ABSTRACT
OBJECTIVE: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. METHODS: We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. RESULTS: We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. INTERPRETATION: KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.
Subject(s)
Epilepsy, Benign Neonatal/diagnosis , Epilepsy, Benign Neonatal/genetics , KCNQ2 Potassium Channel/genetics , Mutation/genetics , Phenotype , Child , Child, Preschool , Epilepsy, Benign Neonatal/physiopathology , Female , Humans , MaleABSTRACT
OBJECTIVES: Reports about the nature of the ingredients responsible for allergic contact dermatitis caused by specific cosmetic products are scarce. METHODS: Between January 2000 and December 2010, the specific cosmetic products having caused allergic contact dermatitis, as well as the individual allergenic cosmetic ingredients present in them, were recorded by use of a standardized form. RESULTS: Among 11 different categories of cosmetic product, skin care products, followed by hair care and body-cleansing products, were most often involved. The presence of the allergenic ingredient(s) in a specific cosmetic product was confirmed according to the ingredient label in 959 of 1448 records. Six hundred and twenty-one of 959 concerned non-fragrance components, preservatives being responsible for 58% of them. Reactions to formaldehyde and formaldehyde-releasers were most often correlated with body-cleansing products, particularly 2-bromo-2-nitropropane-1,3-diol and skin care products. They were followed by the methylchloroisothiazolinone/methylisothiazolinone mixture, most frequently found as allergens in hair care and intimate hygiene products, and facial cleansers (in the last category together with diazolidinyl urea). Octocrylene was by far the most frequent (photo)allergen in sun care products. CONCLUSIONS: This study provides information on the presence and frequency of allergens in specific causal cosmetic products.
Subject(s)
Allergens/adverse effects , Cosmetics/adverse effects , Cosmetics/chemistry , Dermatitis, Allergic Contact/etiology , Preservatives, Pharmaceutical/adverse effects , Acrylates/adverse effects , Antioxidants/adverse effects , Cross-Sectional Studies , Databases, Factual , Emulsifying Agents/adverse effects , Ethylene Glycols/adverse effects , Formaldehyde/adverse effects , Humans , Hydantoins/adverse effects , Methacrylates/adverse effects , Methenamine/adverse effects , Methenamine/analogs & derivatives , Nickel/adverse effects , Parabens/adverse effects , Plant Extracts/adverse effects , Propylene Glycols/adverse effects , Sunscreening Agents/adverse effects , Thiazoles/adverse effects , Urea/adverse effects , Urea/analogs & derivativesABSTRACT
BACKGROUND: Together with preservative agents, fragrance components are the most important sensitizing culprits in cosmetic products. OBJECTIVES: To identify the nature of the fragrance ingredients responsible for allergic contact dermatitis (ACD) from specific cosmetic products. METHODS: Between 2000 and 2009, positive patch test reactions or positive usage tests with the patients' own cosmetic products, were recorded using a standardised form. RESULTS: Of the 806 cosmetic records, corresponding to 485 patient files, 344 concerned reactions to fragrance ingredients that according to the label were present ('Presence Confirmed' [PC n = 301]) or suspected to be present ('Presence Not Confirmed' [PNC n = 376]) in the causal cosmetic products used, which belonged to 15 different categories, toilet waters/fine perfumes being the most frequent. Geraniol in fragrance mix I (FM I) and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) in FM II were the most frequent PC, and together with hydroxycitronellal and Evernia prunastri (oak moss) the most frequent PNC ingredients in the causal cosmetic products. Limonene was the most frequent PC confirmed fragrance allergen. CONCLUSIONS: This study not only underlines the usefulness of fragrance-ingredient labelling in order to identify the causal allergen(s) present in specific cosmetic products, but may also provide information on trends in the actual use of sensitizing fragrance ingredients in them.
