64, 1351–1367 (2023). sourceSupported

Onset of focal seizures or myoclonic-atonic seizures in CLN2 disease occurs at 2-4 years of age in a child with normal development or isolated language delay.

“Onset of focal seizures or myoclonic-atonic seizures occurs at 2-4 years of age in a child with normal development or isolated language delay.”

• cites [147] Nickel, M. et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child. Adolesc. Health 2, 582–590 (2018). sourcePartly supported

  The Results report a median age of 37 months at first seizure, and the Discussion identifies seizures and language delay as common early signs. The Discussion describes variable seizure types but does not establish focal or myoclonic-atonic seizures specifically as the presenting seizures, or establish normal development at their onset. Page numbers were not provided in our copy. (LLM, conf=0.87)

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LOF and GOF variants in GRIA2, encoding the GluA2 subunit of the AMPA receptor, cause DEEs such as IESS.

“LOF and GOF variants in GRIA2, encoding the GluA2 subunit of the AMPA receptor, cause DEEs such as IESS 79 .”

• cites [79] Coombs, I. D. et al. A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment. Epilepsia 63, e156–e163 (2022). sourcePartly supported

  The Introduction reports that previously studied GRIA2 variants primarily cause AMPA-receptor loss of function, while the Results identify a gain-of-function GRIA2 variant in a child with developmental delay, epileptic spasms, and hypsarrhythmia. The paper therefore supports both functional mechanisms and a gain-of-function case resembling IESS, but it does not establish that loss-of-function GRIA2 variants cause IESS specifically. (LLM, conf=0.82)

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De novo pathogenic variants in GNAI1 in a series of 24 individuals caused developmental delay, substantial speech impairment, and seizures in 75% of individuals.

“De novo pathogenic variants in GNAI1 in a series of 24 individuals caused developmental delay, substantial speech impairment, and seizures in 75% of individuals 133 .”

• cites [133] Muir, A. M. et al. Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. Genet. Med. 23, 881–887 (2021). sourcePartly supported

  The Results report developmental delay in all 24 individuals, substantial speech impairment, and epilepsy in 17 of 23 individuals with available data (74%, approximately 75%). However, the Results also state that one of the 24 variants was inherited from a mosaic parent, so the claim's description of the entire series as having de novo variants is not fully supported. (LLM, conf=0.88)

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Pathogenic variants in SYNGAP1 cause a generalised DEE with myoclonic-atonic seizures, absence with eyelid myoclonia, eating-induced reflex seizures and photosensitivity.

“Pathogenic variants in SYNGAP1 cause a generalised DEE with myoclonic-atonic seizures, absence with eyelid myoclonia, eating-induced reflex seizures and photosensitivity [108][109][110] .”

• cites [108] Carvill, G. L. et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825–830 (2013). sourcePartly supported

  The Introductory section reports five truncating SYNGAP1 variants in patients with epileptic encephalopathy and multiple seizure types. It does not specify myoclonic-atonic seizures, absence with eyelid myoclonia, eating-induced reflex seizures, or photosensitivity for those patients; its photosensitivity finding concerns CHD2. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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• cites [109] Hamdan, F. F. et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol. Psychiatry 69, 898–901 (2011). sourceNot checked — no full text of the source
• cites [110] Vlaskamp, D. R. M. et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology 92, E96–E107 (2019). sourceSupported

LGS may occur with GOF and LOF CACNA1A variants.

“LGS may occur with GOF and LOF CACNA1A variants 64,65 .”

• cites [64] Epi4K Consortium & Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). sourcePartly supported

  The paper’s Abstract (page unavailable) reports a de novo CACNA1A mutation in a cohort comprising patients with infantile spasms and LGS. It does not identify which diagnosis the CACNA1A carrier had or establish that both gain-of-function and loss-of-function CACNA1A variants may occur with LGS; its loss-of-function result concerns mutations across the cohort, not CACNA1A specifically. (LLM, conf=0.82)

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• cites [65] Jiang, X. et al. Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox–Gastaut syndrome. Epilepsia 60, 1881–1894 (2019). sourceNot checked — no full text of the source

Pathogenic variants in PURA cause severe myoclonic DEE with respiratory insufficiency and hypotonia.

“PURA, is involved in transcriptional regulation 139 , and pathogenic variants cause severe myoclonic DEE with respiratory insufficiency and hypotonia 140 .”

• cites [139] Hunt, D. et al. Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability. J. Med. Genet. 51, 806–813 (2014). sourcePartly supported

  The Discussion (page not provided) links de novo PURA mutations to neurodevelopmental delay, commonly with hypotonia and respiratory difficulties. The Results for Patient 4 (page not provided) describe severe hypotonia, central apnoea and difficult-to-control seizures, but identify the seizures as spasms, tonic seizures and focal dyscognitive seizures—not myoclonic DEE. The paper describes a variable syndrome rather than severe epilepsy in all affected individuals. (LLM, conf=0.88)

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• cites [140] Johannesen, K. M. et al. PURA-related developmental and epileptic encephalopathy: phenotypic and genotypic spectrum. Neurol. Genet. 7, e613 (2021). sourcePartly supported

  The Discussion describes PURA-related developmental and epileptic encephalopathy (DEE) with neonatal hypotonia and respiratory difficulties, which can progress to respiratory insufficiency. The Results (Epilepsy Phenotype) report myoclonic seizures in 22.5% of patients with reported seizure types, while 59.2% of the overall cohort had epilepsy. Thus, the paper supports these features but not the characterization of PURA-related DEE as uniformly myoclonic. (LLM, conf=0.87)

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LOF variants in GABRA1, GABRA2, GABRB2 and GABRB3, which encode GABAA subunits, lead to decreased neuronal inhibition resulting in many DEE phenotypes.

“LOF variants in GABRA1, GABRA2, GABRB2 and GABRB3, which encode GABAA subunits, lead to decreased neuronal inhibition resulting in many DEE phenotypes 64,[69][70][71][72] .”

• cites [64] Epi4K Consortium & Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). sourcePartly supported

  The section labeled “De novo mutations in the classic epileptic encephalopathies > Abstract” (page unavailable) reports GABA-receptor-subunit mutations in patients with epileptic encephalopathies, including GABRA1 and GABRB3, and implicates GABRB3 as a cause. It identifies GABRB1—not GABRA2 or GABRB2—as the third subunit gene observed. It does not establish that the cited variants are loss-of-function or demonstrate decreased neuronal inhibition as the mechanism. (LLM, conf=0.87)

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• cites [69] Orenstein, N. et al. A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder. Eur. J. Paediatr. Neurol. 22, 516–524 (2018). sourceNot checked — no full text of the source
• cites [70] Hernandez, C. C. et al. Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors. Brain Commun. 3, fcab033 (2021). sourcePartly supported

  The Introduction and Discussion (page unavailable in our copy) link GABAA-receptor variants to developmental epileptic encephalopathies and describe receptor dysfunction as causing disinhibition. The Discussion includes all four named genes among those associated with early-onset epileptic encephalopathy, but the paper does not establish that loss-of-function variants in each of the four cause the claimed range of phenotypes; its functional findings focus on GABRA1, GABRB2 and GABRG2. (LLM, conf=0.84)

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mTOR pathway inhibitors, including everolimus and sirolimus, may be beneficial as a targeted treatment.

