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1.
Am J Hum Genet ; 109(11): 2080-2087, 2022 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-36288729

RESUMEN

Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.


Asunto(s)
Epilepsia , Convulsiones Febriles , Niño , Humanos , Linaje , Electroencefalografía , Convulsiones Febriles/genética , Fenotipo , Epilepsia/genética
2.
Am J Hum Genet ; 108(1): 176-185, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33245860

RESUMEN

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.


Asunto(s)
Encefalopatías/genética , Epilepsia/genética , Factores de Crecimiento de Fibroblastos/genética , Mutación Missense/genética , Isoformas de Proteínas/genética , Adolescente , Secuencia de Aminoácidos , Niño , Exones/genética , Femenino , Mutación con Ganancia de Función/genética , Genes Ligados a X/genética , Heterocigoto , Humanos , Masculino , Canal de Sodio Activado por Voltaje NAV1.6/genética , Neuronas/fisiología , Convulsiones/genética
3.
Epilepsia ; 64(11): 3099-3108, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37643892

RESUMEN

OBJECTIVE: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. METHODS: We linked whole-exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)-derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. RESULTS: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty-six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure-free. There was no significant difference between the outcome groups in terms of the exome-wide and gene-based burden of rare and deleterious genetic variants. SIGNIFICANCE: We successfully uploaded, annotated, and linked genetic sequence data and NLP-derived seizure frequency data to anonymized health care records in this proof-of-concept study. We did not detect a genetic influence on real-world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes.


Asunto(s)
Epilepsia , Adulto , Humanos , Femenino , Masculino , Secuenciación del Exoma , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Convulsiones/tratamiento farmacológico , Atención a la Salud , Almacenamiento y Recuperación de la Información , Anticonvulsivantes/uso terapéutico
4.
Epilepsia ; 62(7): 1604-1616, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34046890

RESUMEN

OBJECTIVE: This study was undertaken to determine whether epilepsy and antiepileptic drugs (including enzyme-inducing and non-enzyme-inducing drugs) are associated with major cardiovascular events using population-level, routinely collected data. METHODS: Using anonymized, routinely collected, health care data in Wales, UK, we performed a retrospective matched cohort study (2003-2017) of adults with epilepsy prescribed an antiepileptic drug. Controls were matched with replacement on age, gender, deprivation quintile, and year of entry into the study. Participants were followed to the end of the study for the occurrence of a major cardiovascular event, and survival models were constructed to compare the time to a major cardiovascular event (cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or a cardiovascular death) for individuals in the case group versus the control group. RESULTS: There were 10 241 cases (mean age = 49.6 years, 52.2% male, mean follow-up = 6.1 years) matched to 35 145 controls. A total of 3180 (31.1%) cases received enzyme-inducing antiepileptic drugs, and 7061 (68.9%) received non-enzyme-inducing antiepileptic drugs. Cases had an increased risk of experiencing a major cardiovascular event compared to controls (adjusted hazard ratio = 1.58, 95% confidence interval [CI] = 1.51-1.63, p < .001). There was no notable difference in major cardiovascular events between those treated with enzyme-inducing antiepileptic drugs and those treated with non-enzyme-inducing antiepileptic drugs (adjusted hazard ratio = .95, 95% CI = .86-1.05, p = .300). SIGNIFICANCE: Individuals with epilepsy prescribed antiepileptic drugs are at an increased risk of major cardiovascular events compared with population controls. Being prescribed an enzyme-inducing antiepileptic drug is not associated with a greater risk of a major cardiovascular event compared to treatment with other antiepileptic drugs. Our data emphasize the importance of cardiovascular risk management in the clinical care of people with epilepsy.


