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PURPOSE: To ascertain the cause of mortality and incidence of sudden unexpected death in epilepsy (SUDEP) in patients with supernumerary isodicentric chromosome 15 (idic15). METHODS: Cases were obtained from those reported to the Dup15q Alliance (www.dup15q.org) between April 2006 and June 2012; ~709 families were registered in their database. We performed a case-control study comparing reported SUDEP cases to living patients with epilepsy from the Dup15q Alliance registry who volunteered to be interviewed to examine clinical risk factors. KEY FINDINGS: There were nineteen deaths with idic15; 17 had epilepsy, and nine deaths were due to probable or definite SUDEP (4 females, median age of death was 13.5years, range: 3-26years). Possible SUDEP occurred in 2 others. The remainder died from status epilepticus (3), pneumonia (3), aspiration (1), and drowning (1). Nonambulatory status and lack of seizure control were more common among SUDEP cases than living dup15q patients. SIGNIFICANCE: Our findings suggest that SUDEP is a common cause of death among children and young adults with isodicentric chromosome 15q11.2q13 duplications and patients with the most severe neurologic dysfunction may be at highest risk. Further studies are needed to examine if this specific genetic defect plays a role in the mechanism of SUDEP in these patients.
Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/mortalidade , Morte Súbita , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Estudos de Casos e Controles , Causas de Morte , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Convulsões/tratamento farmacológico , Convulsões/etiologia , Convulsões/mortalidade , Adulto JovemRESUMO
OBJECTIVE: Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population. METHODS: A detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in Dup15q. RESULTS: There were 95 responses from Dup15q families. For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common seizure types were tonic-clonic, atonic, myoclonic, and focal. Only 3 of 12 individuals with int dup(15) had seizures. Broad spectrum antiepileptic drugs (AEDs) were the most effective medications, but carbamazepine and oxcarbazepine were also effective, although typical benzodiazepines were relatively ineffective. There was a 24% response rate (>90% seizure reduction) to the first AED tried. For those with infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin. SIGNIFICANCE: This is the largest study assessing seizures in Duplication 15q syndrome, but because this was a questionnaire-based study with a low return rate, it is susceptible to bias. Seizures are common in idic(15) and typically difficult to control, often presenting with infantile spasms and progressing to a Lennox-Gastaut-type syndrome. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. In addition to broad spectrum AED, medications such as carbamazepine and oxcarbazepine are also relatively effective in controlling seizures in this population, suggesting a possible multifocal etiology, which may also explain the high rate of infantile spasms. Our small sample suggests a relative lack of efficacy of vigabatrin and other γ-aminobutyric acid (GABA)ergic medications, such as typical benzodiazepines, which may be attributable to abnormal GABAergic transmission resulting from the duplication of a cluster of GABAß3 receptor genes in the 15q11.2-13 region.
Assuntos
Anticonvulsivantes/uso terapêutico , Coleta de Dados/métodos , Convulsões/tratamento farmacológico , Convulsões/genética , Trissomia/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Feminino , Humanos , Masculino , Convulsões/diagnóstico , Síndrome , Resultado do TratamentoRESUMO
The objective of our study was to characterize the influence of multiple mutations in the MECP2 gene in a cohort of individuals with Rett syndrome. Further analysis demonstrated that nearly all resulted from de novo in cis mutations, where the disease severity was indistinguishable from single mutations. Our methods involved enrolling participants in the RTT Natural History Study (NHS). After providing informed consent through their parents or principal caretakers, additional molecular assessments were performed in the participants and their parents to assess the presence and location of more than one mutation in each. Clinical severity was assessed at each visit in those participants in the NHS. Non-contiguous MECP2 gene variations were detected in 12 participants and contiguous mutations involving a deletion and insertion in three participants. Thirteen of 15 participants had mutations that were in cis; four (of 13) had three MECP2 mutations; two (of 15) had mutations that were both in cis and in trans (i.e., on different alleles). Clinical severity did not appear different from NHS participants with a single similar mutation. Mutations in cis were identified in most participants; two individuals had mutations both in cis and in trans. The presence of multiple mutations was not associated with greater severity. Nevertheless, multiple mutations will require greater thought in the future, if genetic assignment to drug treatment protocols is considered.
Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/genética , Feminino , Humanos , Masculino , Pais , Síndrome de Rett/etiologiaRESUMO
Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett syndrome. As a chromatin-associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. Although neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here, we report the identification of several MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors.
