RESUMEN

Objective:To investigate the clinical phenotype and genetic characteristics of developmental epileptic encephalopathy 18 (DEE18) caused by SZT2 gene variants. Methods:Clinical data of 2 children with SZT2 related DEE18 who visited the Department of Pediatric Neurology, Linyi People′s Hospital in March 2020 and July 2023 were collected. The whole exome sequencing (WES) and Sanger sequencing were applied to verify the child and their parents. SWISS-MODEL software was used to perform protein 3D modeling for the selected SZT2 gene variants. Results:Both of the 2 cases showed severe global developmental delay, epileptic seizures, autism, megacephaly, facial deformity, hypotonia, corpus callosum malformation, persistent cavum septum pellucidum, and slow background activity and focal discharge in video electroencephalography. Case 1 was easy to startle and thin in stature; case 2 had immune deficiency and clustered seizures. WES results showed that case 1 carried a compound heterozygous variant of c.5811G>A (p.W1937X) (paternal) and c.9269delG (p.S3090Ifs *94) (maternal), while case 2 carried a compound heterozygous variant of c.6302A>C(p.H2101P) (paternal) and c.7584dupA (p.E2529Rfs *20) (maternal), the parents of both patients with normal clinical phenotypes. The 4 mutations mentioned above were novel variations that had not yet been reported domestically or internationally. According to the American College of Medical Genetics and Genomics variant classification criteria and guidelines, the p.S3090Ifs *94 variant was interpreted as pathogenic; p.W1937X variant was interpreted as pathogenic; p.E2529Rfs *20 variant was interpreted as likely pathogenic; p.H2101P variant was interpreted as uncertain significance. 3D modeling showed that the variant of p.H2101P resulted in a significant change in the hydrogen bond around the 2 101st amino acid encoded, leading to a decrease in protein stability. The other 3 variants led to early truncation of peptide chain and obvious changes in protein structure. Conclusions:DEE18 caused by SZT2 gene mutation is mainly an autosome recessive genetic disease, and its clinical manifestations include global developmental delay, epileptic seizures, autism, craniofacial malformation, hypotonia, epileptic discharge, corpus callosum malformation, persistent cavum septum pellucidum, shock, small and thin stature, and immune deficiency. Four novel variants related to the SZT2 gene may be the genetic etiology of DEE18 patients in this study.

RESUMEN

PURPOSE: Seizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. METHOD: We analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. RESULT: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00 %), seizures (36/40, 90.00 %), cranial deformity (27/40, 67.50 %), facial deformity (22/40, 55.00 %), hypotonia (22/40, 55.00 %), abnormal interseizure EEG discharge (26/40, 65.00 %), slow background activity (20/40, 50.00 %), corpus callosum deformity (18/40, 45.00 %). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. CONCLUSION: The compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

Asunto(s)

Trastorno del Espectro Autista , Epilepsia , Malformaciones del Sistema Nervioso , Niño , Masculino , Humanos , Agenesia del Cuerpo Calloso/complicaciones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/complicaciones , Hipotonía Muscular/complicaciones , Epilepsia/complicaciones , Malformaciones del Sistema Nervioso/complicaciones , Fenotipo , Proteínas del Tejido Nervioso/genética

RESUMEN

BACKGROUND: The seizure threshold 2 (SZT2) gene encodes a protein of unknown function, which is widely expressed, confers a low seizure threshold, and enhances epileptogenesis. It also comprises the KICSTOR protein complex, which inhibits the mTORC1 pathway. A pathogenic variant in the SZT2 gene could result in hyperactive mTORC1 signaling, which can lead to several neurological disorders. AIM OF THE STUDY: To review every reported case and present two novel cases to expand the current knowledge and understanding of the mutation. METHODS: Whole exome sequencing (WES) was used to identify the novel cases and present their clinical and radiological findings. A detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data were extracted. RESULTS: The study included 16 female patients and 13 male patients in addition to the 2 novel male cases. Eighteen patients had heterozygous mutations; others were homozygous. The majority presented with facial dysmorphism (n = 22). Seizures were noted as the predominant hallmark (n = 26). Developmental delay and hypotonia were reported in 27 and 15 patients, respectively. The majority of patients had multifocal epileptiform discharges on the electroencephalogram (EEG) and short and thick corpus callosum on the magnetic resonance imaging (MRI). CONCLUSION: Several promising features are becoming strongly linked to patients with SZT2 mutations. High variability among the cases was observed. Developmental delay and facial dysmorphism can be investigated as potential hallmarks; aiding clinicians in diagnosing the condition and optimizing management plans.