Subject(s)
Allergens/analysis , Cosmetics/chemistry , Dermatitis, Allergic Contact/etiology , Perfume/chemistry , Cross-Sectional Studies , HumansABSTRACT
Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na(+) channel Na(V)1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na(+) channel Na(V)1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na(+) current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of Na(V)1.2 and of another voltage-gated Na(+) channel, Na(V)1.6, using immunohistochemistry and real-time reverse transcription-polymerase chain reaction in mouse brain slices. We found that Na(V)1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by Na(V)1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant Na(V)1.2 channels.
Subject(s)
Epilepsy, Benign Neonatal/genetics , Mutation , Nerve Tissue Proteins/genetics , Sodium Channels/genetics , Adult , Aging/metabolism , Animals , Axons/metabolism , Base Sequence , Cell Line , Electrophysiology , Epilepsy, Benign Neonatal/physiopathology , Hippocampus/metabolism , Humans , Immunohistochemistry , Infant , Infant, Newborn , Male , Mice , Mice, Inbred C57BL , NAV1.2 Voltage-Gated Sodium Channel , NAV1.6 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/metabolism , Pedigree , Protein Isoforms , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sodium Channels/metabolismABSTRACT
Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34 patients with early-onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1 glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1 deficiency underlies a significant proportion of early-onset absence epilepsy, which has both genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1 deficiency.
Subject(s)
Epilepsy, Absence/genetics , Glucose Transporter Type 1/deficiency , Glucose Transporter Type 1/genetics , Mutation, Missense/genetics , Age of Onset , Child , Child, Preschool , Diet, Ketogenic , Epilepsy, Absence/diagnosis , Epilepsy, Absence/diet therapy , Female , Glucose Transporter Type 1/metabolism , Humans , Male , Treatment OutcomeABSTRACT
A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.
Subject(s)
Abnormalities, Multiple/genetics , Epilepsy/complications , Epilepsy/genetics , Seizures, Febrile/etiology , Seizures, Febrile/genetics , Sodium Channels/genetics , Abnormalities, Multiple/physiopathology , Amino Acid Sequence , Amino Acid Substitution/genetics , Animals , Base Sequence , DNA Mutational Analysis , Electroshock , Epilepsy/physiopathology , Female , Gene Knock-In Techniques , Humans , Kindling, Neurologic/physiology , Male , Mice , Molecular Sequence Data , Mutation/genetics , NAV1.1 Voltage-Gated Sodium Channel , NAV1.7 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/genetics , Pedigree , Protein Subunits/genetics , Seizures, Febrile/physiopathology , Sequence Alignment , Sodium Channels/chemistry , SyndromeABSTRACT
Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-) versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.
Subject(s)
Epilepsies, Myoclonic/genetics , Epilepsies, Myoclonic/physiopathology , Polymorphism, Single Nucleotide/genetics , Sodium Channels/genetics , Animals , Arginine/genetics , Biophysics , Cell Line, Transformed , Cysteine/genetics , DNA Mutational Analysis , Disease Models, Animal , Electric Stimulation , Epilepsies, Myoclonic/mortality , Female , Green Fluorescent Proteins/genetics , Hippocampus/pathology , Humans , In Vitro Techniques , Infant , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , NAV1.1 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/deficiency , Oocytes , Sodium Channels/deficiency , Temperature , Transfection , Twins , Voltage-Gated Sodium Channel beta-1 Subunit , Xenopus laevisABSTRACT
The neuronal voltage-gated sodium channel Na(v)1.1 encoded by the SCN1A gene plays an important role in the generation and propagation of action potentials in the central nervous system. Altered function of this channel due to mutations in SCN1A leads to hypersynchronous neuronal discharges resulting in seizures or migrainous attaques. A large number of distinct sequence variants in SCN1A are associated with diverse epilepsy and migraine syndromes. We developed an online and freely available database containing all reported sequence variants in SCN1A (http://www.molgen.ua.ac.be/SCN1AMutations/). We verified 623 distinct sequence variants, listed them using standard nomenclature for description and classified them according to their putative pathogenic nature. We provided links to relevant publications and information on the associated phenotype. The database can be queried using cDNA or protein position, phenotype, variant type or publication. By listing all SCN1A variants in a comprehensive manner, this database will facilitate interpretation of newly identified sequence variants and provide better insight into the genotype-phenotype relations of the growing number of SCN1A mutations.