Asunto(s)
Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Enfermedades Cardiovasculares/etiología , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Inducción Enzimática/efectos de los fármacos , Epilepsia/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Reino Unido/epidemiología , Gales , Adulto Joven
5.
Epilepsy Behav ; 111: 107196, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32554230

RESUMEN

OBJECTIVE: The objective of the study was to assess the long-term outcomes of epilepsy surgery between 1995 and 2015 in South Wales, UK, linking case note review, postal questionnaire, and routinely collected healthcare data. METHOD: We identified patients from a departmental database and collected outcome data from patient case notes, a postal questionnaire, and the QOLIE-31-P and linked with Welsh routinely collected data in the Secure Anonymised Information Linkage (SAIL) databank. RESULTS: Fifty-seven patients were included. Median age at surgery was 34 years (11-70), median: 24 years (2-56) after onset of habitual seizures. Median follow-up was 7 years (2-19). Twenty-eight (49%) patients were free from disabling seizures (Engel Class 1), 9 (16%) experienced rare disabling seizures (Class 2), 13 (23%) had worthwhile improvements (Class 3), and 7 (12%) had no improvement (Class 4). There was a 30% mean reduction in total antiepileptic drug (AED) load at five years postsurgery. Thirty-eight (66.7%) patients experienced tonic-clonic seizures presurgery verses 8 (14%) at last review. Seizure-free patients self-reported a greater overall quality of life (QOL; QOLIE-31-P) when compared with those not achieving seizure freedom. Seizure-free individuals scored a mean of 67.6/100 (100 is best), whereas those with continuing seizures scored 46.0/100 (p < 0.006). There was a significant decrease in the median rate of hospital admissions for any cause after epilepsy surgery (9.8 days per 1000 patient days before surgery compared with 3.9 after p < 0.005). SIGNIFICANCE: Epilepsy surgery was associated with significant improvements in seizures, a reduced AED load, and an improved QOL that closely correlated with seizure outcomes and reduced hospital admission rates following surgery. Despite this, there was a long delay from onset of habitual seizures to surgery. The importance of long-term follow-up is emphasized in terms of evolving medical needs and health and social care outcomes.


Asunto(s)
Análisis de Datos , Epilepsia/cirugía , Aceptación de la Atención de Salud , Medición de Resultados Informados por el Paciente , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Epilepsia/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Gales/epidemiología , Adulto Joven
6.
Ann Neurol ; 84(6): 829-842, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30362156

RESUMEN

OBJECTIVE: Cortical gray matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration, and meningeal inflammation contribute to pathology at early stages of MS to better predict long-term outcome. METHODS: Tissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non-diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization. RESULTS: Cortical GM demyelination was extensive in some cases of acute MS (range = 1-48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68+ ) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid-like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid-like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM. INTERPRETATION: Our findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. Ann Neurol 2018;84:829-842.


Asunto(s)
Corteza Cerebral/patología , Inflamación/complicaciones , Meninges/patología , Esclerosis Múltiple/complicaciones , Vaina de Mielina/patología , Adulto , Anciano , Antígenos CD/metabolismo , Corteza Cerebral/metabolismo , Estudios de Cohortes , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Femenino , Sustancia Gris/metabolismo , Sustancia Gris/patología , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Meninges/metabolismo , Microglía/metabolismo , Microglía/patología , Persona de Mediana Edad , Vaina de Mielina/metabolismo , Factores de Transcripción/metabolismo , Adulto Joven
7.
Brain ; 141(3): 651-661, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29390050

RESUMEN

Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1-/- neurons expressing Thorase mutantHis357Argfs*15 display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Encefalopatías/genética , Regulación de la Expresión Génica/genética , Mutación/genética , Neuronas/patología , Receptores AMPA/metabolismo , Adenosina Trifosfatasas/metabolismo , Encefalopatías/diagnóstico por imagen , Encefalopatías/patología , Proteínas Portadoras/metabolismo , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Homocigoto , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mitocondrias/genética , Mitocondrias/patología , Modelos Moleculares , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/ultraestructura , Consumo de Oxígeno/genética , Transporte de Proteínas/genética , ARN Mensajero/metabolismo
8.
Brain ; 141(3): 698-712, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29365063

RESUMEN

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.


