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1.
Am J Hum Genet ; 108(4): 722-738, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33798445

RESUMEN

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.


Asunto(s)
Dolicoles/metabolismo , Mutación/genética , Epilepsias Mioclónicas Progresivas/genética , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Femenino , Glicosilación , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Epilepsias Mioclónicas Progresivas/clasificación , Secuenciación del Exoma , Adulto Joven
2.
Acta Paediatr ; 112(2): 273-276, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36271909

RESUMEN

Sudden infant death syndrome (SIDS) occurs more often in male than in female infants, suggesting involvement of the X-chromosome. Histopathological studies have suggested that altered expression of the Neurokinin-1 receptor may also play a role in the pathogenesis of SIDS. It was hypothesised that genetic variants in three X-chromosome-encoded microRNA (miRNA/miR), known to down-regulate expression of the Neurokinin-1 receptor, may contribute to SIDS. AIM: To identify sequence variants in the miRNAs within a study cohort (27 cases of SIDS and 28 controls) and determine if there was a difference in the frequencies in male and female SIDS infants. METHODS: Genomic DNA prepared from stored blood spots was amplified and sequenced to identify genetic variants in miR500A, miR500B and miR320D2. RESULTS: No novel variants in the miRNAs were identified in our study cohort. We identified one known single-nucleotide polymorphism (SNP) in miR320D2: rs5907732 G/T, in both cases and controls. No significant difference in the SNP frequency was observed between male and female SIDS cases. CONCLUSION: This pilot study suggests that sequence variants in three miRNAs do not contribute to the reported higher prevalence of SIDS in male infants and do not contribute to the pathogenesis of SIDS in our cohort.


Asunto(s)
MicroARNs , Muerte Súbita del Lactante , Lactante , Humanos , Masculino , Femenino , Receptores de Neuroquinina-1/genética , Muerte Súbita del Lactante/genética , Muerte Súbita del Lactante/epidemiología , MicroARNs/genética , Proyectos Piloto , Polimorfismo de Nucleótido Simple
3.
Brain ; 144(12): 3635-3650, 2021 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-34114611

RESUMEN

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.


Asunto(s)
Epilepsia/genética , Proteínas del Tejido Nervioso/genética , Canales de potasio activados por Sodio/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación , Fenotipo , Adulto Joven
4.
Int J Mol Sci ; 23(23)2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36499459

RESUMEN

KCNT1 (K+ channel subfamily T member 1) is a sodium-activated potassium channel highly expressed in the nervous system which regulates neuronal excitability by contributing to the resting membrane potential and hyperpolarisation following a train of action potentials. Gain of function mutations in the KCNT1 gene are the cause of neurological disorders associated with different forms of epilepsy. To gain insights into the underlying pathobiology we investigated the functional effects of 9 recently published KCNT1 mutations, 4 previously studied KCNT1 mutations, and one previously unpublished KCNT1 variant of unknown significance. We analysed the properties of KCNT1 potassium currents and attempted to find a correlation between the changes in KCNT1 characteristics due to the mutations and severity of the neurological disorder they cause. KCNT1 mutations identified in patients with epilepsy were introduced into the full length human KCNT1 cDNA using quick-change site-directed mutagenesis protocol. Electrophysiological properties of different KCNT1 constructs were investigated using a heterologous expression system (HEK293T cells) and patch clamping. All mutations studied, except T314A, increased the amplitude of KCNT1 currents, and some mutations shifted the voltage dependence of KCNT1 open probability, increasing the proportion of channels open at the resting membrane potential. The T314A mutation did not affect KCNT1 current amplitude but abolished its voltage dependence. We observed a positive correlation between the severity of the neurological disorder and the KCNT1 channel open probability at resting membrane potential. This suggests that gain of function KCNT1 mutations cause epilepsy by increasing resting potassium conductance and suppressing the activity of inhibitory neurons. A reduction in action potential firing in inhibitory neurons due to excessively high resting potassium conductance leads to disinhibition of neural circuits, hyperexcitability and seizures.


Asunto(s)
Epilepsia , Proteínas del Tejido Nervioso , Humanos , Canales de potasio activados por Sodio/genética , Células HEK293 , Proteínas del Tejido Nervioso/metabolismo , Epilepsia/genética , Mutación , Potasio/metabolismo
5.
Ann Neurol ; 79(4): 522-34, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26704558

RESUMEN

OBJECTIVE: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. METHODS: Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. RESULTS: The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. INTERPRETATION: A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.


