2025/04/07 by Rima Nabbout, Mathieu Kuchenbuch · 1 voice
Medicine · #Fetal and Pediatric Neurological Disorders #Tuberous Sclerosis Complex Research #Epilepsy research and treatment
paper · pdf · doi:10.1111/epi.18285
openalex publication_date 2025/04/07 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Since Guthrie's pioneering work in 1963 on phenylketonuria, the spectrum of diseases addressed in neonatal screening programs has broadened. Ethical considerations regarding the conditions qualifying for neonatal screening were raised as early as the 1960s.1, 2 In 1968, the World Health Organization established recommendations for identifying disease candidates that could benefit from such an approach.3 The main criteria outlined in this report include the importance of the impact of the disease on health, the understanding of its natural history, and the availability of suitable diagnostic tests and of acceptable treatment. In many high-income countries, national committees have been established to determine the diseases candidate to be included in neonatal screening programs.4 The number of conditions in newborn screening currently spans from 2 (Bosnia and Herzegovina) to 40 (Italy) in Europe,5 and from 33 (Montana and Louisiana) to 74 (Connecticut) in the United States.6 The Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) founded in the United States to advise the Secretary of Health and Human Services on this topic developed, in 2006, an instrument to assess the suitability of disorders for inclusion in newborn screening programs (Figure 1).7 This score enabled the distinction between high-scoring conditions (e.g., congenital hypothyroidism and galactosemia, scoring at or above 1200), low-scoring conditions (e.g., X-linked adrenoleukodystrophy and fragile X syndrome, scoring below 1000), and a middle group scoring between 1000 and 1199 (e.g., congenital toxoplasmosis and malonic acidemia). Using this score, 29 conditions with high scores were identified for inclusion in the recommended uniform screening panel (RUSP), whereas an additional 25 were selected from the middle group due to their relevance in the differential diagnosis of the core panel conditions.7 Progressively, this number increased to include 37 conditions in the core panel and 26 conditions in the secondary panel, that is, “conditions that are part of the differential diagnosis of a core panel condition.”8 The inclusion of spinal muscular atrophy (SMA) in this core panel in 2018, mainly due to the revolution of its treatment landscape with the implementation of gene and antisense oligonucleotide (ASO) therapies, marked a significant milestone as it represents one of the first instances of genetic screening being integrated into routine newborn screening programs. Recently, patients' advocacy groups and physicians highlighted to the committee that the nomination process for the RUSC is arduous and overlooks major factors valued by the families.9 Consequently, the committee has chosen to suspend nominations of new conditions for a period of 6 months (from December 2023 to May 2024) to ensure a consistent and standardized pathway, thereby preventing inconsistencies in the nomination processes. The updated process, introduced in May 2024, simplifies the nominations by implementing a two-step approach, starting with a lighter preliminary form to assess appropriateness before requiring a full nomination package. In addition to reducing the initial burden, the updated process allows an improved review involving different stakeholders and necessitating multidisciplinary consensus validation.10 The patients' advocacy groups underscored the extension of the role of neonatal screening, beyond disorders with available cure, to the reduction of diagnostic odyssey, early access to innovative therapies as soon as they become available, and the ability to plan for the child's future needs. However, it is worth noting that, to date, no monogenic epilepsies, mainly no developmental and epileptic encephalopathy (DEE), is included in these various official screening panels. We are witnessing a significant shift in the field of epilepsy classification, adding to well-defined electroclinical syndromes a precision classification based on etiologies, particularly for monogenic and metabolic diseases. This shift is supported by the rise of precision medicine and disease-modifying therapies, along with a deeper understanding of the substantial social, societal, and economic impacts of early-onset epilepsies. This urges the need to evaluate epilepsies and epileptic syndromes that are strong candidates for neonatal screening or may be close to meeting the inclusion criteria of these screening panels. We have chosen to categorize epilepsy and epilepsy syndromes based on the potential impact that neonatal screening may have on the outcomes trajectories of affected individuals. This classification allows for tailoring the screening and treatment strategies according to the specific characteristics of each group, thereby optimizing early intervention. The first group encompasses rare epilepsies that have available precision therapies targeting molecular pathways or mechanisms. It currently includes epilepsies associated with metabolic disorders that have substitution therapies, as well as epilepsies linked to an overactivation of the mechanistic Target Of Rapamycin (mTOR) signaling pathway.11 In these disorders, diagnostic tests are available and early management improves the outcome. For instance, giving pyridoxine or