Asunto(s)
Mutación/genética , Proteínas del Tejido Nervioso/genética , Polimicrogiria/genética , Receptores de N-Metil-D-Aspartato/genética , Animales , Niño , Preescolar , Análisis Mutacional de ADN , Agonistas de Aminoácidos Excitadores/farmacología , Salud de la Familia , Femenino , Ácido Glutámico/farmacología , Glicina/metabolismo , Glicina/farmacología , Células HEK293 , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Potenciales de la Membrana/genética , Modelos Moleculares , Mutagénesis/genética , N-Metilaspartato/farmacología , Técnicas de Placa-Clamp , Polimicrogiria/diagnóstico por imagen , Ratas , Transfección
9.
J Neurol Neurosurg Psychiatry ; 89(7): 736-740, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29588327

RESUMEN

OBJECTIVE: Small prospective studies have identified that children exposed to valproate in utero have poorer scores on cognitive testing. We wanted to identify whether children exposed to antiepileptic drugs (AEDs) in utero have poorer school performance. METHODS: We used anonymised, linked, routinely collected healthcare records to identify children born to mothers with epilepsy. We linked these children to their national attainment Key Stage 1 (KS1) tests in mathematics, language and science at the age of 7 and compared them with matched children born to mothers without epilepsy, and with the national KS1 results. We used the core subject indicator (CSI) as an outcome measure (the proportion of children achieving a minimum standard in all subjects) and the results in individual subjects. RESULTS: We identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers being prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (-12.7% less than the control group), mathematics (-12.1%), language (-10.4%) and in science (-12.2%). Even fewer children with mothers being prescribed multiple AEDs during pregnancy achieved a national minimum standard: CSI (by -20.7% less than the control group), mathematics (-21.9%), language (-19.3%) and science (-19.4%). We did not observe any significant difference in children whose mothers were prescribed carbamazepine or were not taking an AED when compared with the control group. CONCLUSIONS: In utero exposure to AEDs in combination, or sodium valproate alone, is associated with a significant decrease in attainment in national educational tests for 7-year-old children compared with both a matched control group and the all-Wales national average. These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Hijo de Padres Discapacitados/psicología , Escolaridad , Epilepsia/tratamiento farmacológico , Complicaciones del Embarazo/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/psicología , Estudios de Casos y Controles , Niño , Desarrollo Infantil , Femenino , Humanos , Masculino , Embarazo , Reino Unido
10.
Epilepsia ; 59(7): 1410-1420, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29901232

RESUMEN

OBJECTIVE: There is little detailed phenotypic characterization of bilateral hippocampal sclerosis (HS). We therefore conducted a multicenter review of people with pharmacoresistant epilepsy and bilateral HS to better determine their clinical characteristics. METHODS: Databases from 11 EPIGEN centers were searched. For identified cases, clinicians reviewed the medical notes, imaging, and electroencephalographic (EEG), video-EEG, and neuropsychometric data. Data were irretrievably anonymized, and a single database was populated to capture all phenotypic information. These data were compared with phenotyped cases of unilateral HS from the same centers. RESULTS: In total, 96 patients with pharmacoresistant epilepsy and bilateral HS were identified (43 female, 53 male; age range = 8-80 years). Twenty-five percent had experienced febrile convulsions, and 27% of patients had experienced status epilepticus. The mean number of previously tried antiepileptic drugs was 5.32, and the average number of currently prescribed medications was 2.99; 44.8% of patients had cognitive difficulties, and 47.9% had psychiatric comorbidity; 35.4% (34/96) of patients continued with long-term medical therapy alone, another 4 being seizure-free on medication. Sixteen patients proceeded to, or were awaiting, neurostimulation, and 11 underwent surgical resection. One patient was rendered seizure-free postresection, with an improvement in seizures for 3 other cases. By comparison, of 201 patients with unilateral HS, a significantly higher number (44.3%) had febrile convulsions and only 11.4% had experienced status epilepticus. Importantly, 41.8% (84/201) of patients with unilateral HS had focal aware seizures, whereas such seizures were less frequently observed in people with bilateral HS, and were never observed exclusively (P = .002; Fisher's exact test). SIGNIFICANCE: The current work describes the phenotypic spectrum of people with pharmacoresistant epilepsy and bilateral HS, highlights salient clinical differences from patients with unilateral HS, and provides a large platform from which to develop further studies, both epidemiological and genomic, to better understand etiopathogenesis and optimal treatment regimes in this condition.


Asunto(s)
Dominancia Cerebral/fisiología , Epilepsia Refractaria/fisiopatología , Epilepsias Parciales/fisiopatología , Hipocampo/patología , Fenotipo , Estado Epiléptico/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Epilepsia Refractaria/diagnóstico , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/cirugía , Femenino , Hipocampo/cirugía , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Esclerosis , Estado Epiléptico/diagnóstico , Estado Epiléptico/cirugía , Adulto Joven
11.
Hum Mol Genet ; 24(18): 5313-25, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26130693

RESUMEN

Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.