Asunto(s)
Arritmias Cardíacas/genética , Muerte Súbita/etiología , Epilepsia/genética , Exoma , Trastornos Respiratorios/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Genes Dominantes , Humanos , Lactante , Síndrome de QT Prolongado/genética , Masculino , Persona de Mediana Edad , Mutación , Adulto Joven
6.
Ann Neurol ; 79(1): 120-31, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26505888

RESUMEN

OBJECTIVE: Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy. METHODS: We used targeted capture and next-generation sequencing to analyze 404 unrelated probands with focal epilepsy. We performed exome sequencing on two families with multiple members affected with focal epilepsy and linkage analysis on one of these. RESULTS: In our cohort of 404 unrelated focal epilepsy patients, we identified five mutations in NPRL2 and five in NPRL3. Exome sequencing analysis of two families with focal epilepsy identified NPRL2 and NPRL3 as the top candidate-causative genes. Some patients had focal epilepsy associated with brain malformations. We also identified 18 new mutations in DEPDC5. INTERPRETATION: We have identified NPRL2 and NPRL3 as two new focal epilepsy genes that also play a role in the mTOR-signaling pathway. Our findings show that mutations in GATOR1 complex genes are the most significant cause of familial focal epilepsy identified to date, including cases with brain malformations. It is possible that deregulation of cellular growth control plays a more important role in epilepsy than is currently recognized.


Asunto(s)
Epilepsias Parciales/genética , Proteínas Activadoras de GTPasa/genética , Complejos Multiproteicos/metabolismo , Proteínas Represoras/genética , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Supresoras de Tumor/genética , Exoma , Perfilación de la Expresión Génica , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Mutación , Linaje , Análisis de Secuencia de ADN
7.
Ann Neurol ; 79(3): 428-36, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26677014

RESUMEN

OBJECTIVE: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases. METHODS: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup. RESULTS: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement. INTERPRETATION: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.


Asunto(s)
Corea/genética , Epilepsia Benigna Neonatal/genética , Predisposición Genética a la Enfermedad/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Polimorfismo de Nucleótido Simple/genética , Niño , Preescolar , Corea/diagnóstico , Epilepsia Benigna Neonatal/diagnóstico , Femenino , Humanos , Masculino , Mutación/genética
8.
J Med Genet ; 53(4): 217-25, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26740507

RESUMEN

Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.


Asunto(s)
Epilepsias Parciales/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Epilepsias Parciales/patología , Epilepsia/clasificación , Epilepsia/patología , Humanos , Discapacidad Intelectual/patología , Mutación , Canales de potasio activados por Sodio
9.
Am J Med Genet A ; 170(11): 3033-3038, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27480663

RESUMEN

Recessive mutations in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome, a phenotype characterized by neonatal microcephaly, hypertonia, and refractory epilepsy with premature death by age 2 years. Recently, attenuated disease variants have been described, suggesting that a wider clinical spectrum of BRAT1-associated neurodegeneration exists than was previously thought. Here, we report two affected siblings with compound heterozygous truncating mutations in BRAT1 and intra-familial phenotypic heterogeneity, with a less severe disease course in the female sibling. This phenotypic variability should be taken into account when treating patients with BRAT1-associated neurodegenerative disease. Mildly affected individuals with BRAT1 mutations show that BRAT1 must be considered as a cause in childhood refractory epilepsy and microcephaly with survival beyond infancy. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Estudios de Asociación Genética , Mutación , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Proteínas Nucleares/genética , Fenotipo , Edad de Inicio , Alelos , Exoma , Resultado Fatal , Femenino , Genes Recesivos , Sitios Genéticos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Linaje , Hermanos
10.
EMBO Rep ; 15(6): 723-9, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24668262

RESUMEN

Genetic variation in SLC12A5 which encodes KCC2, the neuron-specific cation-chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co-segregating variant (KCC2-R952H) in an Australian family with febrile seizures. We show that KCC2-R952H reduces neuronal Cl(-) extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2-R952H which likely contributes to the functional deficits. Our data suggest that KCC2-R952H is a bona fide susceptibility variant for febrile seizures.


