RESUMO
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.
Assuntos
Epilepsia , Humanos , Feminino , Epilepsia/genética , Adolescente , Di-Hidro-Orotase/genética , Mutação de Sentido Incorreto , Estado Epiléptico/genética , Disfunção Cognitiva/genética , Idade de Início , Aspartato Carbamoiltransferase , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)RESUMO
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.
Assuntos
Epilepsia Generalizada , Humanos , Feminino , Adolescente , Homozigoto , Encéfalo , Convulsões , Região do CaribeRESUMO
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.
Assuntos
Encefalopatias , Epilepsias Mioclônicas , Epilepsia , Síndrome de Lennox-Gastaut , Espasmos Infantis , Humanos , Epilepsia/diagnóstico , Epilepsias Mioclônicas/diagnóstico , Encefalopatias/genética , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Fenótipo , ConvulsõesRESUMO
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.