Subject(s)
Databases, Genetic , Nerve Tissue Proteins/genetics , Point Mutation , Sodium Channels/genetics , Gene Rearrangement , Humans , NAV1.1 Voltage-Gated Sodium Channel , PhenotypeABSTRACT
OBJECTIVE AND BACKGROUND: Severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome) is a malignant epilepsy syndrome characterized by prolonged febrile hemiconvulsions or generalized seizures starting in the first year of life. Later on myoclonic, atypical absence, and complex partial seizures appear. When one of these seizure forms is lacking the syndrome of borderline SMEI (SMEB) is defined. Psychomotor delay resulting in mental retardation is observed during the second year of life. In most patients a de novo sodium channel alpha-1 subunit (SCN1A) mutation can be identified. By reviewing the clinical, laboratory, and neuroimaging data of our SMEI patients diagnosed between 2000 and 2008, we would like to share our experiences in this rare but challenging syndrome. Our results will facilitate the earlier and better diagnosis of Hungarian children with SMEI. PATIENTS AND METHODS: Clinical, EEG, MRI and DNA mutation data of 20 SMEI patients treated in the Bethesda Children's Hospital (Budapest) were reviewed. RESULTS: The first seizure appeared at age 6.3+/-3.0 months. At least one of the first two seizures were complex febrile seizures in 19/20 and unilateral seizures in 12/20 children. All children except for one showed hemiconvulsions at least once; all children had seizures lasting longer than 15 minutes. Eight of twenty patients had SMEB. DNA diagnostics identified an SCN1A mutation in 17 patients (6 missense, 4 nonsense, 4 frameshift, 2 splice site, 1 deletion) while 3 children had no mutation. CONCLUSION: Early diagnosis of SMEI is important for the avoiding unnecessary examinations and false therapies as well as for genetic counselling. Typical symptoms of SMEI are early and prolonged febrile hemiconvulsions with neurological symptoms, mental retardation and secondary seizure types later on. The presence of an SCN1A mutation supports the diagnosis. We propose the availability of molecular diagnostics and stiripentol therapy for SMEI children in Hungary
Subject(s)
Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/genetics , Mutation , Nerve Tissue Proteins/genetics , Sodium Channels/genetics , Adolescent , Anticonvulsants/therapeutic use , Child , Child, Preschool , DNA Mutational Analysis , Dioxolanes/therapeutic use , Electroencephalography , Epilepsies, Myoclonic/complications , Epilepsies, Myoclonic/drug therapy , Epilepsy, Absence/diagnosis , Epilepsy, Absence/genetics , Epilepsy, Complex Partial/diagnosis , Epilepsy, Complex Partial/genetics , Female , Humans , Hungary/epidemiology , Infant , Intellectual Disability/etiology , Magnetic Resonance Imaging , Male , Myoclonic Epilepsy, Juvenile/diagnosis , Myoclonic Epilepsy, Juvenile/genetics , NAV1.1 Voltage-Gated Sodium Channel , Psychomotor Disorders/complications , Psychomotor Disorders/etiology , Seizures, Febrile/etiologyABSTRACT
Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome.