Asunto(s)
Espinas Dendríticas/patología , Predisposición Genética a la Enfermedad/genética , Modelos Moleculares , Mutación Missense/genética , Neuronas/metabolismo , Convulsiones Febriles/genética , Simportadores/genética , Secuencia de Aminoácidos , Animales , Australia , Western Blotting , Cloruros/metabolismo , Espinas Dendríticas/genética , Humanos , Ratones , Ratones Endogámicos ICR , Microscopía Fluorescente , Datos de Secuencia Molecular , Linaje , Conformación Proteica , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Simportadores/metabolismo , Cotransportadores de K Cl
11.
Am J Hum Genet ; 90(1): 152-60, 2012 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-22243967

RESUMEN

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).


Asunto(s)
Atetosis/genética , Corea/genética , Epilepsia Benigna Neonatal/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Convulsiones/genética , Edad de Inicio , Animales , Secuencia de Bases , Encéfalo/patología , Preescolar , Cromosomas Humanos Par 16/genética , Humanos , Lactante , Masculino , Ratones , Datos de Secuencia Molecular , Mutación , Linaje
12.
Ann Neurol ; 75(5): 782-7, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24585383

RESUMEN

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.


Asunto(s)
Encéfalo/anomalías , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/genética , Mutación/genética , Proteínas Represoras/genética , Serina-Treonina Quinasas TOR/genética , Adulto , Niño , Femenino , Proteínas Activadoras de GTPasa , Humanos , Masculino , Linaje , Adulto Joven
13.
Ann Neurol ; 75(4): 581-90, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24591078

RESUMEN

OBJECTIVE: Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels. METHODS: Here we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300 µM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined. RESULTS: We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there is a significant group difference in gain of function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain of function for all mutations studied. INTERPRETATION: These results establish direction for a targeted therapy and potentially exemplify a translational paradigm for in vitro studies informing novel therapies in a neuropsychiatric disease.


Asunto(s)
Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Quinidina/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microinyecciones , Oocitos , Técnicas de Placa-Clamp , Canales de potasio activados por Sodio , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Factores de Tiempo , Xenopus laevis
14.
Epilepsia ; 56(9): e114-20, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26122718

RESUMEN

Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.


Asunto(s)
Epilepsias Parciales/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Adolescente , Edad de Inicio , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Canales de potasio activados por Sodio , Muerte Súbita del Lactante/genética
15.
Hum Mol Genet ; 21(24): 5359-72, 2012 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-22949513

RESUMEN

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.


Asunto(s)
Epilepsia Generalizada/genética , Estudio de Asociación del Genoma Completo , Alelos , Epilepsia Tipo Ausencia/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Homeodominio/genética , Humanos , Epilepsia Mioclónica Juvenil/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Proteínas Serina-Treonina Quinasas/genética , Receptor Muscarínico M3/genética , Proteínas Represoras/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc
16.
Am J Hum Genet ; 88(5): 657-63, 2011 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-21549339

RESUMEN

The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.


Asunto(s)
Mutación , Epilepsias Mioclónicas Progresivas/genética , Proteínas Qb-SNARE/genética , Degeneraciones Espinocerebelosas/genética , Secuencia de Aminoácidos , Niño , Consanguinidad , Femenino , Genes Recesivos , Marcadores Genéticos , Aparato de Golgi/genética , Homocigoto , Humanos , Escala de Lod , Masculino , Datos de Secuencia Molecular , Epilepsias Mioclónicas Progresivas/patología , Linaje , Fenotipo , Proteínas SNARE/genética , Degeneraciones Espinocerebelosas/patología
17.
Brain ; 136(Pt 4): 1146-54, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23449775

RESUMEN

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.


Asunto(s)
Mutación , Epilepsias Mioclónicas Progresivas/genética , Epilepsias Mioclónicas Progresivas/fisiopatología , Fenotipo , Proteínas Qb-SNARE/genética , Adolescente , Adulto , Ataxia/genética , Ataxia/fisiopatología , Niño , Electroencefalografía , Europa (Continente) , Femenino , Humanos , Masculino , Mutación/genética , Epilepsias Mioclónicas Progresivas/mortalidad , Mar del Norte , Adulto Joven
18.
Dev Med Child Neurol ; 56(1): 85-90, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24328833

