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2.
Neuroscience ; 148(1): 164-74, 2007 Aug 10.
Article in English | MEDLINE | ID: mdl-17629415

ABSTRACT

Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel beta1 subunit have been identified in individuals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 alpha subunit with wild type or mutant beta1 subunits in human embryonic kidney (HEK)-293T cells. Patch clamp studies confirmed the regulatory role of beta1 in that relative to NaV1.2 alone the NaV1.2+beta1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+beta1 current entered fast inactivation slightly faster than NaV1.2 channels alone. The beta1(R85C) subunit appears to be a complete loss of function in that none of the modulating effects of the wild type beta1 were observed when it was co-expressed with NaV1.2. Interestingly, the beta1(R85H) subunit also failed to modulate fast kinetics, however, it shifted the voltage dependence of steady state slow inactivation in the same way as the wild type beta1 subunit. Immunohistochemical studies revealed cell surface expression of the wild type beta1 subunit and undetectable levels of cell surface expression for both mutants. The functional studies suggest association of the beta1(R85H) subunit with the alpha subunit where its influence is limited to modulating steady state slow inactivation. In summary, the mutant beta1 subunits essentially fail to modulate alpha subunits which could increase neuronal excitability and underlie GEFS+ pathogenesis.


Subject(s)
Brain Chemistry/genetics , Epilepsy, Generalized/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Seizures, Febrile/genetics , Sodium Channels/genetics , Action Potentials/genetics , Brain/metabolism , Brain/physiopathology , Cell Line , Epilepsy, Generalized/metabolism , Epilepsy, Generalized/physiopathology , Humans , Ion Channel Gating/genetics , Membrane Potentials/genetics , NAV1.1 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/genetics , Patch-Clamp Techniques , Protein Subunits/genetics , Seizures, Febrile/metabolism , Seizures, Febrile/physiopathology , Synapses/genetics , Synapses/metabolism , Synaptic Transmission/genetics , Transfection , Voltage-Gated Sodium Channel beta-1 Subunit
3.
Neurology ; 62(7): 1115-9, 2004 Apr 13.
Article in English | MEDLINE | ID: mdl-15079010

ABSTRACT

BACKGROUND AND OBJECTIVES: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. METHODS: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4. RESULTS: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. CONCLUSION: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.


Subject(s)
Epilepsy, Partial, Sensory/genetics , Epilepsy, Temporal Lobe/genetics , Mutation, Missense , Proteins/genetics , Adult , Age of Onset , Aged , Amino Acid Sequence , Animals , Conserved Sequence , DNA Mutational Analysis , Extracellular Matrix Proteins/genetics , Family , Female , Genes, Dominant , Genetic Testing , Humans , Intracellular Signaling Peptides and Proteins , Male , Mice , Middle Aged , Molecular Sequence Data , Nerve Tissue Proteins , Pedigree , Rats , Sequence Alignment
4.
Neurology ; 61(6): 765-9, 2003 Sep 23.
Article in English | MEDLINE | ID: mdl-14504318

ABSTRACT

BACKGROUND: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS+ in a significant proportion of patients with SMEI. Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. METHOD: The authors screened SCN1A in 24 patients with SMEI and 23 with IS. RESULTS: Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. CONCLUSIONS: The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS+ could interact with other loci to cause SMEI in cases with a family history of GEFS+. This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.


Subject(s)
Myoclonic Epilepsy, Juvenile/genetics , Nerve Tissue Proteins/genetics , Sodium Channels/genetics , Spasms, Infantile/genetics , Amino Acid Sequence , Amino Acid Substitution , Australia , Child , Child, Preschool , Codon, Nonsense , DNA Mutational Analysis , Exons/genetics , Female , Genetic Heterogeneity , Humans , Infant , Male , Models, Molecular , Molecular Sequence Data , Mutation, Missense , NAV1.1 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/chemistry , Polymorphism, Single-Stranded Conformational , Protein Structure, Tertiary , RNA Splice Sites/genetics , Seizures, Febrile/genetics , Sequence Alignment , Sequence Deletion , Sequence Homology, Amino Acid , Sodium Channels/chemistry , Structure-Activity Relationship
5.
Neurology ; 59(3): 348-56, 2002 Aug 13.
Article in English | MEDLINE | ID: mdl-12177367

ABSTRACT

OBJECTIVE: To describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder. METHODS: The authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach. RESULTS: All six affected boys had myoclonic seizures and TCS; two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2-22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX). CONCLUSIONS: XMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX; MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.