RESUMEN

Background: Recessive SZT2 variants are reported to be associated with developmental and epileptic encephalopathy 18 (DEE-18) and occasionally neurodevelopment abnormalities (NDD) without seizures. This study aims to explore the phenotypic spectrum of SZT2 and the genotype-phenotype correlation. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported SZT2 mutations were systematically reviewed to analyze the genotype-phenotype correlations. Results: SZT2 variants were identified in six unrelated cases with heterogeneous epilepsy, including one de novo null variant and five pairs of biallelic variants. These variants had no or low frequencies in controls. All missense variants were predicted to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients with null variants exhibited DEE. The patients with biallelic null mutations presented severe DEE featured by frequent spasms/tonic seizures and diffuse cortical dysplasia/periventricular nodular heterotopia. The three patients with biallelic missense variants presented mild partial epilepsy with favorable outcomes. Analysis of previously reported cases revealed that patients with biallelic null mutations presented significantly higher frequency of refractory seizures and earlier onset age of seizure than those with biallelic non-null mutations or with biallelic mutations containing one null variant. Significance: This study suggested that SZT2 variants were potentially associated with partial epilepsy with favorable outcomes without NDD, expanding the phenotypic spectrum of SZT2. The genotype-phenotype correlation helps in understanding the underlying mechanism of phenotypic variation.

RESUMEN

Mutations in the SZT2 gene have been associated with developmental and epileptic encephalopathy-18, a rare severe autosomal recessive neurologic disorder, characterized by psychomotor impairment/intellectual disability, dysmorphic facial features and early onset of refractory seizures. Here we report the generation of the first induced pluripotent stem cell (iPSC) lines from a patient with treatment-resistant epilepsy, carrying compound heterozygous mutations in SZT2 (Mut1: c.498G>T and Mut2: c.6553C>T), and his healthy heterozygous parents. Peripheral blood mononuclear cells were reprogrammed by a non-integrating Sendai virus-based reprogramming system. The generated human iPSC lines exhibited expression of the main pluripotency markers, the potential to differentiate into all three germ layers and presented a normal karyotype. These lines represent a valuable resource to study neurodevelopmental alterations, and to obtain mature, pathology-relevant neuronal populations as an in vitro model to perform functional assays and test the patient's responsiveness to novel antiepileptic treatments.

Asunto(s)

Epilepsia Generalizada , Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Leucocitos Mononucleares , Mutación , Heterocigoto , Proteínas del Tejido Nervioso/metabolismo

RESUMEN

Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions, but these variants are increasingly detected and reported by clinical genetic testing in individuals with epilepsy. To exemplify this latter point, here we describe a cohort of 12 individuals with biallelic SZT2 variants and phenotypic overlap with SZT2-related neurodevelopmental disorders. However, the majority of individuals carried one or more SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterization to determine, which, if any, of these VUS were pathogenic. Thus, we developed a novel individualized platform to identify SZT2 loss-of-function variants in the context of mTORC1 signalling and reclassify VUS. Using this platform, we identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis revealed that this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Moreover, this approach allowed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five individuals with biallelic pathogenic or likely pathogenic variants. Clinical features of these five individuals consisted of early-onset seizures (median 24 months), focal seizures, developmental delay and macrocephaly similar to previous reports. However, we also show a widening of the phenotypic spectrum, as none of the five individuals had corpus callosum abnormalities, in contrast to previous reports. Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals of Ashkenazi Jewish ancestry, and demonstrate that corpus callosum abnormalities is not a hallmark feature of this condition. Our approach is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

Asunto(s)

Epilepsias Parciales , Epilepsia , Megalencefalia , Epilepsia/genética , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Megalencefalia/genética , Proteínas del Tejido Nervioso/genética , Proteínas Supresoras de Tumor/genética

RESUMEN

BACKGROUND: Developmental and epileptic encephalopathy (DEE) exhibits phenotypic and genetic heterogeneity. Biallelic variants of the SZT2 gene can lead to DEE18, of which few cases have been reported. This study aimed to analyze the potential pathogenic factors in three cases of DEE18. METHODS: Trio-whole exome sequencing and crystal structure simulation analysis were performed, along with a literature review of DEE18 cases. RESULTS: All three patients had compound heterozygous variants in the SZT2 gene (patient 1, c.2887A > G/c.7970G > A; patient 2, c.3508A > G/c.7936C > T; and patient 3, c.2489G > T/c.8640_8641insC). The variants were predicted to have structural effects on the protein. Particularly, c.3508A > G/p.Ser1170Gly may lead to impaired binding of SZT2 to GATOR1, potentially resulting in the overactivation of the mTORC1 signaling pathway, causing seizures. Through the literature review, we observed that 27 patients with DEE had different degrees of intellectual and developmental disorders (DDs), and the variants leading to protein truncation cause severe DD and refractory epilepsy. Therefore, the phenotypic severity of patients may be related to the residual activity of variant SZT2 protein. CONCLUSION: We provide recently developed knowledge on the DEE18 genotype-phenotype spectrum and suggest that gene detection is of great value for the accurate diagnosis of patients with early-onset epilepsy. Further research is required for the development of individualized interventions for patients with DEE.