“mTOR pathway inhibitors, including everolimus and sirolimus may be beneficial as a targeted treatment 131 .”

• cites [131] French, J. A. et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388, 2153–2163 (2016). This randomized controlled trial analysed the efficacy of an mTOR inhibitor for drug-resistant focal epilepsy in tuberous sclerosis, showing that a precision therapy approach is efficacious for this disease. sourcePartly supported

  The Discussion (page unavailable in our copy) describes everolimus as targeting the dysregulated mTOR pathway and reports improved seizure control in patients with tuberous sclerosis complex. The paper does not establish a treatment benefit for sirolimus, so it supports the claim for everolimus but not for both named drugs. (LLM, conf=0.85)

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GNAO1 GOF variants cause an early-onset movement disorder with or without epilepsy.

“By contrast, GNAO1 GOF variants cause an early-onset movement disorder with or without epilepsy 132 .”

• cites [132] Feng, H. et al. Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. Neurology 89, 762–770 (2017). sourceSupported

Disruptions of NRXN1, and rarely NRXN2, pre-synaptic neuronal adhesion proteins, cause DEEs including EIDEE.

“Disruptions of NRXN1, and rarely NRXN2, pre-synaptic neuronal adhesion proteins, cause DEEs including EIDEE 114 .”

• cites [114] Castronovo, P. et al. Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: a systematic review. Clin. Genet. 97, 125–137 (2020). sourcePartly supported

  The review identifies neurexins as presynaptic cell-adhesion molecules and reports NRXN1 deficiency in a patient with severe epileptic encephalopathy beginning at six months (figure and table legends). But it does not substantiate the claim that NRXN2 disruptions cause DEEs, and it describes heterozygous NRXN1 deletions as risk factors with incomplete penetrance rather than invariably causal (section 3.1; clinical-practice recommendations). (LLM, conf=0.87)

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Autosomal recessive LOF variants in TBC1D24 lead to DEEs with myoclonic seizures and EIMFS, with dystonia.

“Autosomal recessive LOF variants in TBC1D24, encoding a GTPase-activating protein essential for synaptic vesicle trafficking 105 , lead to DEEs with myoclonic seizures and EIMFS, with dystonia 106 .”

• cites [105] Finelli, M. J. et al. The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons. Hum. Mol. Genet. 28, 584–597 (2019). sourcePartly supported

  The Introduction and Results (page numbers unavailable) link predominantly recessive TBC1D24 mutations and likely loss-of-function alleles to myoclonic epilepsy and early-onset epileptic encephalopathy. The paper does not identify EIMFS or dystonia as associated phenotypes, so those specifics are not supported. (LLM, conf=0.88)

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• cites [106] Balestrini, S. et al. TBC1D24 genotype-phenotype correlation: epilepsies and other neurologic features. Neurology 87, 77–85 (2016). sourcePartly supported

  The Results (Genotype–phenotype correlation; page unavailable) associate biallelic TBC1D24 mutations with epilepsy and loss-of-function mutations with more severe disease. The Results (Seizures and treatment responsiveness; page unavailable) report myoclonic epilepsy and EIMFS, including early-onset epileptic encephalopathy. The copy does not establish that loss-of-function variants specifically cause each of those phenotypes or dystonia; dystonia appears only in a cited reference title. (LLM, conf=0.87)

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De novo heterozygous missense variants in GRIN1 cause a neonatal DEE with a hyperkinetic movement disorder, stereotypies and oculogyric crises.

“De novo heterozygous missense variants cause a neonatal DEE with a hyperkinetic movement disorder, stereotypies and oculogyric crises 64,81 ; whereas, truncating heterozygous variants do not cause disease.”

• cites [64] Epi4K Consortium & Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). sourcePartly supported

  The paper’s Abstract (page not provided) lists GRIN1 among genes with de novo mutations in patients with infantile spasms or Lennox–Gastaut syndrome. It does not establish that GRIN1 missense variants cause the specified neonatal phenotype or report hyperkinetic movements, stereotypies, or oculogyric crises; the Additional Methods, ‘Study subjects’ (page not provided), say patients with neonatal seizures were excluded. (LLM, conf=0.86)

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• cites [81] Lemke, J. R. et al. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy. Neurology 86, 2171–2178 (2016). sourcePartly supported

  The Results report that heterozygous de novo GRIN1 variants were associated with developmental delay often apparent in the neonatal period, hyperkinetic movement disorders, stereotypic movements, and oculogyric crises. The Discussion says all reported de novo variants were missense. However, the Results report epilepsy in 16 of 23 patients, with onset ranging from day 1 to 11 years, and say the epilepsy usually did not resemble a specific epileptic encephalopathy; the paper therefore does not support describing the phenotype generally as a neonatal DEE. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Autosomal recessive null and missense variants in GRIN1 lead to a more severe phenotype with increased mortality.

“Autosomal recessive null and missense variants lead to a more severe phenotype with increased mortality 81,82 .”

• cites [81] Lemke, J. R. et al. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy. Neurology 86, 2171–2178 (2016). sourcePartly supported

  The Results section on recessive inheritance reports severe neurodevelopmental phenotypes in families with a homozygous missense variant and a homozygous truncating variant. All three siblings with the truncating variant died in infancy, but the paper does not report increased mortality for the missense variant. The Discussion describes overlap with heterozygous cases rather than establishing that recessive variants are generally more severe. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [82] Blakes, A. J. M., English, J., Banka, S. & Basu, H. A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy. Am. J. Med. Genet. A 188, 595–599 (2022). sourceNot checked — no full text of the source

Germline LOF variants in proteins that comprise the GATOR1 complex (DEPDC5, NPRL2, NPRL3) cause both nonlesional focal epilepsy and epilepsy associated with focal cortical dysplasia (FCD) type II.

“Germline LOF variants in proteins that comprise the GATOR1 complex (DEPDC5, NPRL2, NPRL3), responsible for sensing amino acid levels, cause both nonlesional focal epilepsy and epilepsy associated with focal cortical dysplasia (FCD) type II 122 .”

• cites [122] Lee, W. S. et al. Cortical dysplasia and the mTOR pathway: how the study of human brain tissue has led to insights into epileptogenesis. Int. J. Mol. Sci. 23, 1344 (2022). sourcePartly supported

  Section 4 links predominantly truncating germline DEPDC5 variants to nonlesional focal epilepsy and reports FCDII features in some carriers. Section 5 reports germline variants in all three GATOR1 genes in people with FCD. The copy does not establish that loss-of-function variants in each of the three genes cause both presentations; it also describes a somatic second hit as a possible explanation for focal lesions. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

With rapid advances in next generation sequencing, 50% of patients with DEEs have a pathogenic variant of major effect identified.

“With the rapid advances in next generation sequencing, 50% of patients with DEEs have a pathogenic variant of major effect identified 167 .”