Subject(s)
Chorea/genetics , Epilepsy/genetics , Glucose Transporter Type 1/genetics , Mutation , Adolescent , Adult , Blood Glucose/metabolism , Chorea/complications , Chorea/diagnostic imaging , Chorea/diet therapy , Chromosome Mapping , DNA Mutational Analysis/methods , Electroencephalography , Epilepsy/complications , Epilepsy/diagnostic imaging , Epilepsy/diet therapy , Exercise , Female , Glucose/cerebrospinal fluid , Humans , Lod Score , Magnetic Resonance Imaging , Male , Middle Aged , Pedigree , Phenotype , Positron-Emission TomographyABSTRACT
PURPOSE: Mutations in the ATP1A2 gene have been described in families with familial hemiplegic migraine (FHM). FHM is a variant of migraine with aura characterized by the occurrence of hemiplegia during the aura. Within several FHM families, some patients also had epileptic seizures. In this study we tested the hypothesis that mutations in ATP1A2 may be common in patients presenting with epilepsy and migraine. METHODS: We selected 20 families with epilepsy and migraine and performed mutation analysis of ATP1A2 in the probands by direct sequencing of all exons and splice-site junctions. RESULTS: Novel ATP1A2 mutations were found in two of the 20 families (10%). The p.Gly900Arg mutation was present in a family with epilepsy and FHM, and the p.Cys702Tyr mutation occurred in a family with occipitotemporal epilepsy and migraine with and without visual aura. In the two families together, six mutation carriers had the combination of epilepsy and migraine, two had only epilepsy, and six had only migraine. DISCUSSION: This study shows that a history of migraine and a family history of both epilepsy and migraine should be obtained in all patients presenting with epilepsy in the epilepsy clinic. It may be worthwhile to screen patients with a combination of epilepsy and migraine and a positive family history of either migraine or epilepsy for mutations in the ATP1A2 gene.
Subject(s)
Epilepsy/genetics , Migraine with Aura/genetics , Mutation/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Adult , Age of Onset , Amino Acid Sequence , Belgium/epidemiology , Comorbidity , DNA Mutational Analysis , Epilepsy/epidemiology , Exons/genetics , Family , Female , Gene Frequency/genetics , Humans , Male , Middle Aged , Migraine with Aura/epidemiology , Pedigree , Phenotype , RNA Splice Sites/genetics , White People/geneticsABSTRACT
We report the clinical, neuroradiological, and molecular genetic findings in a patient with lipoid proteinosis or Urbach-Wiethe disease. Interestingly, in this patient epilepsy and migraine were the symptoms leading to the diagnosis of the disease, contrary to most patients in whom skin abnormalities are the first recognized symptoms.
Subject(s)
Epilepsy/complications , Lipoid Proteinosis of Urbach and Wiethe/complications , Migraine Disorders/complications , Adult , Female , Humans , Lipoid Proteinosis of Urbach and Wiethe/diagnosis , Lipoid Proteinosis of Urbach and Wiethe/diagnostic imaging , Lipoid Proteinosis of Urbach and Wiethe/genetics , Magnetic Resonance Imaging , RadiographyABSTRACT
Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.
Subject(s)
Epilepsies, Myoclonic/genetics , Gene Deletion , Nerve Tissue Proteins/genetics , Sodium Channels/genetics , Child , Chromosome Mapping , Codon, Nonsense , DNA Mutational Analysis , Epilepsies, Myoclonic/diagnosis , Female , Genetic Testing/methods , Haplotypes , Humans , In Situ Hybridization, Fluorescence , Infant , Male , Mutation, Missense , NAV1.1 Voltage-Gated Sodium Channel , Polymerase Chain Reaction , Polymorphism, Single NucleotideABSTRACT
A mutation in the voltage-gated sodium-channel Scn2a results in moderate epilepsy in transgenic Scn2a(Q54) mice maintained on a C57BL/6J strain background. The onset of progressive epilepsy begins in adults with short-duration partial seizures that originate in the hippocampus. The underlying abnormality is an increase in persistent sodium current in hippocampal neurons. The voltage-gated potassium channel Kcnq2 is responsible for generating M current (I(KM)) that is thought to control excitability and limit repetitive firing of hippocampal neurons. To determine whether impaired M current would exacerbate the seizure phenotype of Scn2a(Q54) mice, we carried out genetic crosses with two mutant alleles of Kcnq2. Szt1 mice carry a spontaneous deletion that removes the C-terminal domain of Kcnq2. A novel Kcnq2 missense mutation V182M was identified by screening the offspring of ENU-treated males for reduced threshold to electrically evoked minimal clonic seizures. Double mutant mice carrying the Scn2a(Q54) transgene together with either of the Kcnq2 mutations exhibited severe epilepsy with early onset, generalized tonic-clonic seizures and juvenile lethality by 3 weeks of age. This dramatic exacerbation of the sodium-channel mutant phenotype indicates that M current plays a critical role in preventing seizure initiation and spreading in this animal model. The genetic interaction between Scn2a and Kcnq2 demonstrates that combinations of mild alleles of monogenic epilepsy genes can result in severe disease and provides a model for complex inheritance of human epilepsy. The data suggest that interaction between these genes might contribute to the variable expressivity observed in human families with sodium-channel mutations. In a screen of 23 SMEI patients with missense mutations of SCN1A, no second-site mutations in KCNQ2 were identified.