Subject(s)
Drosophila Proteins/genetics , Epilepsies, Myoclonic/genetics , Genes, Homeobox/genetics , Genetic Linkage/genetics , Learning Disabilities/genetics , Muscle Spasticity/genetics , Mutation, Missense/genetics , X Chromosome/genetics , Adult , Aged , Child , Child, Preschool , Female , Genetic Carrier Screening , Humans , Male , Middle Aged , Pedigree
6.
Neurology ; 58(9): 1426-9, 2002 May 14.
Article in English | MEDLINE | ID: mdl-12011299

ABSTRACT

Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.


Subject(s)
Epilepsy, Generalized/genetics , Protein Subunits , Seizures, Febrile/genetics , Sodium Channels/genetics , Amino Acid Substitution , Child , Child, Preschool , Comorbidity , Epilepsy, Generalized/epidemiology , Female , Genetic Linkage , Genetic Markers , Genetic Testing , Haplotypes/genetics , Humans , Infant , Infant, Newborn , Male , Mutation , Nerve Tissue Proteins/genetics , Pedigree , Phenotype , Queensland/epidemiology , Seizures, Febrile/epidemiology , Voltage-Gated Sodium Channel beta-2 Subunit
7.
Nat Genet ; 28(1): 49-52, 2001 May.
Article in English | MEDLINE | ID: mdl-11326275

ABSTRACT

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants. We have found a mutation in a gene encoding a GABA(A) receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.


Subject(s)
Epilepsy, Absence/genetics , Receptors, GABA-A/genetics , Seizures, Febrile/genetics , Age of Onset , Anticonvulsants/pharmacology , Child , Chromosome Segregation , Diazepam/pharmacology , Electrophysiology , Exons , Female , GABA Modulators/pharmacology , Humans , Male , Molecular Sequence Data , Pedigree , Protein Subunits
8.
Am J Hum Genet ; 68(4): 859-65, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11254444

ABSTRACT

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.


Subject(s)
Epilepsy, Generalized/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Seizures, Febrile/genetics , Sodium Channels/genetics , Amino Acid Sequence , Amino Acid Substitution/genetics , Chromosomes, Human, Pair 2/genetics , Cloning, Molecular , DNA Mutational Analysis , Exons/genetics , Female , Gene Frequency/genetics , Genetic Variation/genetics , Humans , Male , Molecular Sequence Data , NAV1.1 Voltage-Gated Sodium Channel , Pedigree , Polymorphism, Single-Stranded Conformational , Protein Subunits , Sequence Alignment , Syndrome
10.
Eur J Prosthodont Restor Dent ; 8(3): 103-6, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11307562

ABSTRACT

This paper examines the effect of tobacco use on the failure rates of dental implants. A review of 56 dental implant patients with a total of 187 endosseous dental implants, placed over a four year period, demonstrated a significant association between increased implant failure rates and cigarette smoking with failure rates of 16.6% in smokers compared to 6.9% in non-smokers. Also implant length was shown to be a significant factor with shorter implants (< or = 10 mm) being more susceptible to failure in smokers. A chi-square test was used for data analysis. Current recommendations that should be given to implant patients who smoke are included.


Subject(s)
Dental Implants , Dental Restoration Failure , Smoking/adverse effects , Chi-Square Distribution , Dental Implantation, Endosseous , Dental Prosthesis Design , Female , Humans , Male , Osseointegration , Retrospective Studies
11.
Ann Neurol ; 44(6): 890-9, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9851433

ABSTRACT

Familial partial epilepsy with variable foci (FPEVF) joins the recently recognized group of inherited partial epilepsies. We describe an Australian family with 10 individuals with partial seizures over four generations. Detailed electroclinical studies were performed on all affected and 17 clinically unaffected family members. The striking finding was that the clinical features of the seizures and interictal electroencephalographic foci differed among family members and included frontal, temporal, occipital, and centroparietal seizures. Mean age of seizure onset was 13 years (range, 0.75-43 years). Two individuals without seizures had epileptiform abnormalities on electroencephalographic studies. Penetrance of seizures was 62%. A genome-wide search failed to demonstrate definitive linkage, but a suggestion of linkage was found on chromosome 2q with a LOD score of 2.74 at recombination fraction of zero with the marker D2S133. FPEVF differs from the other inherited partial epilepsies where partial seizures in different family members are clinically similar. The inherited nature of this new syndrome may be overlooked because of relatively low penetrance and because of the variability in age at onset and electroclinical features between affected family members.