• cites [167] Palmer, E. E. et al. Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: evidence of clinical utility and cost effectiveness. Mol. Genet. Genom. Med. 6, 186–199 (2018). sourcePartly supported

  The Results (Diagnostic yield; page not provided) report diagnoses for 16 of 32 patients (50%) under a pathway incorporating trio exome sequencing, with pathogenic or likely pathogenic variants identified. The Methods (Study design/Patient cohort and inclusion/exclusion criteria; page not provided) restrict the cohort to selected patients with undiagnosed infantile-onset epileptic encephalopathy. The claim overgeneralizes this cohort-specific yield to all patients with DEEs and omits the 'likely pathogenic' qualification. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

DEEs often include motor dysfunction such as cerebral palsy, movement disorders and gait decline.

“They often include motor dysfunction such as cerebral palsy 42 , movement disorders 151 and gait decline 31 ;”

• cites [42] Weckhuysen, S. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15–25 (2012). sourceNot checked — no full text of the source
• cites [151] van der Veen, S. et al. Movement disorders in patients with genetic developmental and epileptic encephalopathies. Neurology 101, e1884–e1892 (2023). sourceSupported
• cites [31] Rodda, J. M., Scheffer, I. E., McMahon, J. M., Berkovic, S. F. & Graham, H. K. Progressive gait deterioration in adolescents with Dravet syndrome. Arch. Neurol. 69, 873–878 (2012). sourceNot checked — no full text of the source

Acquired causes, such as ischaemic injury, infection, and hypoglycaemia, are a small but important group of DEE causes.

“Acquired causes, such as ischaemic injury, infection, and hypoglycaemia, are a small but important group 166 .”

• cites [166] Howell, K. B. et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 59, 1177–1187 (2018). sourcePartly supported

  The Results (Etiology; page unavailable) report acquired brain injury in 14 of 114 infants with severe epilepsies of infancy, and the Discussion identifies hypoxic-ischemic encephalopathy as an example. This supports acquired causes as a small group, but the copy does not identify infection or hypoglycaemia as examples, or establish the proportion for DEE more broadly. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

DEEs often include speech, sleep, respiratory and gastrointestinal problems.

“speech 154 , sleep 155 , respiratory and gastrointestinal problems.”

• cites [154] Turner, S. J. et al. Dysarthria and broader motor speech deficits in Dravet syndrome. Neurology 88, 743–749 (2017). sourcePartly supported

  Citation 154 is attached to speech problems, not to sleep, respiratory, or gastrointestinal problems. The Abstract identifies Dravet syndrome as a developmental epileptic encephalopathy, and the Discussion reports speech and language impairment in its 20-patient cohort. This supports Dravet syndrome as an example, but the paper does not establish how often speech problems occur across DEEs generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [155] Licheni, S. H., McMahon, J. M., Schneider, A. L., Davey, M. J. & Scheffer, I. E. Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev. Med. Child. Neurol. 60, 192–198 (2018). sourceSupported

An EEG during sleep often provides additional findings that guide epilepsy syndrome classification, such as generalized paroxysmal fast activity in LGS and spike-wave activation in sleep in EE-SWAS and DEE-SWAS, directing therapy selection.

“Often, an EEG during sleep provides additional findings that guide epilepsy syndrome classification (such as generalized paroxysmal fast activity in LGS and spike-wave activation in sleep in the syndromes of epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) and DEE-SWAS), directing therapy selection 170 .”

• cites [170] Viswanathan, S. et al. Solving the etiology of developmental and epileptic encephalopathy with spike-wave activation in Sleep (D/EE-SWAS). Ann Neurol. https://doi.org/10.1002/ana.27041 (2024). sourcePartly supported

  The Introduction identifies sleep-activated spike-wave activity as the EEG signature of EE-SWAS and DEE-SWAS. The Results report that paroxysmal fast activity emerged in three patients who evolved from DEE-SWAS to LGS, and the Discussion links syndrome differentiation to different therapeutic approaches. The paper does not establish that sleep EEG often provides these additional findings across epilepsy syndromes, specify that the LGS activity was generalized or detected during sleep, or show that these particular EEG findings direct therapy selection. Page numbers were not available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Dravet syndrome is relatively genetically homogeneous with >90% of patients having a pathogenic variant in SCN1A.

“For example, Dravet syndrome is relatively genetically homogeneous with >90% of patients having a pathogenic variant in SCN1A 12 ,”

• cites [12] Li, W., Schneider, A. L. & Scheffer, I. E. Defining Dravet syndrome: an essential pre-requisite for precision medicine trials. Epilepsia 62, 2205–2217 (2021). sourceSupported

Epileptic and non-epileptic seizures and movement disorders can be distinguished by video-EEG.

“Epileptic and non-epileptic seizures and movement disorders can be distinguished 151 , providing vital information in guiding patient management.”

• cites [151] van der Veen, S. et al. Movement disorders in patients with genetic developmental and epileptic encephalopathies. Neurology 101, e1884–e1892 (2023). sourcePartly supported

  The Discussion (passage 1; page not specified) says video-EEG monitoring can make a definitive diagnosis when movement disorders are difficult to distinguish from epileptic motor seizures, and can guide management. It does not separately address distinguishing non-epileptic seizures, so that part of the claim is unsupported. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

DEEs often include psychiatric features such as ASD, behavioural problems, mood disorders and psychosis.

“psychiatric features such as ASD 110 , behavioural problems 152 , mood disorders, psychosis 153 ;”

• cites [110] Vlaskamp, D. R. M. et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology 92, E96–E107 (2019). sourceSupported
• cites [152] Stamberger, H. et al. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genet. Med. 23, 363–373 (2021). sourceCould not verify

  Citation 153 is attached to mood disorders and psychosis, rather than the separately cited ASD and behavioural problems. The Discussion (p. 9) reports ASD, behavioural problems and other neuropsychiatric features in NEXMIF encephalopathy, but the passages found when searching for psychosis, mood disorders and related terms do not address either mood disorders or psychosis. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [153] Vlaskamp, D. R. M. et al. Schizophrenia is a later-onset feature of PCDH19 girls clustering epilepsy. Epilepsia 60, 429–440 (2019). sourcePartly supported

  Section 3.1 reports psychotic disorders in 8 of 60 females with PCDH19 Girls Clustering Epilepsy and a coexisting major depressive disorder in one patient. This supports psychosis and an example of a mood disorder in that specific condition, but not the broader claim that DEEs often include mood disorders and psychosis. The other citations in the printed sentence are attached to ASD and behavioural problems. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Children with Landau-Kleffner syndrome may present with behavioural problems due to auditory agnosia during which they cannot comprehend common sounds in their environment.

“For example, children with Landau-Kleffner syndrome may present with behavioural problems due to their auditory agnosia during which they cannot comprehend common sounds in their environment 7, 149 .”

• cites [7] Specchio, N. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1398–1442 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in childhood and includes DEEs. sourcePartly supported

  Section 5.3 identifies Landau-Kleffner syndrome as a subtype marked by acquired auditory agnosia and describes behavioral regression in the broader EE-SWAS spectrum (page unavailable). It does not specifically say that auditory agnosia causes behavioral problems in these children or describe an inability to comprehend common environmental sounds. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [149] Tassinari, C. A. et al. in Epileptic Syndromes in Infancy, Childhood and Adolesence 6th edn (eds Bureau, M. et al.) 261–284 (Libbey Eurotext, 2019).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

As the child grows, many morbidities, such as behaviour, become the main concern for families who are already skilled at managing seizures.

“As the child grows, many of these morbidities, such as behaviour, become the main concern for families who are already skilled at managing seizures 156 .”