Subject(s)
Epilepsy/genetics , Epilepsy/metabolism , KCNQ2 Potassium Channel/genetics , KCNQ2 Potassium Channel/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Sodium Channels/genetics , Sodium Channels/metabolism , Amino Acid Sequence , Animals , Epilepsy/etiology , Ethylnitrosourea/toxicity , Genetic Testing , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Molecular Sequence Data , Mutation, Missense , NAV1.1 Voltage-Gated Sodium Channel , NAV1.2 Voltage-Gated Sodium ChannelABSTRACT
Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.
Subject(s)
Chromosomes, Human, Pair 5 , Epilepsy/genetics , Genetic Linkage , Genome, Human , Mutation , Receptors, G-Protein-Coupled/genetics , Seizures, Febrile/genetics , Adolescent , Adult , Aged , Child , Chromosome Mapping , Female , Genotype , Humans , Male , Middle Aged , PedigreeABSTRACT
Technological improvements shifted sequencing from low-throughput, work-intensive, gel-based systems to high-throughput capillary systems. This resulted in a broad use of genomic resequencing to identify sequence variations in genes and regulatory, as well as extended genomic regions. We describe a software package, novoSNP, that conscientiously discovers single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (INDELs) in sequence trace files in a fast, reliable, and user-friendly way. We compared the performance of novoSNP with that of PolyPhred and PolyBayes on two data sets. The first data set comprised 1028 sequence trace files obtained from diagnostic mutation analyses of SCN1A (neuronal voltage-gated sodium channel alpha-subunit type I gene). The second data set comprised 9062 sequence trace files from a genomic resequencing project aiming at the construction of a high-density SNP map of MAPT (microtubule-associated protein tau gene). Visual inspection of these data sets had identified 38 sequence variations for SCN1A and 488 for MAPT. novoSNP automatically identified all 38 SCN1A variations including five INDELs, while for MAPT only 15 of the 488 variations were not correctly marked. PolyPhred detected far fewer SNPs as compared to novoSNP and missed nearly all INDELs. PolyBayes, designed for the sequence analysis of cloned templates, detected only a limited number of the variations present in the data set. Besides the significant improvement in the automated detection of sequence variations both in diagnostic mutation analyses and in SNP discovery projects, novoSNP also offers a user-friendly interface for inspecting possible genetic variations.
Subject(s)
Genomics/methods , Polymorphism, Single Nucleotide , Software , Animals , Base Sequence , DNA/genetics , Genetic Variation , Genomics/statistics & numerical data , Humans , Polymorphism, Genetic , Sequence Analysis, DNAABSTRACT
Severe myoclonic epilepsy in infancy, or Dravet syndrome, is one of the catastrophic epilepsy syndromes. In the past, treatment was mainly based on valproate and phenobarbital. Recently, some of the new antiepilepsy drugs, such as topiramate and stiripentol, have been shown to be promising in the treatment of this epilepsy syndrome. The treatment regimen of 12 children with Dravet syndrome and proven mutations in the alpha subunit of the sodium channel SCN1A is reported here. Five patients on the "traditional" treatment regimen are compared with seven children on an "optimal" treatment regimen based on a combination of valproate and topiramate. With respect to the literature and our own experience, we propose guidelines for "optimal" treatment of children with severe myoclonic epilepsy in infancy. This includes prevention of hyperthermia, rigorous treatment of fever, avoiding stressful situations, maintenance treatment based on a combination of only two antiepilepsy drugs (ie, valproate and topiramate), and a strict acute seizure treatment based on benzodiazepines. To prevent long-lasting periods of status epilepticus, this acute seizure treatment must be taught to parents and caregivers.
