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Epilepsy, characterized by recurrent seizures, impacts 70-80% of patients, leading to cognitive deficits. The intricate relationship between seizure control and cognitive impairment remains complex. Epileptic encephalopathy (EE), an intensified form often rooted in genetic factors, is detectable through next-generation sequencing, aiding in precise diagnoses, family counseling, and potential treatment strategies. We present a case involving two sisters with refractory generalized seizures evolving into dysarthria, dysphagia, ataxia, and cognitive decline. Despite normal physical exams, abnormal electroencephalogram results consistent with epilepsy were noted. Whole Exome Sequencing identified heterozygous variants in the alanyl-tRNA synthetase (AARS) and Calcium Voltage-Gated Channel Subunit Alpha 1 (CACNA1A) genes. The AARS variant (c.C2083T, p.R695*) was maternal, while the CACNA1A variant (c.G7400C, p.R2467P) was paternal. Patients A and B exhibited a unique blend of neurological and psychiatric conditions, distinct from common disorders that begin adolescence, like Juvenile Myoclonic Epilepsy. Whole Exome Sequencing uncovered an AARS gene and CACNA1A gene, linked to various autosomal dominant phenotypes. Presence in both parents, coupled with familial reports of migraines and seizures, provides insight into accelerated symptom progression. This study underscores the importance of genetic testing in decoding complex phenotypes and emphasizes the value of documenting family history for anticipating related symptoms and future health risks.

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INTRODUCTION: CAD (MIM*114010) encodes a large multifunctional protein with the enzymatic activity of the first three enzymes initiating and controlling the de novo pyrimidine biosynthesis pathway. Biallelic pathogenic variants in CAD cause the autosomal recessive developmental and epileptic encephalopathy 50 (MIM #616457) or CAD deficiency presenting with epilepsy, status epilepticus (SE), neurological deterioration and anemia with anisopoikilocytosis. Mortality is around 9% of patients, mainly related to the no use of its specific treatment with uridine. Majority of reported cases have an early onset during infancy, with some few starting later in childhood. CASE REPORT: Here we report a deceased female patient with CAD deficiency whose epilepsy started at 14 years. She showed a rapid neurologic deterioration including cognitive decline, electroencephalographic background slowing which later evolved to a fatal refractory SE and supra and infratentorial atrophy on neuroimaging. Anemia developed after SE onset. METHODS AND RESULTS: her post-mortem whole exome sequencing identified biallelic missense variants in CAD (NM_004341.5): c.[2944G > A];[5366G > A] p.[(Asp982Asn)];[(Arg1789Gln)]. Our review of twenty-eight reported cases (2015-2023) revealed an epilepsy age onset from neonatal period to 7 years and the SE prevalence of 46 %. DISCUSSION: With our case, we highlight the relevance of suspecting this treatable condition in older patients and in SE with no evident etiology.

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BACKGROUND: Epileptic encephalopathy (EE) is defined as the presence of frequent epileptiform activity that adversely impacts development, typically causing the slowing or regression of developmental skills, and is usually associated with frequent seizures. One of the main disturbances in EE is in the coordination of the upper extremities and hands. Traditional rehabilitation for this type of pathology focuses on the alleviation of gross or fine motor disability. In the last few years, the use of low-cost devices together with customized serious games has shown improvements in motor disorders and enrichments in activities of daily living. OBJECTIVE: This study aims to explore the feasibility of a new serious game for improving fine motor control in children with EE. METHODS: The participants were 4 children with EE (male: n=2, 50%; female: n=2, 50%) who were classified as belonging to level 1 in the Gross Motor Classification System. The children were tested over 10 sessions during the intervention period (before and after treatment). The clinical tests performed were the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition and Pittsburgh Rehabilitation Participation Scale. The subscales of the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition were fine motor precision, fine motor integration, manual dexterity, and upper-limb coordination. At the end of the first session, we used the User Satisfaction Evaluation Questionnaire to analyze user satisfaction. RESULTS: The significance outcomes for a Student t test (1-tailed) were as follows: P=.009 for fine motor precision, P=.002 for fine motor integration, P=.56 for manual dexterity, and P=.99 for upper-limb coordination. The participation rate as measured using the Pittsburgh Rehabilitation Participation Scale was between good and very good, which means that, based on the therapist's evaluation, interest, independence, and motivation were achieved by each participant. The mean User Satisfaction Evaluation Questionnaire score was close to 30, which is the maximum value. CONCLUSIONS: The results support the use of the proposed serious game as a complement in therapeutic sessions during the rehabilitation processes for children with EE. Significant improvements in fine motor control and activities of daily living revealed that the proposed serious game is beneficial for fine motor disorders of this pathology.

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Induced pluripotent stem cells (iPSCs) opened the possibility to use patient cells as a model for several diseases. iPSCs can be reprogrammed from somatic cells collected in a non-invasive way, and then differentiated into any other cell type, while maintaining the donor´s genetic background. CYFIP2 variants were associated with the onset of an early form of epileptic encephalopathy. Studies with patients showed that the R87C variant seems to be one of the variants that causes more severe disease, however, to date there are no studies with a human cell model that allows investigation of the neuronal phenotype of the R87C variant. Here, we generated an iPSC line from a patient with epileptic encephalopathy caused by the CYFIP2 R87C variant. We obtained iPSC clones by reprogramming urinary progenitor cells from a female patient. The generated iPSC line presented a pluripotent stem cell morphology, normal karyotype, expressed pluripotency markers and could be differentiated into the three germ layers. In further studies, this cell line could be used as model for epileptic encephalopathy disease and drug screening studies.