• cites [156] Skluzacek, J. V., Watts, K. P., Parsy, O., Wical, B. & Camfield, P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia 52, 95–101 (2011). sourcePartly supported

  The Comorbid conditions section (p. 2) reports pronounced behavior problems and other difficulties in children with Dravet syndrome. It does not say these become families’ main concern as children grow, or that families are already skilled at managing seizures. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

A RCT in CDKL5 deficiency disorder found a median percentage change in 28-day major motor seizure frequency of -30.7% with ganaxolone, compared with -6.9% for placebo.

“A RCT in CDKL5 deficiency disorder found a median percentage change in 28-day major motor seizure frequency of -30.7% with ganaxolone, compared with -6•9% for placebo.”

• cites [192] Knight, E. M. P. et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 21, 417–427 (2022). sourceSupported

Detection of low-level germline mosaicism in blood-derived DNA requires high-depth sequencing or specialised techniques, such as droplet digital polymerase chain reaction.

“Detection of low-level germline mosaicism in blood-derived DNA requires high-depth sequencing or specialised techniques, such as droplet digital polymerase chain reaction 175 .”

• cites [175] Myers, C. T. et al. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378, 1646–1648 (2018). This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications. sourcePartly supported

  In “TO THE EDITOR” (page unavailable), the authors detected low-level parental mosaicism in blood or saliva using single-molecule molecular inversion probes and recommend targeted high-coverage testing. They did not test gonadal tissue or mention droplet digital polymerase chain reaction, so the specific example and direct detection of germline mosaicism are not supported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Even when an aetiologic genetic diagnosis is made, meaningful change in the treatment paradigm has not yet been possible for most DEEs.

“Even when an aetiologic genetic diagnosis is made, meaningful change in the treatment paradigm has not yet been possible for most DEEs 183 .”

• cites [183] Balestrini, S. et al. Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies. J. Neurol. Neurosurg. Psychiatry 92, 1044–1052 (2021). sourcePartly supported

  The Results report that genetic findings prompted treatment changes in only 94 of 293 patients (32%) with genetic epilepsies, supporting the point that treatment often remained unchanged after diagnosis. The study does not establish this specifically for most developmental and epileptic encephalopathies (DEEs); the Discussion says outcomes of specific genetic epilepsies could not be analysed separately. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In an epidemiological study of severe epilepsies beginning before age 18 months, which excluded patients with Dravet syndrome for methodological reasons, the aetiology was determined in 67% (76/114) of patients.

“In an epidemiological study of severe epilepsies beginning before age 18 months, which excluded patients with Dravet syndrome for methodological reasons, the aetiology was determined in 67% (76/114) of patients.”

• cites [8] Howell, K. B. et al. The severe epilepsy syndromes of infancy: a population-based study. Epilepsia 62, 358–370 (2021). sourceNot checked — no full text of the source
• cites [166] Howell, K. B. et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 59, 1177–1187 (2018). sourcePartly supported

  The Methods (Inclusion/exclusion criteria and Assessment) describe a population-based cohort of 114 infants meeting severe-epilepsy criteria before 18 months. The Results (Etiology) report that etiology was identified in 76 (67%). Our copy does not state that patients with Dravet syndrome were excluded or give a methodological reason for excluding them. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

SCBs, particularly carbamazepine and phenytoin, are efficacious in GOF-DEEs due to pathogenic variants in sodium channel (SCN1A, SCN2A and SCN8A) and potassium channel (KCNQ2) genes.

“SCBs, particularly carbamazepine and phenytoin, are efficacious in GOF-DEEs due to pathogenic variants in sodium channel (SCN1A 33 , SCN2A 184 and SCN8A 185 ) and potassium channel (KCNQ2 43 ) genes.”

• cites [33] Brunklaus, A. et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain 145, 3816–3831 (2022). This study expands the spectrum of SCN1A DEEs associated with GOF pathogenic variants, highlighting the therapeutic implications for the GOF SCN1A diseases. sourceSupported
• cites [184] Wolff, M., Brunklaus, A. & Zuberi, S. M. Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond. Epilepsia 60, S59–S67 (2019). sourceSupported
• cites [185] Gardella, E. & Møller, R. S. Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes. Epilepsia 60, S77–S85 (2019). sourceSupported

In some individuals, a second genetic hit with a combination of both somatic and germline mutations in the same gene or genes in related pathways (eg mTOR pathway) is identified.

“In some individuals, a second genetic hit with a combination of both somatic and germline mutations in the same gene or genes in related pathways (eg.mTOR pathway) is identified 124 .”

• cites [124] Ribierre, T. et al. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J. Clin. Invest. 128, 2452–2458 (2018). sourcePartly supported

  The Results and Discussion report a child with an inherited DEPDC5 variant and a second, somatic DEPDC5 variant in brain tissue, supporting a two-hit mechanism in the same mTORC1-pathway gene. The paper does not establish a two-hit combination across different genes in related pathways. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Somatic mosaicism can be found in brain-derived DNA at low levels on surgical specimens, cerebrospinal fluid or implanted EEG electrodes.

“Somatic mosaicism can be found in brain-derived DNA at low levels on surgical specimens, cerebrospinal fluid or implanted EEG electrodes 122, 177, 178 .”

• cites [122] Lee, W. S. et al. Cortical dysplasia and the mTOR pathway: how the study of human brain tissue has led to insights into epileptogenesis. Int. J. Mol. Sci. 23, 1344 (2022). sourcePartly supported

  Section 9 reports low-frequency somatic variants in brain tissue specimens, and Section 10 reports detection of brain-specific variants in cell-free DNA from cerebrospinal fluid. The cited paper does not support detection using implanted EEG electrodes; its discussion of electrophysiological data concerns selecting tissue specimens for sequencing, not recovering DNA from electrodes. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [177] Ye, Z. et al. Somatic mosaic mutation gradient detected in trace brain tissue from stereo-EEG depth electrodes. Neurology 99, 1036–1041 (2022). sourceNot checked — no full text of the source
• cites [178] Ye, Z. et al. Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain. Brain Commun. 3, fcaa235 (2021). sourceSupported

Contributory pathogenic CNVs occur in another 4%, in whom the CNV contributes to, but is not wholly causative of, the underlying aetiology.

“Contributory pathogenic CNVs occur in another 4%, in whom the CNV contributes to, but is not wholly causative of, the underlying aetiology 172 .”

• cites [172] Mefford, H. C. et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann. Neurol. 70, 974–985 (2011). sourcePartly supported

  The Results report that 13 of 315 patients (4.1%) had clearly or likely pathogenic CNVs. Another 12 patients had rare CNVs of unclear clinical significance—not an additional 4% classified as contributory pathogenic. The Discussion suggests that some inherited CNVs may contribute to a phenotype alongside other factors, but does not establish that this applies to the additional 12 patients. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In patients thought to have a de novo pathogenic variant, high-depth sequencing of parental blood or salivary samples found that 8% of patients had a parent with low-level mosaicism.

“In patients thought to have a de novo pathogenic variant, high-depth sequencing of parental blood or salivary samples found that 8% of patients had a parent with low-level mosaicism 175 .”