Subject(s)
Chromosomes, Human, Pair 2/genetics , Epilepsies, Partial/genetics , Genetic Linkage/genetics , Adult , Child , Child, Preschool , Electroencephalography , Epilepsies, Partial/diagnosis , Epilepsies, Partial/psychology , Female , Genetic Markers , Humans , Lod Score , Male , Middle Aged , Neuropsychological Tests , Pedigree , Syndrome , Tomography, X-Ray Computed
12.
Nat Genet ; 19(4): 366-70, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9697698

ABSTRACT

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.


Subject(s)
Epilepsy, Generalized/genetics , Genetic Linkage , Point Mutation/genetics , Seizures, Febrile/genetics , Sodium Channels/genetics , Amino Acid Sequence , Animals , Chromosomes, Human, Pair 19/genetics , DNA Mutational Analysis , Female , Humans , Male , Molecular Sequence Data , Oocytes , Patch-Clamp Techniques , Pedigree , Sodium Channels/physiology , Tasmania , Xenopus laevis
13.
J Med Genet ; 33(4): 308-12, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8730286

ABSTRACT

Febrile convulsions affect 2 to 5% of all children under the age of 5 years. These convulsions probably have a variety of causes, but a genetic component has long been recognised. A large and remarkable family is described in which febrile convulsions appear to result from autosomal dominant inheritance at a single major locus. A gene for febrile convulsions was excluded from regions of previously mapped epilepsy genes and extension of exclusion mapping, using microsatellite markers, to the entire genome implied that a locus on chromosome 8q13-21 may be involved. Linkage analysis of markers on chromosome 8 gave a multipoint lod score of 3.40, maximised over different values of penetrance and phenocopy rate, for linkage between the gene for febrile convulsions and the region flanked by markers D8S553 and D8S279. This lod score was calculated assuming the disease has a penetrance of 60% and a phenocopy rate of 3%. Although there was no indication of linkage other than to markers on chromosome 8, linkage remains suggestive rather than significant because of the maximisation procedure applied. The support for linkage involving a major gene, as opposed to an alternative hypothesis of a complex inheritance pattern, relied upon the assumption of low penetrance.


Subject(s)
Chromosomes, Human, Pair 8 , Seizures, Febrile/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Chromosome Mapping , Female , Genetic Linkage , Genetic Markers/genetics , Genotype , Humans , Infant , Male , Middle Aged , Pedigree
14.
Nat Genet ; 11(2): 201-3, 1995 Oct.
Article in English | MEDLINE | ID: mdl-7550350

ABSTRACT

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.


Subject(s)
Chromosomes, Human, Pair 20 , Epilepsy, Frontal Lobe/genetics , Genes, Dominant , Point Mutation , Receptors, Nicotinic/genetics , Amino Acid Sequence , Animals , Base Sequence , Chickens , Chromosome Mapping , DNA Primers , Female , Frontal Lobe/metabolism , Genetic Linkage , Humans , Male , Molecular Sequence Data , Pedigree , Polymerase Chain Reaction , Rats , Receptors, Nicotinic/chemistry , Sequence Homology, Amino Acid
15.
N Z Med J ; 105(935): 215-7, 1992 Jun 10.
Article in English | MEDLINE | ID: mdl-1598142

ABSTRACT

The records of 18 immunocompromised patients with recent onset of pulmonary disease who had fibreoptic bronchoscopy and bronchoalveolar lavage over a two year period (1989-90) were reviewed. The underlying diseases were human immunodeficiency virus (HIV) infection (n = 7), organ transplantation (n = 9), and chemotherapy for malignancy (n = 2). Four patients were receiving prophylactic therapy and 12 had been started on empirical therapy for infection. Patients proceeded to bronchoscopy either because of atypical disease presentation or failure to respond to empirical therapy. Bronchoscopy with bronchoalveolar lavage was diagnostic in 13/18 (72%) patients and provided clinically useful information in 16/18 (89%). There was one diagnostic failure (6%); Pneumocystis carinii pneumonia in an HIV positive patient receiving nebulised pentamidine prophylaxis was missed. Transbronchial biopsies were not routinely performed and provided additional diagnostic information in only 1/6 (17%) patients. Overall, the commonest diagnoses were Pneumocystis carinii pneumonia (61%) and cytomegalovirus pneumonitis (28%). There were no complications of the procedures. In this highly selected setting of diagnostic or therapeutic uncertainty, fibreoptic bronchoscopy with bronchoalveolar lavage remains an effective and safe technique for evaluating pulmonary disease in immunocompromised patients.


Subject(s)
Bronchoalveolar Lavage Fluid , Bronchoscopy , Immunocompromised Host , Lung/pathology , Adult , Antineoplastic Agents/adverse effects , Female , HIV Infections/complications , Humans , Lung Diseases/complications , Lung Diseases/diagnosis , Male , Middle Aged , Organ Transplantation
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