RESUMO
OBJECTIVES: Unverricht-Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients. METHODS: Nine patients with genetically proven ULD were evaluated clinically (medical history collected from patient charts, the Scale for the Assessment and Rating of Ataxia and Unified Myoclonus Rating Scale). Neurophysiological investigations included EEG, surface polymyography, long-loop C-reflexes, somatosensory evoked potentials, EEG jerk-locked back-averaging (JLBA) and oculomotor recordings. All patients underwent brain MRI. Non-parametric Mann-Whitney tests were used to compare ULD patients' oculomotor parameters with those of a matched group of healthy volunteers (HV). RESULTS: Myoclonus was activated by action but was virtually absent at rest and poorly induced by stimuli. Positive myoclonus was multifocal, often rhythmic and of brief duration, with top-down pyramidal temporospatial propagation. Cortical neurophysiology revealed a transient wave preceding myoclonus on EEG JLBA (n=8), enlarged somatosensory evoked potentials (n=7) and positive long-loop C-reflexes at rest (n=5). Compared with HV, ULD patients demonstrated decreased saccadic gain, increased gain dispersion and a higher frequency of hypermetric saccades associated with decreased peak velocity. CONCLUSION: A homogeneous motor pattern was delineated that may represent a ULD clinical and neurophysiological signature. Clinical and neurophysiological findings confirmed the pure cortical origin of the permanent myoclonus. Also, oculomotor findings shed new light on ULD pathophysiology by evidencing combined midbrain and cerebellar dysfunction.
Assuntos
Síndrome de Unverricht-Lundborg/fisiopatologia , Adolescente , Adulto , Idade de Início , Ataxia/etiologia , Ataxia/fisiopatologia , Encéfalo/diagnóstico por imagem , Criança , Eletroencefalografia , Eletromiografia , Potenciais Somatossensoriais Evocados , Movimentos Oculares , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mioclonia/diagnóstico por imagem , Mioclonia/fisiopatologia , Exame Neurológico , Músculos Oculomotores/fisiopatologia , Movimentos Sacádicos , Síndrome de Unverricht-Lundborg/diagnóstico , Adulto JovemRESUMO
Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.
Assuntos
Epilepsia/genética , Mutação , Receptores de GABA-A/genética , Sequência de Aminoácidos , Segregação de Cromossomos , Sequência Conservada , Condutividade Elétrica , Epilepsia Neonatal Benigna/genética , Epilepsia do Lobo Frontal/genética , Epilepsia Generalizada/genética , Feminino , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Subunidades Proteicas , Convulsões Febris/genética , Homologia de Sequência de AminoácidosRESUMO
INTRODUCTION: Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI). OBJECTIVE: To characterise in more detail the mutation spectrum associated with Dravet syndrome. METHODS: A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened. RESULTS: SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients. CONCLUSION: These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.
Assuntos
Epilepsias Mioclônicas/genética , Mutação , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Feminino , Deleção de Genes , Rearranjo Gênico , Humanos , Lactente , Recém-Nascido , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1 , Técnicas de Amplificação de Ácido Nucleico , Análise de Sequência de DNARESUMO
Inborn errors of metabolism (IEMs) represent poorly known causes of epilepsy in adulthood. Although rare, these are important to recognize for several reasons: some IEMs respond to specific treatments, some antiepileptic drugs interfering with metabolic pathways may worsen the clinical condition, and specific genetic counselling can be provided. We review IEMs potentially revealed by epilepsy that can be encountered in an adult neurology department. We distinguished progressive myoclonic epilepsies (observed in some lysosomal storage diseases, respiratory chain disorders and Lafora disease), from other forms of epilepsies (observed in disorders of intermediary metabolism, including porphyrias, creatine metabolism defects, glucose transporter (GLUT-1) deficiency, Wilson disease or succinic semialdehyde dehydrogenase deficiency). We propose a diagnostic approach and point out clinical, radiological and electrophysiological features that suggest an IEM in an epileptic patient.