• cites [175] Myers, C. T. et al. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378, 1646–1648 (2018). This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications. sourceSupported

Sometimes, lower mosaicism levels are associated with milder disease.

“Sometimes, lower mosaicism levels are associated with milder disease 12,175,176 .”

• cites [12] Li, W., Schneider, A. L. & Scheffer, I. E. Defining Dravet syndrome: an essential pre-requisite for precision medicine trials. Epilepsia 62, 2205–2217 (2021). sourcePartly supported

  The Results (Age at first seizure; page unavailable) report a patient with 22% mosaicism whose seizures began at 20 months. The Discussion (page unavailable) contrasts this with a patient with 30% mosaicism and a more severe seizure phenotype, but it does not establish that lower mosaicism levels are associated with milder disease overall; it also notes early onset at mosaicism levels of 13%–40%. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [175] Myers, C. T. et al. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378, 1646–1648 (2018). This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications. sourceSupported
• cites [176] de Lange, I. M. et al. Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes. Epilepsia 59, 690–703 (2018). sourceSupported

There are ASM protocols published for specific DEE syndromes based on expert consensus.

“There are ASM protocols published for specific DEE syndromes based on expert consensus 181,182 .”

• cites [181] Wirrell, E. C. et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia 63, 1761–1777 (2022). sourceSupported
• cites [182] Wilmshurst, J. M. et al. Summary of recommendations for the management of infantile seizures: task force report for the ILAE Commission of Pediatrics. Epilepsia 56, 1185–1197 (2015). sourceSupported

Fenfluramine has also proven effective in reducing drop seizures in LGS in a double-blind, placebo-controlled, parallel-group RCT.

“Fenfluramine has also proven effective in reducing drop seizures in LGS in a double-blind, placebocontrolled, parallel-group RCT 202 .”

• cites [202] Knupp, K. G. et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox–Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 79, 554–564 (2022). sourceSupported

In Dravet syndrome, increased epilepsy severity and behavioural factors were strong predictors of HRQOL at baseline and at 10-year-followup.

“In Dravet syndrome, increased epilepsy severity and behavioural factors were strong predictors of HRQOL at baseline and at 10-year-followup 227 .”

• cites [227] Makiello, P. et al. Comorbidities and predictors of health-related quality of life in Dravet syndrome: a 10-year, prospective follow-up study. Epilepsia 64, 1012–1020 (2023). sourceSupported

Caregivers emphasise the importance of sleep, communication, behaviour, daily activities, motor skills and language problems, which often eclipse seizures in importance as the individual ages.

“Caregivers emphasise the importance of sleep, communication, behaviour, daily activities, motor skills and language problems, which often eclipse seizures in importance as the individual ages 219 .”

• cites [219] Chemaly, N. et al. A European pilot study in Dravet syndrome to delineate what really matters for the patients and families. Epilepsia Open. 9, 388–396 (2021). sourcePartly supported

  The Results report that caregivers rated communication, sleep, behavior, daily activities, and motor skills more highly overall than seizure-related items; the Discussion also names language as a priority beyond seizure control. The age-related claim is broader than the findings: only seizure duration and ER/ICU referral declined in importance with age, while seizure frequency and rescue-treatment priorities remained stable. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Effects on cognition and other neuropsychiatric symptoms were not reported in the EXIST-3 RCT.

“Effects on cognition and other neuropsychiatric symptoms were not reported.”

• cites [131] French, J. A. et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388, 2153–2163 (2016). This randomized controlled trial analysed the efficacy of an mTOR inhibitor for drug-resistant focal epilepsy in tuberous sclerosis, showing that a precision therapy approach is efficacious for this disease. sourceSupported

Most common treatment-emergent adverse events included decreased appetite (22%), somnolence (13%), and fatigue (13%).

“Most common treatment-emergent adverse events included decreased appetite (22%), somnolence (13%), and fatigue (13%).”

• cites [202] Knupp, K. G. et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox–Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 79, 554–564 (2022). sourceSupported

In the EXIST-3 RCT, the mTOR inhibitor everolimus was trialled in patients with drug-resistant focal seizures in the setting of tuberous sclerosis complex, due to pathogenic variants in the mTOR pathway genes, TSC1 or TSC2.

“One example is the EXIST-3 RCT in which the mTOR inhibitor everolimus was trialled in patients with drug-resistant focal seizures in the setting of tuberous sclerosis complex, due to pathogenic variants in the mTOR pathway genes, TSC1 or TSC2.”

• cites [131] French, J. A. et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388, 2153–2163 (2016). This randomized controlled trial analysed the efficacy of an mTOR inhibitor for drug-resistant focal epilepsy in tuberous sclerosis, showing that a precision therapy approach is efficacious for this disease. sourcePartly supported

  The Abstract and Introduction describe EXIST-3 as a randomised trial of the mTOR inhibitor everolimus in patients with tuberous sclerosis complex and treatment-resistant focal seizures. The Introduction links the condition to aberrant mTOR signalling, but our copy does not identify TSC1 or TSC2 as the pathogenic variants responsible or establish those variants in the trial participants (searched: TSC1, TSC2). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Forced normalization, in which psychiatric problems emerge in the setting of seizure control, can occur in patients with longstanding drug-resistant seizures.

“Forced normalization, in which psychiatric problems emerge in the setting of seizure control, can occur in patients with longstanding drug-resistant seizures 217 .”

• cites [217] Calle-Lopez, Y. et al. Forced normalization: a systematic review. Epilepsia 60, 1610–1618 (2019). sourceSupported

A 10 year old girl with Dravet syndrome, who had been seizure-free for 2 years, was found deceased when walking outside on a day with extremely hot temperatures (46.5 degree Celsius).

“For instance, a 10 year old girl with Dravet syndrome, who had been seizure-free for 2 years, was found deceased when walking outside on a day with extremely hot temperatures (46.5 degree Celsius) 206 .”

• cites [206] Sisodiya, S. M., Scheffer, I. E., Lowenstein, D. H. & Free, S. L. Why should a neurologist worry about climate change? Lancet Neurol. 18, 335–336 (2019). sourcePartly supported

  The passage labeled Abstract (no page given) describes a girl with Dravet syndrome who had been seizure-free for two years, went walking outside on a day that reached 46.5°C, and was found dead. It does not state that she was 10 years old. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In the first of two RCTs, fenfluramine in two different doses was added to antiseizure regimens without stiripentol.

“In the first of two RCTs, fenfluramine in two different doses was added to antiseizure regimens without stiripentol 197 .”

• cites [197] Lagae, L. et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 394, 2243–2254 (2019). This randomized controlled trial showed that fenfluramine is highly efficacious in Dravet syndrome, highlighting that trials targeting a repurposed drug in specific epilepsy syndrome can offer major improvements in clinical care. sourceSupported

In the second RCT, an intermediate dose of fenfluramine, owing to drug interactions, was added to stiripentol resulting in >50% (54% vs 5% placebo) and a >75% reduction (35% vs 2% placebo) in convulsive seizures.

“In the second RCT, an intermediate dose of fenfluramine, owing to drug interactions, was added to stiripentol resulting in >50% (54% vs 5% placebo) and a >75% reduction (35% vs 2% placebo) in convulsive seizures 198 .”