Subject(s)
Anticonvulsants/therapeutic use , Benzodiazepines/therapeutic use , Myoclonic Epilepsy, Juvenile/drug therapy , Myoclonic Epilepsy, Juvenile/pathology , Adolescent , Child , Child, Preschool , DNA Mutational Analysis , Drug Therapy, Combination , Female , Fever/complications , Fever/therapy , Humans , Male , Myoclonic Epilepsy, Juvenile/prevention & control , Retrospective Studies , Severity of Illness Index , Sodium Channels/genetics , Stress, Psychological , Treatment Outcome , Voltage-Gated Sodium Channel beta-1 SubunitABSTRACT
Mutations in the alpha-subunit of the first neuronal sodium channel gene SCN1A have been described in isolated patients with severe myoclonic epilepsy in infancy or Dravet syndrome and in families with generalized epilepsy with febrile seizures plus. To find phenotype/genotype correlations, we reviewed all published cases of mutations in SCN1A in addition to four new patients reported here. A total of 60 mutations were observed. Approximately 52% (31/60) are truncating mutations correlating with de novo cases of classical Dravet syndrome in 32 of 34 (94%) patients. Missense mutations in the pore-forming part constitute 27% (16/60) and correspond to a classical type in 12 of 16 (75%) patients. Missense mutations in the voltage sensor were present in 12% (7/60) and correlate with a clinical picture ranging from febrile seizures plus to severe myoclonic epilepsy in infancy. Outside these regions missense mutations are rare and account for only 10% (6/60), corresponding mostly with febrile seizures plus. These results illustrate that the clinical spectrum of SCN1A mutations ranges from febrile seizures, febrile seizures plus, over a milder type to the classical form of severe myoclonic epilepsy in infancy, and confirm the clinical experience that severe myoclonic epilepsy in infancy is the most severe form on this spectrum.
Subject(s)
DNA Mutational Analysis , Epilepsies, Myoclonic/genetics , Epilepsy, Generalized/genetics , Nerve Tissue Proteins/genetics , Seizures, Febrile/genetics , Sodium Channels/genetics , Child , Child, Preschool , Codon, Nonsense/genetics , Electroencephalography , Epilepsies, Myoclonic/diagnosis , Epilepsy, Generalized/diagnosis , Exons/genetics , Female , Frameshift Mutation/genetics , Genotype , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Male , Mutation, Missense/genetics , NAV1.1 Voltage-Gated Sodium Channel , Phenotype , Seizures, Febrile/diagnosis , SyndromeABSTRACT
Severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) is a rare disorder occurring in young children often without a family history of a similar disorder. The earliest disease manifestations are usually fever-associated seizures. Later in life, patients display different types of afebrile seizures including myoclonic seizures. Arrest of psychomotor development occurs in the second year of life and most patients become ataxic. Patients are resistant to antiepileptic drug therapy. Recently, we described de novo mutations of the neuronal sodium channel alpha-subunit gene SCN1A in seven isolated SMEI patients. To investigate the contribution of SCN1A mutations to the etiology of SMEI, we examined nine additional SMEI patients. We observed eight coding and one noncoding mutation. In contrast to our previous study, most mutations are missense mutations clustering in the S4-S6 region of SCN1A. These findings demonstrate that de novo mutations in SCN1A are a major cause of isolated SMEI.