pyridoxal phosphate supplementation within the first 6 months of life, or at birth, for people with pyridoxine-dependent epilepsy, is associated with seizure control and an improved neurodevelopmental outcome.12 Similarly, the age at introduction of the ketogenic diet in individuals with glucose transporter 1 deficiency (GLUT1DS) was correlated with seizure control and improvement of the developmental outcome.13, 14 These two rare forms of genetic DEEs were identified by a panel of experts as the primary candidates for inclusion in future newborn screening programs focused on genetic epilepsy.15 Available specific therapies in this group pave the way for presymptomatic interventions. For instance, the symptoms of pyridoxine-dependent DEE (PD-DEE) are often neonatal but they may appear later in the first weeks of life, leaving a possible window for presymptomatic treatment.16 In individuals with GLUT1DS, the first symptoms may appear also beyond the neonatal period during the first months or years of life. The ketogenic diet, a targeted treatment for this disease, may be initiated during the neonatal period and has the potential to improve clinical outcomes.17 The replacement therapy with early recombinant human tripeptidyl peptidase introduction, has shown significant improvement in the survival and other outcomes in individuals with neuronal ceroid lipofuscinosis type 2 (CLN2),18, 19 a neurodegenerative lethal disease in early infancy.20 The treatment administered presymptomatically for siblings of patients with CLN2 significantly improved the outcome, with mild developmental delay at 4 years of age and no other manifestations of the disease such as epilepsy, sleep disorders, cerebral atrophy on magnetic resonance imaging (MRI), or abnormal electroretinography.20 Another example of presymptomatic treatment may be the use of mTOR inhibitors (rapamycin and everolimus) as targeted therapies for tuberous sclerosis complex (TSC). Indeed, approximately 80 % of individuals with a TSC pathogenic variant in TSC1 or TSC2 will present epilepsy, mainly in the first 2 years of life.21 In clinical trials, everolimus has shown effectiveness for hamartomas (ocular, renal, cutaneous, and cerebral) and epilepsy.22, 23 According to different studies, response rates for mTOR inhibitors in this population ranged from 30% to 71%.24 Of interest, treatments identified as effective in this condition also seem to exert an inhibitory effect on the mTOR pathway, as seen with vigabatrin, ketogenic diet, and cannabidiol.24 A common characteristic in patients with TSC is the frequent latency period for epilepsy of a few months, which creates a window of opportunity for the implementation of the presymptomatic treatment. The long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – Tuberous Sclerosis Complex (EPISTOP) study was the first to support effective preventive strategy for epilepsy in TSC.25 In the preventive group, treated before epilepsy onset by vigabatrin, none experienced epileptic spasms at the age of 2 years, compared to 40% in the conventional treatment group, who received vigabatrin after the onset of seizures. In addition, the occurrence of drug-resistant epilepsy at 2 years was halved (28% vs 60%). However, this approach did not substantially influence the incidence of autism spectrum disorder or developmental delay evaluated at 2 years. The substantial impact of epilepsy on individuals with TSC and their families26 may support this presymptomatic use.26 Currently, prenatal diagnosis of TSC is based on identification of cardiac rhabdomyoma or brain tubers or subependymal nodules on prenatal ultrasound, or on genetic testing in pregnancies with a family history of TSC. Between 2010 and 2020, prenatal diagnosis rates for TSC increased from ~33% before 2010 to 80% for those born during that period.27 Neonatal diagnosis will capture the remaining 20%25, 28 (or more depending on the antenatal ultrasound expertise), enabling electroencephalography (EEG) follow-up to guide presymptomatic therapy and establish the recommended follow-up for hamartoma.29 Indeed, the EEG monitoring schedule is well established,30 and neonatal screening will improve epileptic outcome and possibly developmental outcomes.31 A recent randomized study (PREVeNT) has confirmed a delay of the onset of spasms in infantile epileptic spasms syndrome (IESS) and a reduction of its overall prevalence in the TSC group treated preventively with vigabatrin.32 In the second group, targeted therapies are not yet implemented, although some precision medicine approaches may be available. Channelopathy-associated epilepsies are a good example of this group. These disorders account for ~25% of rare genetic epilepsies. Timely identification of underlying genetic etiologies through neonatal screening would enable close monitoring, reduce diagnostic odyssey, and significantly improve therapeutic management. Identifying these diseases at birth will allow the avoidance of precipitating factors and propose presymptomatic therapy that may prevent, at least partly, the development of the severe phenotype of these disorders. For instance, a retrospective study on encephalopathy related to pertussis vaccination showed that 11 of the 14 individuals reported in this study had a pathogenic variant of sodium voltage-gated channel alpha subunit 1 gene (SCN1A). Pathogenic variants in this gene, with loss of function, mainly result in two phenotypes: Dravet syndrome (DS) and a milder form known as genetic epilepsy with febrile seizures plus (GEFS+). The two key predictors of DS are the SCN1A pathogenic variant genetic score and the age at seizure onset.33 In individuals with a SCN1A pathogenic variant, vaccination may trigger earlier epilepsy onset.34, 35 A retrospective multicenter cohort study revealed that the prophylactic use of benzodiazepines is associated with a substantial reduction in the recurrence of post-vaccination seizures, with a remarkable 30-fold reduction in the likelihood of seizures.36 A case report of two siblings with a novel pathogenic SCN1A variant underscored the importance of individualized management, revealing the severe outcome in the index case and the successful preventive measures, based on regular prophylactic sodium valproate and additional clobazam post-vaccination, used for the sibling.36 Similar to TSC, we could hypothesize that the discovery of early predictive biomarkers for this group will allow timely and personalized neonatal or presymptomatic interventions. In the case of DS, the identification of SCN1A pathogenic variants at birth will also limit contraindicated anti-seizure medications (ASMs) and facilitate a tailored selection of appropriate ones. The worsening effect of sodium channel blockers in patients with DS exacerbates seizures but appears to have also a worsening impact on long-term neurodevelopmental outcome when used during the first 5 years of life.37 Conversely, in cases of SCN2A and SCN8A gain-of-function mutations, sodium channel blockers are recommended as first-line therapies.38-40 The same may apply to potassium channel–related DEEs associated with gain-of-function and the use of potassium blockers medications.41 One may argue that targeted ASM therapy may be adequately guided by rapid genetic testing performed after the first seizure onset. Therefore, we may question the added value of neonatal screening. However, the rapid development of gene and assimilated therapies in these monogenic rare epilepsies will necessitate re-addressing the neonatal screening soon. The presymptomatic period between birth and the onset of the first seizure, existing in many monogenic epilepsies, may be an opportunity window to consider. Approaches based on ASOs are currently under development, primarily for gain-of-function channelopathies (sodium voltage-gated channel alpha subunit 2 gene (SCN2A),42 sodium voltage-gated channel subunit 8 gene (SCN8A),43 potassium sodium-activated channel subfamily T member 1 (KCNT144)) but also for loss-of-function types (SCN1A45). Trials for patients with SCN1A45 and SCN2A46 pathogenic variants are even undergoing phase 1/2 studies with promising results. Along the same line, other monogenic disorders with DEEs are also progressing, with significant results in the preclinical studies and a prompt translation to humans (syntaxin binding protein 1 gene (STXBP1),47 synaptic ras GTPase activating protein 1 gene (SYNGAP1),47 SCN1A,48 cyclin-dependent kinase-like 5 (CDKL5)49…). Additional major challenges in this group concern the pathogenicity of the variants discovered with numerous variants of uncertain significance (VUS) and the identification of the patient's most probable phenotype and prognosis. These uncertainties pose a challenge in clinical decision-making and in the information provided to the family. However, a better understanding of the impact of different variants is currently developing, as well as major research for specific prognosis markers that may delineate the phenotype and patient's outcome with a high level of certainty. The third category of epileptic syndromes should, at this time, be omitted from the neonatal screening list. Several key reasons, often combined, justify the exclusion of these syndromes. First, certain epilepsy syndromes lack diagnostic biomarkers in the neonatal period, including genetic, biochemical, EEG, or imaging markers. For instance, idiopathic generalized epilepsy (20%–30% of all epilepsy syndromes) is presumed to have a polygenic etiology (polygenic risk score).50 In addition, no specific alterations on EEG, imaging, or in biochemical markers have been reported during the neonatal period. Second, some monogenic conditions elude detection in the peripheral blood due to their somatic nature, such as pathogenic variants in GNAQ causing Sturge–Weber syndrome,51 or because they involve a complex combination of genetic predisposition (first hit) and somatic mutations occurring during brain development, as seen in cortical focal dysplasia.52 Third, certain epilepsy syndromes are self-limited, such as self-limited epilepsy with centro-temporal spikes.53 Because these self-limited epilepsies typically resolve spontaneously without significant developmental impact, neonatal screening may not contribute significantly to improved patient management and outcome. Other syndromes may have acquired postnatal causes, such as post-infectious or clastic lesion, as seen in infantile spasms and Lennox–Gastaut syndromes. Finally, syndromes with immune-mediated etiologies (e.g., new-onset refractory status epilepticus, Rasmussen syndrome, febrile infection-related epilepsy syndrome [FIRES], and hemiconvulsion–hemiplegia–epilepsy syndromes) are difficult to propose for such screening due to a lack of clear neonatal biomarkers to date.54, 55 The prevention of these syndromes relies primarily on primary prevention measures, such as improving neonatal care practices and enhancing the diagnosis and treatment of central nervous system infections.11 In summary, the complexity of these syndromes, coupled with the