• cites [198] Nabbout, R. et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 77, 300–308 (2020). sourceSupported

RCTs now include parental questionnaires measuring behaviour and everyday function, which typically aid the descriptive aspects of the study rather than acting as primary or secondary end points.

“RCTs now include parental questionnaires measuring behaviour and everyday function, which typically aid the descriptive aspects of the study rather than acting as primary or secondary end points 199 .”

• cites [199] Bishop, K. I. et al. Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (<5 years) with Dravet syndrome: a critical period for early neurodevelopment. Epilepsy Behav. 138, 108994 (2023). sourcePartly supported

  The Methods (p. 2) describe parent ratings of everyday executive function in the RCT, and the limitations (p. 9) say everyday executive function was not a primary efficacy endpoint; its analysis was post-hoc and exploratory. The paper does not establish that such questionnaires typically serve descriptive purposes across RCTs rather than acting as primary or secondary endpoints. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Patients with DEEs are at high risk of the typical medical complications associated with severe neurodevelopmental impairment, including aspiration pneumonia, feeding problems, constipation, sleep disorders and orthopaedic deformities.

“Patients with DEEs are at high risk of the typical medical complications associated with severe neurodevelopmental impairment, including aspiration pneumonia, feeding problems, constipation, sleep disorders and orthopaedic deformities 110,152,215 .”

• cites [110] Vlaskamp, D. R. M. et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology 92, E96–E107 (2019). sourcePartly supported

  The Results (Other features; Examination findings) report eating and sleep difficulties and orthopedic deformities in the SYNGAP1 cohort. Results (Brain pathology) records one death from aspiration pneumonia, but does not establish that it is a high-risk complication; the passages do not report constipation. Findings from this SYNGAP1 cohort also do not establish the stated risk for patients with DEEs generally. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [152] Stamberger, H. et al. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genet. Med. 23, 363–373 (2021). sourcePartly supported

  The Additional comorbidities section (p. 7) reports comorbidities in 72% of patients with NEXMIF encephalopathy, particularly gastrointestinal problems. The Discussion (p. 9) describes NEXMIF encephalopathy as a form of DEE and says comorbidities were common. These findings support the general point for this specific disorder, but the paper does not establish the claimed risk across DEEs or identify aspiration pneumonia, feeding problems, constipation, sleep disorders, and orthopaedic deformities as that risk. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [215] Villas, N., Meskis, M. A. & Goodliffe, S. Dravet syndrome: characteristics, comorbidities, and caregiver concerns. Epilepsy Behav. 74, 81–86 (2017). sourceNot checked — no full text of the source

The use of SCBs leading to increased seizure frequency was associated with a reduced HRQOL at 10-year-follow-up (F-ratio (1,34) = 4.13, p = +0.05).

“The use of SCBs leading to increased seizure frequency was associated with a reduced HRQOL at 10-year-follow-up (F-ratio (1,34) = 4.13, p = +0.05)227 .”

• cites [227] Makiello, P. et al. Comorbidities and predictors of health-related quality of life in Dravet syndrome: a 10-year, prospective follow-up study. Epilepsia 64, 1012–1020 (2023). sourcePartly supported

  The Results (section 3.2, p. 4) report the stated association and F-ratio, with p = .05. The finding applies specifically to the older patient group and to SCB use leading to increased seizure frequency at initial assessment; the citing sentence omits those limits. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Viral vectors, such as adeno-associated virus 9 (AAV9), enable widespread gene transfer in the adult brain.

“Viral vectors, such as adeno-associated virus 9 (AAV9), enable widespread gene transfer in the adult brain 234 .”

• cites [234] Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016). sourcePartly supported

  The paper reports AAV9-mediated gene transfer in several regions of the adult mouse brain, but identifies the engineered AAV-PHP.B—not AAV9—as the vector that efficiently transduced the entire adult CNS (Abstract, page unavailable). It reports that AAV-PHP.B transferred genes 40–92 times more efficiently than AAV9 in the brain regions examined, so the claim overstates what the paper shows for AAV9. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Trials of antisense oligonucleotides in mouse models of DEEs have shown positive effects for several genes including SCN1A, SCN2A, SCN8A and KCNT1.

“Trials of antisense oligonucleotides in mouse models of DEEs have shown positive effects for several genes including SCN1A, SCN2A, SCN8A and KCNT1 237,238 .”

• cites [237] Burbano, L. E. et al. Antisense oligonucleotide therapy for KCNT1 encephalopathy. JCI Insight 7, e146090 (2022). sourceSupported
• cites [238] Li, M. et al. Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model. J. Clin. Invest. 131, e152079 (2021). sourcePartly supported

  The paper’s opening summary (p. 1) reports that an antisense oligonucleotide reduced seizures and extended life span in a mouse model of SCN2A-related DEE. The cited sentence does not specify which genes this reference supports, and our copy does not establish positive effects for SCN1A, SCN8A, or KCNT1. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant.

“This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications.”

• cites [175] Myers, C. T. et al. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378, 1646–1648 (2018). This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications. sourceSupported

The use of antisense oligonucleotides to increase the production of translated mRNA, termed Targeted Augmentation of Nuclear Gene Output (TANGO), has been used successfully in an animal model of Dravet syndrome to increase the production of sodium channels.

“The use of antisense oligonucleotides to increase the production of translated mRNA, termed Targeted Augmentation of Nuclear Gene Output (TANGO), has been used successfully in an animal model of Dravet syndrome to increase the production of sodium channels 239”

• cites [239] Han, Z. et al. Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Sci. Transl. Med. 12, eaaz6100 (2020). sourceSupported

Fenfluramine is highly efficacious in Dravet syndrome.

“This randomised controlled trial showed that fenfluramine is highly efficacious in Dravet syndrome, highlighting that trials targeting a repurposed drug in specific epilepsy syndrome can offer major improvements to clinical care.”

• cites [197] Lagae, L. et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 394, 2243–2254 (2019). This randomized controlled trial showed that fenfluramine is highly efficacious in Dravet syndrome, highlighting that trials targeting a repurposed drug in specific epilepsy syndrome can offer major improvements in clinical care. sourceSupported

New approaches include targeting regulatory elements of large genes, such as SCN1A, employing cellselective specificity.

“New approaches include targeting regulatory elements of large genes, such as SCN1A, employing cellselective specificity 235 .”

• cites [235] Tanenhaus, A. et al. Cell-selective adeno-associated virus-mediated SCN1A gene regulation therapy rescues mortality and seizure phenotypes in a Dravet syndrome mouse model and is well tolerated in nonhuman primates. Hum. Gene Ther. 33, 579–597 (2022). sourceSupported

Techniques are emerging, such as polygenic risk scores, that aid in understanding the interaction of rare and common variation in determining phenotypic variability.

“Already, techniques are emerging, such as polygenic risk scores, that aid in understanding the interaction of rare and common variation in determining phenotypic variability 244,246 .”

• cites [244] Martins Custodio, H. et al. Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition. Brain 146, 3885–3897 (2023). This study employed polygenic risk scores for longevity and intellect in a relatively small cohort of adults with Dravet syndrome, providing the first insights into the role of common variation in explaining these phenotypic features. sourceSupported
• cites [246] Campbell, C. et al. The role of common genetic variation in presumed monogenic epilepsies. eBioMedicine 81, 104098 (2022). sourceSupported

The disease-modifying potential of new treatments, especially precision and gene therapies, can only be determined if natural history profiles of each genetic DEE are well described.