Asunto(s)

Epilepsia , Proteínas del Tejido Nervioso , China , Epilepsia/genética , Humanos , Mutación/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Secuenciación del Exoma

RESUMEN

Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.

Asunto(s)

Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Mapas de Interacción de Proteínas , Aminoácidos/deficiencia , Animales , Proteínas Sanguíneas/farmacología , Cilios/efectos de los fármacos , Cilios/metabolismo , Perros , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Organogénesis/efectos de los fármacos , Análisis de Componente Principal , Mapas de Interacción de Proteínas/efectos de los fármacos , Sirolimus/farmacología

RESUMEN

Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.

Asunto(s)

Síndromes Epilépticos/genética , Proteínas del Tejido Nervioso/genética , Convulsiones/genética , Espasmos Infantiles/genética , Bromuros/uso terapéutico , Consanguinidad , Electroencefalografía , Resultado Fatal , Femenino , Humanos , Lactante , Recién Nacido , Fenotipo , Compuestos de Potasio/uso terapéutico , Convulsiones/tratamiento farmacológico , Gemelos

RESUMEN

Developmental and epileptic encephalopathy is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability, in which there is additional developmental impairment independent of epileptic activity. Biallelic variants of SZT2, a known seizure threshold regulator gene, have been linked to a wide spectrum of clinical features, ranging from severe intellectual disability with refractory seizures to mild intellectual disability without seizures. Here, we describe a child with developmental and epileptic encephalopathy whose genetic testing led to the identification of novel biallelic variants of SZT2, a paternally inherited c.2798C>T, p.(Ser933Phe) variant and a maternally inherited c.4549C>T, p.(Arg1517Trp) variant. Our patient showed common clinical and radiographic features among patients with SZT2-related encephalopathy. However, neonatal-onset seizures and suppression-burst EEG activity, not previously associated with SZT2-related encephalopathy, were observed in this case. Although the seizures were controlled with carbamazepine, the developmental consequences remained profound, suggesting that the developmental impairments might be attributed to a direct effect of the SZT2 variants rather than the epileptic activity. We propose that SZT2 variants should be regarded among those that are believed to cause neonatal-onset developmental and epileptic encephalopathy with a suppression-burst pattern on EEG.

Asunto(s)

Discapacidades del Desarrollo/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/fisiopatología , Electroencefalografía , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/fisiopatología

RESUMEN

Seizure threshold 2 (SZT2) gene mutations have been associated with developmental and epileptic encephalopathies (DEEs). Following a literature review, we collected 22 patients and identified the main clinical features related to SZT2 variants that are epilepsy with onset within the first years of life, intellectual disability (ID), macrocephaly with dysmorphic facial features, corpus callosum (CC) shape abnormalities, and cortical migration disorders. Moreover, we identified the c.7825T>G homozygous missense variant in SZT2 in two female siblings presenting with focal seizures, mild-moderate ID, behavioral disturbances, and facial dysmorphisms. Interictal Electroencephalogram (EEG) and ictal EEG were both informative and revealed, respectively, temporal bilateral asynchronous slow and epileptiform abnormalities and a focal onset in both of them. Neuroimaging study revealed a thick and abnormally shaped CC. Seizure threshold 2 has been identified as a component of the KICSTOR complex, a newly recognized protein complex involved in the mammalian target of rapamycin (mTOR) pathway. mTOR signaling dysregulation represents common pathogenetic mechanisms that can explain the presence of both epileptogenesis and ID. Even if few cases had been reported, a new clinical phenotype is emerging, and recent hypothesis of hyperactivation of mTORC1 signaling might also open to targeted treatments, challenging an early diagnosis as of paramount importance.

Asunto(s)

Síndromes Epilépticos/genética , Variación Genética/genética , Genómica/métodos , Discapacidad Intelectual/genética , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Niño , Preescolar , Electroencefalografía/métodos , Síndromes Epilépticos/complicaciones , Síndromes Epilépticos/diagnóstico , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Linaje

RESUMEN

PURPOSE: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. METHODS: We use family-based whole-exome sequencing to identify candidate variants. RESULTS: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. CONCLUSION: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.