lack of clear monogenic, underlying and currently from the neonatal screening list. neonatal screening for some epileptic syndromes that have targeted therapies and clear the complexity of other syndromes creates significant challenges for effective screening Therefore, a of the is when on the appropriateness of neonatal screening for such We to the and of based on the scoring system in by the for epilepsy syndromes and etiology related epilepsy based on the classification and (Figure Of interest, the scores were from for to for for the first group, from for DS with SCN1A pathogenic variant to for potassium voltage-gated channel subfamily member 2 DEE for the second group, and from for epilepsy in with focal seizure to for Rasmussen for the third group. Using the same scoring the score for is at This that the first group the criteria for neonatal screening. The in (from months to few and more (from to for a between and have the way for genetic newborn These have the of newborn screening date, have newborn screening gene from 14 to The common of these studies is to and evaluate the of for screening of in also to the and value of at birth as a care However, the that none of the associated with epileptic syndromes appear in all of neonatal screening the in these panels. For instance, GLUT1DS, present in of 8 and deficiency identified in 6 of were the most syndromes, consistent with and the of a precision for type 2 neuronal ceroid lipofuscinosis is a significant impact in presymptomatic the for pathogenic variants in tripeptidyl peptidase 1 gene was included in of the neonatal screening Similarly, and TSC were from of the panels. The this that this exclusion may also the of a screening panel for metabolic including established in these or Finally, the the selection of certain in the of neonatal screening may be For instance, the inclusion of some epilepsies as ceroid lipofuscinosis neuronal gene and a group of neurodegenerative epilepsy syndromes, by drug-resistant epilepsy, with severe and early may be because of the lack of available are also present in the panel, although the for this epilepsy are in Finally, voltage-gated channel subunit A gene a gene causing a of as type 2 including Lennox–Gastaut syndrome and as well as a significant challenge because of the known high of the even within the same a targeted therapy for disorders, has shown in some but research is In addition to the and the implementation of a neonatal screening for epilepsy the of a to ensure timely diagnosis and intervention. The of for rare epilepsies with a of with in epilepsy genetic testing would be in an effective for neonatal screening for epilepsy in These would facilitate the rapid of pathogenic thereby that appropriate therapies through a care The of a multidisciplinary including and care and with the of national consensus for complex be established and The work by and their existing for the care of with the survival pathogenic variant may as a The development of therapies for rare diseases is due to various including the of the treatments and the clinical trials, which are often and This is by the development of therapies for It is that the of these therapies will time, with in therapy and and the development of in clinical for rare diseases with of Therefore, it is that individuals with rare epilepsies who are for targeted therapies not in access to precision therapies beyond is currently treatment patients to the of disease in these disorders. The identification of additional biomarkers will facilitate patient particularly in individuals with epilepsy syndromes that are to precision medicine approaches the potential for significant in of and survival is by these therapies, the will neonatal screening and early treatment and neonatal screening. The of epileptic syndromes and the potential for significant improvement with early therapeutic justify the inclusion of deficiency seizures related to pathogenic variants and deficiency and related to CLN2 and TSC and in neonatal panel screening. In addition, a second group, including some channelopathies and inclusion in the neonatal screening panel due to therapies and the potential for early in the presymptomatic period, such as for In this group, some challenges on the pathogenicity of the variants at birth to be the by the the scoring system may be a good first in a consensus within the epilepsy supported by the and other such as the for in rare and complex epilepsies, the of the and patient advocacy and This will allow to propose and the of epilepsy syndrome candidates for neonatal screening and their implementation in and national However, we that access for born in and In this epilepsy diagnosis is often or and genetic testing is not available. However, such recommendations with a consensus could support increased in diagnostic to facilitate the diagnosis of rare epilepsy syndromes with genetic etiologies in We that, with the identification of additional a better understanding of underlying and the development of targeted therapies, other syndromes will be included as candidates for neonatal screening in the This work was supported by a by the under the integrated into with the is supported by the by by Health and is supported by the under and by by and are of a by the under the integrated into with the The that the research was in the of or that could be as a potential of We that we have the on in and that this report is consistent with those The that support the of this study are available on from the The are not available due to or