“The disease-modifying potential of new treatments, especially precision and gene therapies, can only be determined if natural history profiles of each genetic DEE are well described 243 .”

• cites [243] Palmer, E. E., Howell, K. & Scheffer, I. E. Natural history studies and clinical trial readiness for genetic developmental and epileptic encephalopathies. Neurotherapeutics 18, 1432–1444 (2021). sourceSupported

• AssumptionRests on an assumption: For most DEEs, it is not known whether and how the cognitive outcome would improve if seizures were controlled soon after epilepsy onset.

In animal models, induced (non-genetic) seizures affect early brain development and network formation resulting in cognitive impairment.

“In animal models, induced (non-genetic) seizures affect early brain development and network formation resulting in cognitive impairment 250 .”

• cites [250] Kloc, M. L. et al. Spatial learning impairments and discoordination of entorhinal-hippocampal circuit coding following prolonged febrile seizures. Hippocampus 33, 970–992 (2023). sourcePartly supported

  The Methods (page unavailable) describe inducing prolonged febrile seizures in rat pups, and the Conclusions link altered hippocampal structure and physiology to spatial cognitive deficits. The paper studies this specific seizure model, not induced seizures generally; it proposes disrupted circuit signaling as a mechanism rather than directly demonstrating impaired network formation. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

In Infantile Epileptic Spasms Syndrome, a shorter time to spasm cessation is associated with improved developmental outcome in the group of children without a clear aetiology.

“Finally, in Infantile Epileptic Spasms Syndrome, a shorter time to spasm cessation is associated with improved developmental outcome in the group of children without a clear aetiology 251 .”

• cites [251] O’Callaghan, F. J. K. et al. Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial. Lancet Child. Adolesc. Health 2, 715–725 (2018). sourcePartly supported

  The Developmental outcome section reports that infants whose spasms ceased early had higher developmental scores at 18 months, and that longer delays to treatment were associated with lower scores. It also reports better scores among children with no identified aetiology, but does not establish the early-cessation association specifically within that subgroup. Page numbers were not supplied for these passages. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In people with TSC who developed epilepsy during childhood, 75% felt the disease led to isolation and social withdrawal, negatively affected relationships.

“In people with TSC who developed epilepsy during childhood, 75% felt the disease led to isolation and social withdrawal, negatively affected relationships”

• cites [231] Bar, C. et al. Experience of follow-up, quality of life, and transition from pediatric to adult healthcare of patients with tuberous sclerosis complex. Epilepsy Behav. 96, 23–27 (2019). sourceSupported

Carers of children with Dravet syndrome have more depressive symptoms than carers of patients with other drug-resistant epilepsies or in seizure remission.

“Carers of children with Dravet syndrome have more depressive symptoms than carers of patients with other drug-resistant epilepsies or in seizure remission”

• cites [228] Strzelczyk, A. et al. A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany. Epilepsia 60, 1697–1710 (2019). sourceSupported

In people with TSC who developed epilepsy during childhood, only 15% of respondents were optimistic about their state of health over the next 5 years.

“and only 15% of respondents were optimistic about their state of health over the next 5 years 231 .”

• cites [231] Bar, C. et al. Experience of follow-up, quality of life, and transition from pediatric to adult healthcare of patients with tuberous sclerosis complex. Epilepsy Behav. 96, 23–27 (2019). sourceSupported

Cessation of specific sodium channel blockers, which are contraindicated in Dravet syndrome, leads to improved seizure control and developmental gains in children and adults with Dravet syndrome.

“For example, cessation of specific sodium channel blockers, which are contraindicated in Dravet syndrome, leads to improved seizure control and developmental gains in children and adults with Dravet syndrome 232 .”

• cites [232] Catarino, C. B. et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 134, 2982–3010 (2011). sourcePartly supported

  The Results (Clinical condition and evolution in adulthood; page not supplied) report improved seizure control in three adults after anti-epileptic drug changes, with cognitive and quality-of-life improvement in two. The Discussion describes both withdrawal of drugs that could worsen seizure control and use of appropriate drugs. The paper does not establish that stopping sodium channel blockers alone caused these gains, and it does not report corresponding treatment outcomes in children. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Diagnosis of an epileptic encephalopathy is based on the child showing developmental slowing or regression in association with frequent epileptiform activity on EEG.

“Diagnosis of an epileptic encephalopathy is based on the child showing developmental slowing or regression in association with frequent epileptiform activity on EEG 1 .”

• cites [1] Berg, A. T. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51, 676–685 (2010). sourceNot checked — no full text of the source

Biallelic variants in CNTNAP2 result in a Pitt-Hopkins-like syndrome with early onset epilepsy, hyperventilation, ASD, developmental delay and cortical dysplasia in some patients.

“Biallelic variants result in a Pitt-Hopkins-like syndrome with early onset epilepsy, hyperventilation, ASD, developmental delay and cortical dysplasia in some patients 113 .”

• cites [113] Smogavec, M. et al. Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum. J. Med. Genet. 53, 820–827 (2016). sourceNot checked — no full text of the source

Precision therapy using intracerebroventricular enzyme replacement with recombinant human tripeptidyl peptidase 1 slowed disease progression in one study.

“Precision therapy using intracerebroventricular enzyme replacement with recombinant human tripeptidyl peptidase 1 slowed disease progression in one study 148 .”

• cites [148] Schulz, A. et al. Study of intraventricular cerliponase alfa for CLN2 disease. N. Engl. J. Med. 378, 1898–1907 (2018). sourceNot checked — no full text of the source

Early diagnosis helps to avoid contraindicated ASMs that exacerbate seizures in specific DEEs.

“Early diagnosis also helps to avoid contraindicated ASMs that exacerbate seizures in specific DEEs.”

Patients with DEE or EE who do not fit a recognised syndrome share the increased risk of comorbidities and SUDEP that occur in DEE syndromes.

“They do, however, share the increased risk of comorbidities and SUDEP that occur in DEE syndromes; thus, recognizing the severe nature of their disease is crucial.”

When a child with normal development develops an epileptic encephalopathy, slowing in development can be hard to identify.

“Similarly, when a child with normal development develops an epileptic encephalopathy, slowing in development can be hard to identify.”

Identifying an epileptic encephalopathy can be challenging, especially in children with pre-existing developmental delay.

“This can be challenging to identify, especially in children with pre-existing developmental delay.”

Early targeted treatment with the most appropriate ASMs to control life-threatening seizures can ameliorate the adverse developmental consequences of frequent seizures and status epilepticus.

“This enables early targeted treatment with the most appropriate ASMs to control life-threatening seizures to ameliorate the adverse developmental consequences of frequent seizures and status epilepticus.”

Access to genetic testing means that infants with Dravet syndrome are diagnosed as early as their initial presentation.

“Access to genetic testing means that infants with Dravet syndrome are diagnosed as early as their initial presentation.”

As a group, DEEs are far more complex diseases than just seizure disorders.

“As a group, DEEs are far more complex diseases than just seizure disorders.”

Diagnosis of a DEE can now be made far earlier with increasing recognition of the initial presentation together with prompt access to molecular diagnosis in clinical practice, often even before the EEG shows epileptiform activity and developmental slowing occurs.