Asunto(s)
Cerebelo/patología , Mutación , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Tubulina (Proteína)/genética , Alelos , Encéfalo/patología , Línea Celular , Vermis Cerebeloso/patología , Estudios de Cohortes , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Microtúbulos/química , Microtúbulos/metabolismo , Modelos Moleculares , Malformaciones del Sistema Nervioso/diagnóstico , Fenotipo , Conformación Proteica , Multimerización de Proteína , Relación Estructura-Actividad , Tubulina (Proteína)/química
12.
Am J Hum Genet ; 94(4): 634-41, 2014 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-24702957

RESUMEN

Tubulins, and microtubule polymers into which they incorporate, play critical mechanical roles in neuronal function during cell proliferation, neuronal migration, and postmigrational development: the three major overlapping events of mammalian cerebral cortex development. A number of neuronally expressed tubulin genes are associated with a spectrum of disorders affecting cerebral cortex formation. Such "tubulinopathies" include lissencephaly/pachygyria, polymicrogyria-like malformations, and simplified gyral patterns, in addition to characteristic extracortical features, such as corpus callosal, basal ganglia, and cerebellar abnormalities. Epilepsy is a common finding in these related disorders. Here we describe two unrelated individuals with infantile-onset epilepsy and abnormalities of brain morphology, harboring de novo variants that affect adjacent amino acids in a beta-tubulin gene TUBB2A. Located in a highly conserved loop, we demonstrate impaired tubulin and microtubule function resulting from each variant in vitro and by using in silico predictive modeling. We propose that the affected functional loop directly associates with the alpha-tubulin-bound guanosine triphosphate (GTP) molecule, impairing the intradimer interface and correct formation of the alpha/beta-tubulin heterodimer. This study associates mutations in TUBB2A with the spectrum of "tubulinopathy" phenotypes. As a consequence, genetic variations affecting all beta-tubulin genes expressed at high levels in the brain (TUBB2B, TUBB3, TUBB, TUBB4A, and TUBB2A) have been linked with malformations of cortical development.


Asunto(s)
Giro Dentado/patología , Epilepsia/genética , Mutación Missense , Tubulina (Proteína)/genética , Secuencia de Aminoácidos , Epilepsia/patología , Células HEK293 , Humanos , Lactante , Imagen por Resonancia Magnética , Modelos Moleculares , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Tubulina (Proteína)/química
13.
J Neuroinflammation ; 13(1): 161, 2016 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-27333900

RESUMEN

BACKGROUND: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. METHODS: We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. RESULTS: Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. CONCLUSIONS: Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.


Asunto(s)
Sistema Nervioso Central/patología , Proteínas del Sistema Complemento/metabolismo , Encefalitis/patología , Sustancia Gris/patología , Esclerosis Múltiple/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Clusterina/metabolismo , Estudios de Cohortes , Proteínas Inactivadoras del Complemento 1/metabolismo , Proteína Inhibidora del Complemento C1 , Proteínas del Sistema Complemento/genética , Femenino , Antígenos HLA-D/genética , Antígenos HLA-D/metabolismo , Humanos , Masculino , Microglía/patología , Persona de Mediana Edad , Glicoproteína Mielina-Oligodendrócito/metabolismo , Adulto Joven
14.
BMC Med Genet ; 17(1): 34, 2016 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-27113213

RESUMEN

BACKGROUND: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. METHODS: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. RESULTS: 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. CONCLUSIONS: We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults.


Asunto(s)
Variaciones en el Número de Copia de ADN , Epilepsia/genética , Discapacidad Intelectual/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Eliminación de Secuencia , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Gales , Adulto Joven
15.
Hum Mol Genet ; 22(5): 927-40, 2013 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-23184146

RESUMEN

Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and ß-subunits (GLRB) in a 2α(1):3ß configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.