Assuntos
Cromatina/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/metabolismo , Fosfosserina/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Anticorpos Fosfo-Específicos/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Proteína 2 de Ligação a Metil-CpG/química , Camundongos , Dados de Sequência Molecular , Atividade Motora , Mutação/genética , Fosforilação , Regiões Promotoras Genéticas/genética , Ligação Proteica , RatosRESUMO
We report a three generation family in which five members, three females and two males, demonstrate a 44 bp deletion (1164-1207del44) in the MECP2 gene associated with Rett syndrome, leading to a truncation of the C-terminus of the protein. Two of the three females and both males do not meet RTT criteria whereas the youngest female has classic RTT. Both males demonstrated a clear pattern of progressive involvement including dystonia. The transmitting females do not demonstrate features of RTT as a result of unbalanced X chromosome inactivation (XCI) and were only identified as carriers following the evaluation of the affected males and the girl with classic RTT. As such, accurate assessment of the precise frequency of MECP2 mutations in carrier females with mild cognitive impairment or borderline cognitive function will be under-represented unless an affected offspring is recognized. Strategies for accurate diagnosis in such instances should be considered carefully.
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Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.
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Encéfalo/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Ferro/metabolismo , Mutação , Fosfolipases A/genética , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Masculino , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/metabolismo , Fosfolipases A/química , Fosfolipases A2 , SíndromeRESUMO
Since the identification of mutations in MECP2 in girls and women with apparent Rett syndrome, numerous efforts have been made to develop phenotype-genotype correlations. These studies have produced conflicting results in part related to use of different clinical severity scales, different diagnostic criteria, and different stratification by age and mutation group as well as the possible effects of unbalanced X-chromosome inactivation. The present study applied a revised ordinal scoring system that allowed for correction for patient ages. We analyzed 85 patients with mutation in MECP2. Sixty-five (76%) had one of eight common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the methyl-binding domain (MBD) and the transcriptional repression domain (TRD). However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation including better overall score, later regression, and better language with less motoric impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. Thus, the impact of specific mutations coupled with possible variation in X-chromosome inactivation must be considered carefully in the derivation of phenotype-genotype correlations. These results emphasize the limitations of such analyses in larger mutation groups, either by type or position.
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Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Repressoras , Síndrome de Rett/genética , Idade de Início , Códon sem Sentido , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG , Mutação de Sentido Incorreto , Fenótipo , Síndrome de Rett/diagnóstico , Índice de Gravidade de DoençaRESUMO
In mammals and birds, sex differences in brain function and disease are thought to derive exclusively from sex differences in gonadal hormone secretions. For example, testosterone in male mammals acts during fetal and neonatal life to cause masculine neural development. However, male and female brain cells also differ in genetic sex; thus, sex chromosome genes acting within cells could contribute to sex differences in cell function. We analyzed the sexual phenotype of the brain of a rare gynandromorphic finch in which the right half of the brain was genetically male and the left half genetically female. The neural song circuit on the right had a more masculine phenotype than that on the left. Because both halves of the brain were exposed to a common gonadal hormone environment, the lateral differences indicate that the genetic sex of brain cells contributes to the process of sexual differentiation. Because both sides of the song circuit were more masculine than that of females, diffusible factors such as hormones of gonadal or neural origin also likely played a role in sexual differentiation.
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Encéfalo/fisiologia , Aves Canoras/fisiologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , DNA/genética , Feminino , Hormônios Esteroides Gonadais/fisiologia , Hibridização In Situ , Masculino , Modelos Neurológicos , Dados de Sequência Molecular , Ovário/anatomia & histologia , Fenótipo , Caracteres Sexuais , Cromossomos Sexuais/genética , Diferenciação Sexual , Aves Canoras/anatomia & histologia , Aves Canoras/genética , Aves Canoras/crescimento & desenvolvimento , Testículo/anatomia & histologia , Vocalização Animal/fisiologiaRESUMO
Although MECP2 was initially identified as the causative gene in classic Rett syndrome (RTT), the gene has now been implicated in several phenotypes that extend well beyond the clinically defined disorder. MECP2 mutations have been found in people with various disorders, including neonatal onset encephalopathy, X-linked recessive mental retardation (MRX), classic and atypical RTT, autism, and Angelman syndrome, as well as mildly affected females and normal carrier females. To make matters more complex, in approximately 20% of classic sporadic RTT cases and more than 50% of affected sister pairs, no mutation in MECP2 has been found. X-chromosome inactivation patterns can clearly affect the phenotypic expression in females, while the effect of the type and position of the mutation is more apparent in the broader phenotype than in RTT. Both males and females are at risk, although an excess of paternally derived mutations are found in most cases of classic RTT. Thus, because of the range of disparate phenotypes, the gene may account for a relatively large portion of mental retardation in the population.
Assuntos
Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Mutação/genética , Fenótipo , Proteínas Repressoras , Síndrome de Rett/genética , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Feminino , Triagem de Portadores Genéticos , Ligação Genética/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett/diagnóstico , Cromossomo XRESUMO
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementia arising from abnormal arteriolar vascular smooth muscle cells. CADASIL results from mutations in Notch3 that alter the number of cysteine residues in the extracellular epidermal growth factor-like repeats, important for ligand binding. It is not known whether CADASIL mutations lead to loss or gain of Notch3 receptor function. To examine the functional consequences of CADASIL mutations, we engineered 4 CADASIL-like mutations into rat Notch3 and have shown that the presence of an unpaired cysteine does not impair cell-surface expression or ligand binding.