RESUMEN

AIM: To show that atypical multifocal Dravet syndrome is a recognizable, electroclinical syndrome associated with sodium channel gene (SCN1A) mutations that readily escapes diagnosis owing to later cognitive decline and tonic seizures. METHOD: Eight patients underwent electroclinical characterization. SCN1A was sequenced and copy number variations sought by multiplex ligation-dependent probe amplification. RESULTS: All patients were female (age range at assessment 5-26y) with median seizure onset at 6.5 months (range 4-19mo). The initial seizure was brief in seven and status epilepticus only occurred in one; three were febrile. Focal seizures occurred in four patients and bilateral convulsion in the other four. All patients developed multiple focal seizure types and bilateral convulsions, with seizure clusters in six. The most common focal seizure semiology (six out of eight) comprised unilateral clonic activity. Five also had focal or asymmetric tonic seizures. Rare or transient myoclonic seizures occurred in six individuals, often triggered by specific antiepileptic drugs. Developmental slowing occurred in all: six between 3 years and 8 years, and two around 1 year 6 months. Cognitive outcome varied from severe to mild intellectual disability. Multifocal epileptiform discharges were seen on electroencephalography. Seven out of eight patients had SCN1A mutations. INTERPRETATION: Atypical, multifocal Dravet syndrome with SCN1A mutations may not be recognized because of later cognitive decline and frequent tonic seizures.


Asunto(s)
Trastornos del Conocimiento/etiología , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/diagnóstico , Discapacidad Intelectual/etiología , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genética , Adolescente , Adulto , Edad de Inicio , Niño , Desarrollo Infantil , Trastornos del Conocimiento/genética , Variaciones en el Número de Copia de ADN , Electroencefalografía , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/genética , Datos de Secuencia Molecular , Convulsiones/genética , Convulsiones/fisiopatología
19.
J Med Genet ; 50(3): 133-9, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23343561

RESUMEN

Mutations in the gene PRRT2 encoding proline-rich transmembrane protein 2 have recently been identified as the cause of three clinical entities: benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis (ICCA) syndrome, and paroxysmal kinesigenic dyskinesia (PKD). Patients with ICCA have both BFIE and PKD and families with ICCA may contain individuals who exhibit all three phenotypes. These three phenotypes were all mapped by linkage analyses to the pericentromeric region of chromosome 16, and were hypothesised to have the same genetic basis due to the co-occurrence of the disorders in some families. Despite considerable effort, the gene or genes for BFIE, ICCA, and PKD were not identified for many years after the linkage region was identified. Mutations in the gene PRRT2 were identified in several Chinese families with PKD, suggesting that the gene may also be responsible for ICCA and BFIE in families linked to the chromosome 16 locus. This was demonstrated to be the case, with the majority of families with ICCA and BFIE found to have PRRT2 mutations. The vast majority of these mutations are truncating and are predicted to lead to haploinsufficiency. PRRT2 is a largely uncharacterised protein. It is expressed in the brain and has been demonstrated to interact with SNAP-25, a component of the molecular machinery involved in the release of neurotransmitters at the presynaptic membrane. Therefore, the PRRT2 protein may play a role in this process. However, the molecular mechanisms underlying the remarkable pleiotropy associated with PRRT2 mutations have still to be determined.


Asunto(s)
Corea/genética , Discinesias/genética , Epilepsia Benigna Neonatal/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Convulsiones/genética , Animales , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Mutación
20.
J Mol Neurosci ; 74(2): 50, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38693434

RESUMEN

Aneuploidy, having an aberrant genome, is gaining increasing attention in neurodegenerative diseases. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. A growing body of research from numerous laboratories suggests that many neurodegenerative disorders, especially Alzheimer's disease and frontotemporal dementia, are characterised by neuronal aneuploidy and the ensuing apoptosis, which may contribute to neuronal loss. Using Drosophila as a model, we investigated the effect of induced aneuploidy in GABAergic neurons. We found an increased proportion of aneuploidy due to Mad2 depletion in the third-instar larval brain and increased cell death. Depletion of Mad2 in GABAergic neurons also gave a defective climbing and seizure phenotype. Feeding animals an antioxidant rescued the climbing and seizure phenotype. These findings suggest that increased aneuploidy leads to higher oxidative stress in GABAergic neurons which causes cell death, climbing defects, and seizure phenotype. Antioxidant feeding represents a potential therapy to reduce the aneuploidy-driven neurological phenotype.


Asunto(s)
Aneuploidia , Neuronas GABAérgicas , Estrés Oxidativo , Fenotipo , Animales , Neuronas GABAérgicas/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Convulsiones/genética , Convulsiones/metabolismo , Drosophila melanogaster/genética , Encéfalo/metabolismo , Drosophila/genética
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