Assuntos
Epilepsia/diagnóstico , Epilepsia/etiologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Adulto , Árvores de Decisões , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/complicações , Convulsões/complicações , SíndromeRESUMO
INTRODUCTION: Gaucher's disease (GD), the most prevalent inherited lysosomal storage disorder, is caused by deficient glucocerebrosidase activity. The resulting accumulation of glucocerebrosides in lysosomes of macrophages leads to hepatosplenomegaly, anemia, thrombocytopenia, and various bone manifestations. Gaucher's disease is classified into 3 types based on the nature of its effects on the central nervous system. Type 1, the most common variant, is classically nonneuronopathic. However, the occurrence of Parkinsonism seems to be more frequent in type I Gaucher's disease than in the general population. Furthermore, heterozygotes for certain glucocerebrosidase gene mutations have a higher risk to develop Parkinson's disease. OBSERVATIONS: We report our experience about 9 patients with Gaucher's disease and their association with neurological manifestations. CONCLUSION: These recent data may discuss Gaucher's classification and the existence of a continuum between neurologic and non-neurologic forms of the disease.
Assuntos
Doença de Gaucher/classificação , Doença de Gaucher/fisiopatologia , Sistema Nervoso/fisiopatologia , Adulto , Idade de Início , Idoso , Feminino , Glucosilceramidase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/classificação , Transtornos Parkinsonianos/complicações , Fenótipo , Reflexo Anormal , Tremor/complicaçõesRESUMO
Neuronal intranuclear inclusions were recently found in the brain of patients with inherited neurodegenerative disorders characterized by the expansion of a polyglutamine stretch in the mutated protein. These inclusions are ubiquitinated and, for some of these diseases, the presence of the mutated protein could be also identified. Using immunohistochemistry, we show here that ubiquitinated intranuclear inclusions are also observed postmortem in the brain of patients suffering from Huntington's disease characterized by small polyglutamine expansions and adult onset. We were, however, unable to detect the mutated form of huntingtin in these inclusions. These intranuclear inclusions were detected only in the affected cerebral regions, suggesting that their presence is probably linked to the neurodegenerative process.
Assuntos
Núcleo Celular/ultraestrutura , Doença de Huntington/patologia , Corpos de Inclusão/ultraestrutura , Proteínas do Tecido Nervoso/genética , Neurônios/ultraestrutura , Proteínas Nucleares/genética , Adulto , Idade de Início , Anticorpos Monoclonais , Estudos de Casos e Controles , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Proteínas do Tecido Nervoso/análise , Proteínas Nucleares/análise , Repetições de Trinucleotídeos , Ubiquitinas/análiseRESUMO
Major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly spectacular with respect to idiopathic epilepsies, with the discovery that mutations in ion channel subunits are implicated. However, important advances have also been made in many inherited symptomatic epilepsies, for which direct molecular diagnosis is now possible, simplifying previously complex investigations, it is expected that identification of the genes implicated in familial forms of epilepsies will lead to a better understanding of the underlying pathophysiological mechanisms of these disorders and to the development of experimental models and new therapeutic strategies, in this article, we review the clinical and genetic data concerning most of the inherited human epilepsies.
RESUMO
Major advances have recently been made in the understanding of the genetic bases of monogenic inherited epilepsies. For several idiopathic epilepsies, mutations in genes encoding subunits of ion channels or ligand receptors have been demonstrated. This is the case for some generalized idiopathic epilepsies and generalized epilepsies associated with febrile seizures. In this Article, we review the recent clinical and genetic data of these forms of epilepsy.
Assuntos
Epilepsia/genética , Epilepsia/fisiopatologia , Canais Iônicos/fisiologia , Convulsões Febris/genética , Convulsões Febris/fisiopatologia , Canais de Cloro CLC-2 , Criança , Canais de Cloreto/genética , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Humanos , Mutação/fisiologia , Epilepsia Mioclônica Juvenil/genética , Receptores de GABA-A/genéticaRESUMO
Familial encephalopathy with neuroserpin inclusion bodies is a recently described neurodegenerative disease that is responsible for progressive myoclonic epilepsy or presenile dementia. In a French family with the S52R mutation of the neuroserpin gene, progressive myoclonic epilepsy was associated with a frontal syndrome. The typical cerebral inclusions (Collins bodies) were abundant in the frontal cortex and in the head of the caudate nucleus but spared the cerebellum.