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BACKGROUND: CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants. CASE REPORTS: We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations. CONCLUSIONS: CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.

INTRODUCCIÓN: El síndrome por deficiencia de CDKL5 es originado por variantes patogénicas en el gen CDKL5, con un espectro clínico variable que va desde pacientes con características del trastorno del espectro autista hasta epilepsia de inicio temprano y refractaria al tratamiento. Inicialmente fue considerado como una forma atípica de síndrome de Rett. CASOS CLÍNICOS: Presentamos tres pacientes no relacionadas, evaluadas por retraso global del desarrollo y epilepsia refractaria. Los tres casos eran hemicigotos a una variante patógena de CDKL5. En una paciente se realizó panel de 306 genes asociados con epilepsia; en las otras dos se realizó microarreglo genómico comparativo. Las características clínicas y los hallazgos en el electroencefalograma y la resonancia magnética cerebral se han descrito clásicamente en el espectro de manifestaciones de este síndrome. CONCLUSIONES: El síndrome por deficiencia de CDKL5 representa un reto para los médicos, ya que en muchos casos las manifestaciones clínicas y los estudios electroencefalográficos y de neuroimagen pueden ser inespecíficos. Debe sospecharse este síndrome ante la presencia de retraso global del desarrollo, fenotipo conductual autista y epilepsia, asociado o no con dismorfias. Dada la similitud entre diversas encefalopatías epilépticas, se deben solicitar paneles multigénicos que incluyan la secuenciación y el análisis de duplicación/deleción en los que se contemple este gen y sus posibles diagnósticos diferenciales, aunque sin olvidar la utilidad de las técnicas genómicas en casos poco claros.

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Sleep-related phenotypes have been frequently reported in early on-set epileptic encephalopathies and in developmental delay syndromes, in particular in syndromes related to autism spectrum disorder. Yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown. We first performed a gene enrichment study that identified shared risk genes among rare epileptic encephalopathies/neurodevelopmental disorders, rare developmental delay genetic syndromes and sleep disturbances. We then determined cellular and molecular pathways enriched among genes shared between sleep phenotypes and those two early onset mental illnesses, aiming to identify genetic disparities and commonalities among these phenotypic groups. The sleep gene set was observed as significantly overlapped with the two gene lists associated to rare genetic syndromes (i.e., epileptic encephalopathies/neurodevelopmental disorders and developmental delay gene sets), suggesting shared genetic contribution. Similarities across significantly enriched pathways between the two intersect lists comprehended mostly synapse-related pathways, such as retrograde endocannabinoid signaling, serotonergic, and GABAergic synapse. Network analysis indicates epileptic encephalopathies/neurodevelopmental disorders versus sleep-specific clusters and developmental delay versus sleep-specific clusters related to synaptic and transcriptional regulation, respectively. Longstanding functional patterns previously described in epileptic encephalopathies and neurodevelopmental disorders genetic architecture were recaptured after dissecting the overlap between the genes associated to those developmental phenotypes and sleep disturbances, suggesting that during neurodevelopment different molecular and functional mechanisms are related to alterations on circadian rhythm. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between sleep disturbances and rare developmental syndromes.

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BACKGROUND: SYNJ1 encodes Synaptojanin-1, a dual-function poly-phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy. METHODS: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. RESULTS: We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years. CONCLUSIONS: We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1-related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.

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Resumen Introducción: El síndrome por deficiencia de CDKL5 es originado por variantes patogénicas en el gen CDKL5, con un espectro clínico variable que va desde pacientes con características del trastorno del espectro autista hasta epilepsia de inicio temprano y refractaria al tratamiento. Inicialmente fue considerado como una forma atípica de síndrome de Rett. Casos clínicos: Presentamos tres pacientes no relacionadas, evaluadas por retraso global del desarrollo y epilepsia refractaria. Los tres casos eran hemicigotos a una variante patógena de CDKL5. En una paciente se realizó panel de 306 genes asociados con epilepsia; en las otras dos se realizó microarreglo genómico comparativo. Las características clínicas y los hallazgos en el electroencefalograma y la resonancia magnética cerebral se han descrito clásicamente en el espectro de manifestaciones de este síndrome. Conclusiones: El síndrome por deficiencia de CDKL5 representa un reto para los médicos, ya que en muchos casos las manifestaciones clínicas y los estudios electroencefalográficos y de neuroimagen pueden ser inespecíficos. Debe sospecharse este síndrome ante la presencia de retraso global del desarrollo, fenotipo conductual autista y epilepsia, asociado o no con dismorfias. Dada la similitud entre diversas encefalopatías epilépticas, se deben solicitar paneles multigénicos que incluyan la secuenciación y el análisis de duplicación/deleción en los que se contemple este gen y sus posibles diagnósticos diferenciales, aunque sin olvidar la utilidad de las técnicas genómicas en casos poco claros.

Abstract Background: CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants. Case reports: We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations. Conclusions: CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.

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INTRODUCTION: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. METHODS: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. RESULTS: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown significance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. DISCUSSION: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the detected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dravet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mientras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases moleculares de las EED en población latino americana.

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Abstract Introduction: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. Methods: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. Results: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown sig nificance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. Discussion: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the de tected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Resumen Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dra vet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mien tras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases mole culares de las EED en población latino americana.