Asunto(s)
Epilepsia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipertonía Muscular/genética , Receptores de Glicina/genética , Reflejo Anormal/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Epilepsia/fisiopatología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Predisposición Genética a la Enfermedad , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Hipertonía Muscular/fisiopatología , Mutación , Linaje , Conformación Proteica , Sitios de Empalme de ARN/genética , Receptores de Glicina/química , Receptores de Glicina/metabolismo , Relación Estructura-Actividad
16.
Epilepsia ; 56(4): 585-91, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25873180

RESUMEN

OBJECTIVE: To investigate whether the link between epilepsy and deprivation is due to factors associated with deprivation (social causation) or factors associated with a diagnosis of epilepsy (social drift). METHODS: We reviewed electronic primary health care records from 2004 to 2010, identifying prevalent and incident cases of epilepsy and recording linked deprivation scores. Logistic and Poisson regression models were used to calculate odds ratios and incidence rate ratios. The change in deprivation was measured 10 years after the initial diagnosis of epilepsy for a cohort of people. RESULTS: Between 2004 and 2010, 8.1 million patient-years of records were reviewed. Epilepsy prevalence and incidence were significantly associated with deprivation. Epilepsy prevalence ranged from 1.13% (1.07-1.19%) in the most deprived decile to 0.49% (0.45-0.53%) in the least deprived decile (adjusted odds ratio 0.92, p < 0.001). Epilepsy incidence ranged from 40/100,000 per year in the most deprived decile to 19/100,000 per year in the least deprived decile (adjusted incidence rate ratio 0.94, p < 0.001). There was no statistically significant change in deprivation index decile 10 years after a new diagnosis of epilepsy (mean difference -0.04, p = 0.85). SIGNIFICANCE: Epilepsy prevalence and incidence are strongly associated with deprivation; the deprivation score remains unchanged 10 years after a diagnosis of epilepsy. These findings suggest that increasing rates of epilepsy in deprived areas are more likely explained by social causation than by social drift. The nature of the association between incident epilepsy and social deprivation needs further exploration.


Asunto(s)
Recolección de Datos , Registros Electrónicos de Salud , Epilepsia/diagnóstico , Epilepsia/psicología , Necesidades y Demandas de Servicios de Salud , Carencia Psicosocial , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Epilepsia/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Gales/epidemiología , Adulto Joven
17.
Nat Genet ; 38(7): 801-6, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16751771

RESUMEN

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.


Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Mutación , Reflejo de Sobresalto/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Línea Celular , Femenino , Proteínas de Transporte de Glicina en la Membrana Plasmática/química , Proteínas de Transporte de Glicina en la Membrana Plasmática/fisiología , Humanos , Técnicas In Vitro , Recién Nacido , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Oocitos/metabolismo , Terminales Presinápticos/fisiología , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Reflejo de Sobresalto/fisiología , Transfección , Xenopus laevis
18.
J Biol Chem ; 288(47): 33745-33759, 2013 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-24108130

RESUMEN

Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus ß subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.


Asunto(s)
Regulación de la Expresión Génica , Rigidez Muscular/metabolismo , Mutación Missense , Receptores de Glicina/metabolismo , Sustitución de Aminoácidos , Femenino , Humanos , Masculino , Rigidez Muscular/genética , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores de Glicina/genética
19.
Neurobiol Dis ; 64: 131-141, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24407264

RESUMEN

Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS+). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS+ and screened for variations in the γ2 subunit of the γ-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136*) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and extended behavioural presentation. The GABRG2(p.R136*) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that γ2(p.R136*) subunits were produced, but had reduced cell-surface and total expression. When γ2(p.R136*) subunits were co-expressed with α1 and ß2 subunits in HEK 293T cells, GABA-evoked currents were reduced. Furthermore, γ2(p.R136*) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136*) mutation extends the spectrum of GABRG2 mutations identified in GEFS+ and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism.


Asunto(s)
Epilepsia Generalizada/genética , Fenotipo , Mutación Puntual , Receptores de GABA-A/genética , Convulsiones Febriles/genética , Adulto , Animales , Células COS , Células Cultivadas , Corteza Cerebral/fisiopatología , Niño , Preescolar , Chlorocebus aethiops , Estudios de Cohortes , Familia , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Neuronas/fisiología , Células PC12 , Ratas , Receptores de GABA-A/metabolismo
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