Assuntos
Substituição de Aminoácidos , Demência/genética , Lobo Frontal/fisiopatologia , Mutação de Sentido Incorreto , Epilepsias Mioclônicas Progressivas/genética , Neuropeptídeos/genética , Mutação Puntual , Serpinas/genética , Adulto , Demência/epidemiologia , Éxons/genética , Feminino , França/etnologia , Lobo Frontal/patologia , Genótipo , Humanos , Corpos de Inclusão , Masculino , Epilepsias Mioclônicas Progressivas/epidemiologia , Linhagem , Fenótipo , Suíça , NeuroserpinaAssuntos
Transtorno Autístico/epidemiologia , Epilepsia/epidemiologia , Adolescente , Adulto , Transtorno Autístico/psicologia , Transtorno Autístico/terapia , Dano Encefálico Crônico/epidemiologia , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Epilepsia/psicologia , Epilepsia/terapia , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/psicologia , Deficiência Intelectual/terapia , Masculino , Exame Neurológico , Prognóstico , Adulto JovemRESUMO
Huntington's disease is an autosomal dominant disorder with degeneration of medium size striatal neurones. As the disease evolves, other neuronal populations are also progressively affected. A transgenic mouse model of the disease (R6/2) that expresses exon 1 of the human Huntington gene with approximately 150 CAG repeats has been developed, but GABA concentrations are reported to be normal in the striatum of these animals. In the present study, we analysed the status of GABAergic systems by means of glutamic acid decarboxylase (GAD)67 mRNA in situ hybridization in the brain of R6/2 transgenic mice and wild-type littermates. We show that GAD67 expression is normal in the striatum, cerebellum and septum but decreased in the frontal cortex, parietal cortex, globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata of R6/2 mice. These data, which may, in part, account for the behavioural changes seen in these animals, indicate that at 12.5 weeks of age the pathological features seen in the mice differ from those seen in humans with Huntington's disease.
Assuntos
Encéfalo/metabolismo , Glutamato Descarboxilase/genética , Doença de Huntington/metabolismo , Isoenzimas/genética , RNA Mensageiro/metabolismo , Animais , Encéfalo/parasitologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Doença de Huntington/patologia , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Expansão das Repetições de TrinucleotídeosRESUMO
An expanded and unstable CAG repeat in the coding region of the MJD1 gene is the mutation responsible for spinocerebellar ataxia 3/Machado-Joseph disease. In order to determine whether there was a higher degree of instability in affected regions, the size of the expanded CAG repeat was analyzed in different regions of the central nervous system, in two unrelated SCA3/MJD patients. The degree of somatic mosaicism was quantified and compared to that in a SCA1 patient. Instability of the expanded CAG repeat was observed in peripheral tissues as well as in CNS of the three patients, but there was no correlation between the degree of mosaicism and the selective vulnerability of CNS structures. As in the other diseases caused by expanded CAG repeats, a lower degree of mosaicism was found in the cerebellar cortex of both SCA1 and SCA3/MJD patients, probably reflecting specific properties of this structure. In SCA3/MJD, the degree of mosaicism seemed to correlate with age at death rather than with the size of the expanded CAG repeat. Finally, somatic instability was more pronounced in SCA1 than in SCA3/MJD patients.
Assuntos
Doença de Machado-Joseph/genética , Mosaicismo , Repetições de Trinucleotídeos , Adulto , Ataxina-1 , Ataxinas , Autorradiografia , Química Encefálica/genética , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genéticaRESUMO
Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.