Asunto(s)

Epilepsia/genética , Salud de la Familia , Discapacidad Intelectual/genética , Megalencefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adulto , Análisis Mutacional de ADN , Epilepsia/complicaciones , Epilepsia/diagnóstico por imagen , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico por imagen , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Megalencefalia/complicaciones , Megalencefalia/diagnóstico por imagen , Secuenciación del Exoma , Adulto Joven

RESUMEN

Epileptic encephalopathies are genetically heterogeneous disorders which leads to epilepsy and cause neurological disorders. Seizure threshold 2 (SZT2) gene located on chromosome 1p34.2 encodes protein mainly expressed predominantly in the parietal and frontal cortex and dorsal root ganglia in the brain. Previous studies in mice showed that mutation in this gene can confers low seizure threshold, enhance epileptogenesis and in human may leads to facial dysmorphism, intellectual disability, seizure and macrocephaly. Objective of this study was to find out novel gene or novel mutation related to the gene phenotype. We have identified a large consanguineous Saudi family segregating developmental delay, intellectual disability, epilepsy, high forehead and macrocephaly. Exome sequencing was performed in affected siblings of the family to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation study. Our results showed a novel homozygous mutation (c.9368G>A) in a substitution of a conserved glycine residue into a glutamic acid in the exon 67 of SZT2 gene. The mutation was ruled out in 100 unrelated healthy controls. The missense variant has not yet been reported as pathogenic in literature or variant databases. In conclusion, the here detected homozygous SZT2 variant might be the causative mutation that further explain epilepsy and developmental delay in this Saudi family.

Asunto(s)

Discapacidades del Desarrollo/complicaciones , Epilepsia/genética , Megalencefalia/complicaciones , Mutación Missense , Proteínas del Tejido Nervioso/genética , Niño , Preescolar , Electroencefalografía , Epilepsia/complicaciones , Epilepsia/fisiopatología , Femenino , Homocigoto , Humanos , Arabia Saudita

RESUMEN

Early-onset epileptic encephalopathies (EOEEs) are a genetically heterogeneous collection of severe epilepsies often associated with psychomotor regression. Mutations in SZT2, a known seizure threshold regulator gene, are a newly identified cause of EOEE. We present an individual with EOEE, macrocephaly, and developmental regression with compound heterozygous mutations in SZT2 as identified by whole exome sequencing. Serial imaging characterized the novel finding of progressive loss of central myelination. This case expands our clinical understanding of the SZT2-phenotype and emphasizes the role of this gene in the diagnostic investigation for EOEE and leukoencephalopathies.

Asunto(s)

Leucoencefalopatías/genética , Mutación , Proteínas del Tejido Nervioso/genética , Espasmos Infantiles/genética , Sistemas de Transporte de Aminoácidos Acídicos/deficiencia , Sistemas de Transporte de Aminoácidos Acídicos/genética , Antiportadores/deficiencia , Antiportadores/genética , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/etiología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Heterocigoto , Humanos , Lactante , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etiología , Imagen por Resonancia Magnética , Megalencefalia/diagnóstico por imagen , Megalencefalia/genética , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/etiología , Enfermedades Mitocondriales/genética , Trastornos Psicomotores/diagnóstico por imagen , Trastornos Psicomotores/etiología , Trastornos Psicomotores/genética , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/etiología

RESUMEN

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.

Asunto(s)

Epilepsia Generalizada/genética , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Espasmos Infantiles/genética , Preescolar , Epilepsia Generalizada/diagnóstico por imagen , Epilepsia Generalizada/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Mutación Missense/genética , Linaje , Sitios de Empalme de ARN/genética , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/patología , Secuenciación del Exoma

RESUMEN

Advances in genetic testing have led to the identification of increasing numbers of novel gene mutations that underlie infantile-onset epileptic encephalopathies. Recently, a mutagenesis screen identified a novel gene, SZT2, with no known protein function that has been linked to epileptogenesis in mice. Thus far, two clinical reports have identified children with different recessive mutations in SZT2 and varying clinical phenotypes. One case report described patients with epileptic encephalopathy and the other noted patients with cognitive deficiencies, but normal MRI and no epilepsy. This case report identifies novel mutations (a compound heterozygous frameshift and a nonsense variant) in the SZT2 gene with distinct clinical and radiographic findings relative to those previously reported. Our patient presented with intractable epilepsy at 2 months of age. Seizures were refractory to numerous antiepileptic medications and the patient finally achieved seizure cessation at age 3 years with a combination of divalproex and lamotrigine. Our patient had similar facial dysmorphisms (macrocephaly, high forehead, and down-slanted palpebral fissures) to a previous case with truncating mutation. While developmental delay and cognitive deficiencies were present, our case had unique MRI findings suggesting migrational abnormalities not previously reported in other cases.

Asunto(s)

Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/genética , Mutación , Proteínas del Tejido Nervioso/genética , Heterotopia Nodular Periventricular/genética , Triazinas/uso terapéutico , Ácido Valproico/uso terapéutico , Encéfalo/diagnóstico por imagen , Preescolar , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/tratamiento farmacológico , Electroencefalografía , Humanos , Lactante , Lamotrigina , Imagen por Resonancia Magnética , Masculino , Heterotopia Nodular Periventricular/diagnóstico por imagen , Heterotopia Nodular Periventricular/tratamiento farmacológico , Resultado del Tratamiento