“Diagnosis of a DEE can now be made far earlier with increasing recognition of the initial presentation together with prompt access to molecular diagnosis in clinical practice, often even before the EEG shows epileptiform activity and developmental slowing occurs.”

The percentage of patients who have a causative variant identified varies markedly across different DEE syndromes.

“The percentage of patients who have a causative variant identified varies markedly across different DEE syndromes.”

Genetic DEEs implicating a range of disease mechanisms may also be associated with structural changes in the brain, such as MCD, that likely result from changes in gene expression during early brain development.

“Genetic DEEs implicating a range of disease mechanisms may also be associated with structural changes in the brain, such as MCD, that likely result from changes in gene expression during early brain development.”

DEEs have historically been diagnosed on the basis of their electroclinical presentation.

“DEEs have historically been diagnosed on the basis of their electroclinical presentation 1 .”

• cites [1] Berg, A. T. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51, 676–685 (2010). sourceNot checked — no full text of the source

DEEs are multimorbidity diseases typically affecting a range of systems.

“They are multimorbidity diseases typically affecting a range of systems.”

Knowing the gene is not sufficient, as each gene is typically associated with a spectrum of phenotypes.

“Knowing the gene is not sufficient, as each gene is typically associated with a spectrum of phenotypes.”

Many patients with a DEE or an epileptic encephalopathy do not fit neatly into a recognised epilepsy syndrome diagnosis.

“Despite the epilepsy syndrome informing diagnosis, aetiology and management, many patients with a DEE or an epileptic encephalopathy do not fit neatly into a recognised epilepsy syndrome diagnosis.”

This approach can be particularly problematic for DEEs, in which a lack of diagnosis of the epilepsy syndrome may result in inappropriate prescription of an ASM that causes seizure exacerbation with potential adverse developmental consequences.

“This approach can be particularly problematic for DEEs, in which a lack of diagnosis of the epilepsy syndrome may result in inappropriate prescription of an ASM that causes seizure exacerbation with potential adverse developmental consequences 159 .”

• cites [159] Scheffer, I. E. & Liao, J. Deciphering the concepts behind “epileptic encephalopathy” and “developmental and epileptic encephalopathy”. Eur. J. Paediatr. Neurol. 24, 11–14 (2020). sourceNot checked — no full text of the source

Traditional ASMs can be used as precision therapies when the functional effect of the pathogenic variant is understood.

“Traditional ASMs can be used as precision therapies when the functional effect of the pathogenic variant is understood (Supplementary Table 1).”

Stiripentol was more effective, in association with clobazam, in individuals with Dravet syndrome.

“Stiripentol was more effective, in association with clobazam, in individuals with Dravet syndrome 194 .”

• cites [194] Perez, J. et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia 40, 1618–1626 (1999). sourceNot checked — no full text of the source

Episignatures, derived from disruption in genome-wide DNA methylation profiles, are recognised for many genes resulting in neurodevelopmental disorders including ASD, with some relevant to DEEs.

“Episignatures, derived from disruption in genome-wide DNA methylation profiles, are recognised for many genes resulting in neurodevelopmental disorders including ASD, with some relevant to DEEs 143 .”

• cites [143] Aref-Eshghi, E. et al. Diagnostic utility of genome-wide DNA methylation testing in genetically unsolved individuals with suspected hereditary conditions. Am. J. Hum. Genet. 104, 685–700 (2019). sourceNot checked — no full text of the source

By comparing phenotypic features, such as seizure type and frequency with HRQOL, studies identify predictors of outcome.

“By comparing phenotypic features, such as seizure type and frequency with HRQOL, studies identify predictors of outcome.”

Cross-sectional studies in DEEs demonstrate considerably worse HRQOL than in both the general population and unselected childhood epilepsy cohorts.

“Cross-sectional studies in DEEs demonstrate considerably worse HRQOL than in both the general population and unselected childhood epilepsy cohorts 226 .”

• cites [226] Brunklaus, A., Dorris, L. & Zuberi, S. M. Comorbidities and predictors of health-related quality of life in Dravet syndrome. Epilepsia 52, 1476–1482 (2011). sourceNot checked — no full text of the source

In a RCT on stable doses of clobazam and valproate, 71% of children with Dravet syndrome receiving add-on stiripentol compared with only 5% receiving placebo achieved a >50% reduction in seizures.

“In a RCT on stable doses of clobazam and valproate, 71% of children with Dravet syndrome receiving add-on stiripentol compared with only 5% receiving placebo achieved a >50% reduction in seizures 193 .”

• cites [193] Chiron, C. et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 356, 1638–1642 (2000). sourceNot checked — no full text of the source

Certain ASMs may lead to seizure exacerbation in specific genetic DEEs.

“Certain ASMs may lead to seizure exacerbation in specific genetic DEEs.”

Given the young age at presentation, intellectual disability and comorbidities in patients with DEEs, HRQOL assessments comprise proxy questionnaires completed by caregivers.

“Given the young age at presentation, intellectual disability and comorbidities in patients with DEEs, HRQOL assessments comprise proxy questionnaires completed by caregivers.”

The aetiologies of comorbidities in DEEs are multifactorial, reflecting the underlying neurobiology of the DEE, exacerbated by poorly controlled seizures, frequent epileptiform activity on EEG, sedative and psychiatric adverse effects of medication, restrictions, and social stigma.

“The aetiologies are multifactorial, reflecting the underlying neurobiology of the DEE, exacerbated by poorly controlled seizures, frequent epileptiform activity on EEG, sedative and psychiatric adverse effects of medication, restrictions, and social stigma 216 .”

• cites [216] Guerrini, R. et al. Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum. Physiol. Rev. 103, 433–513 (2023). sourceNot checked — no full text of the source

Early, appropriate treatment of seizures may reduce the likelihood of status epilepticus.

“Early, appropriate treatment of seizures may reduce the likelihood of status epilepticus 210 .”

• cites [210] Guerrini, R., Parrini, E., Marini, C. & Mei, D. What is the role of next generation sequencing in status epilepticus? Epilepsy Behav. 101, 106373 (2019). sourceNot checked — no full text of the source

Even early postnatal delivery of gene therapy is probably too late to fully reverse the formation of abnormal brain networks.

“Thus, even early postnatal delivery of gene therapy is probably too late to fully reverse the formation of abnormal brain networks.”

TANGO is currently undergoing clinical trials in Dravet syndrome.

“and is currently undergoing clinical trials in Dravet syndrome 240 .”

• cites [240] US National Library of Medicine. ClinicalTrials.gov ClinicalTrials.gov/show/NCT04442295 (2024).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Several lines of evidence suggest that ongoing seizures and/or epileptiform activity worsen outcomes.

“However, several lines of evidence suggest that ongoing seizures and/or epileptiform activity worsen outcomes.”

Trials targeting a repurposed drug in a specific epilepsy syndrome can offer major improvements to clinical care.

“This randomised controlled trial showed that fenfluramine is highly efficacious in Dravet syndrome, highlighting that trials targeting a repurposed drug in specific epilepsy syndrome can offer major improvements to clinical care.”

Parental mosaicism in DEE has significant reproductive counselling implications.

“This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications.”