Assuntos
Núcleo Celular/patologia , Corpos de Inclusão/patologia , Proteínas do Tecido Nervoso/genética , Degenerações Espinocerebelares/patologia , Ataxina-7 , Encéfalo/patologia , Núcleo Celular/química , Criança , Glutamina/genética , Glutamina/metabolismo , Humanos , Imuno-Histoquímica , Corpos de Inclusão/química , Masculino , Neurônios/química , Neurônios/patologia , Neuropeptídeos/análise , Proteínas Nucleares/análiseRESUMO
We report a clinical and genetic study of a family with a phenotype resembling generalized epilepsy with febrile seizures plus (GEFS+), described by Berkovic and colleagues. Patients express a very variable phenotype combining febrile seizures, generalized seizures often precipitated by fever at age >6 years, and partial seizures, with a variable degree of severity. Linkage analysis has excluded both the beta 1 subunit gene (SCN1B) of a voltage-gated sodium (Na+) channel responsible for GEFS+ and the two loci, FEB1 and FEB2, previously implicated in febrile seizures. A genomewide search, under the assumption of incomplete penetrance at 85% and a phenocopy rate of 5%, permitted identification of a new locus on chromosome 2q21-q33. The maximum pairwise LOD score was 3.00 at recombination fraction 0 for marker D2S2330. Haplotype reconstruction defined a large (22-cM) candidate interval flanked by markers D2S156 and D2S2314. Four genes coding for different isoforms of the alpha-subunit voltage-gated sodium channels (SCN1A, SCN2A1, SCN2A2, and SCN3A) located in this region are strong candidates for the disease gene.
Assuntos
Cromossomos Humanos Par 2/genética , Epilepsia Generalizada/genética , Convulsões Febris/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Mapeamento Cromossômico , Epilepsia Generalizada/epidemiologia , Epilepsia Generalizada/fisiopatologia , Feminino , França/epidemiologia , Marcadores Genéticos/genética , Haplótipos/genética , Humanos , Lactente , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Penetrância , Convulsões Febris/epidemiologia , Convulsões Febris/fisiopatologia , Canais de Sódio/genéticaRESUMO
Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion of a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mutation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution and intracellular location as normal huntingtin, we analyzed immunohistochemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous throughout the brain, but is not limited to vulnerable neurons in Huntington's disease, supporting the hypothesis that the presence of the mutated huntingtin in a neuron is not in itself sufficient to lead to neuronal death. Moreover, whereas normal huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.
Assuntos
Química Encefálica , Doença de Huntington/metabolismo , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Repetições de Trinucleotídeos , Adulto , Idoso , Especificidade de Anticorpos , Morte Celular/genética , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas do Tecido Nervoso/imunologia , Proteínas Nucleares/imunologiaRESUMO
Expansion of trinucleotide CAG repeats coding for polyglutamine has been implicated in five neurodegenerative disorders, including spinocerebellar ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms of type I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibody which specifically recognizes large polyglutamine tracts, particularly those that are expanded, we recently reported the detection of proteins with pathological glutamine expansions in lymphoblasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II. We now have screened a large series of patients with ADCA or isolated cases with cerebellar ataxia, for the presence of proteins with polyglutamine expansions. A 150 kDa SCA2 protein was detected in 16 out of 40 families with ADCA type I. This corresponds to 24% of all ADCA type I families, which is much more frequent than SCA1 in this series of patients (13%). The signal intensity of the SCA2 protein was negatively correlated to age at onset, as expected for an expanded and unstable trinucleotide repeat mutation. The disease segregated with markers closely linked to the SCA2 locus in all identified SCA2 families. In addition, a specific 130 kDa protein, which segregated with the disease, was detected in lymphoblasts of patients from nine families with ADCA type II. It was also visualized in the cerebral cortex of one of the patients, demonstrating its translation in the nervous system. Finally, no new disease-related proteins containing expanded polyglutamine tracts could be detected in lymphoblasts from the remaining patients with ADCA or isolated cases with cerebellar ataxia.