Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.

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Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1468-2982.2007.01288.x

The Global Burden of Headache: A Documentation of Headache Prevalence and Disability Worldwide:

The blood-brain barrier: an overview: structure, regulation, and clinical implications.

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.

Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

DNA methylation has recently moved to centre stage in the aetiology of human neurodevelopmental syndromes such as the fragile X, ICF and Rett syndromes. These diseases result from the misregulation of genes that occurs with the loss of appropriate epigenetic controls during neuronal development. Recent advances have connected DNA methylation to chromatin-remodelling enzymes, and understanding this link will be central to the design of new therapeutic tools.

DNA methylation in health and disease

OBJECTIVE: To describe the prevalence and characteristics of epilepsy in patients with cerebral palsy in a tertiary center. METHODS: a total of 100 consecutive patients with cerebral palsy were retrospectively studied. Criteria for inclusion were follow-up period for at least 2 years. Types and incidence of epilepsy were correlated with the different forms of cerebral palsy. Other factors associated with epilepsy such as age of first seizure, neonatal seizures and family history of epilepsy were also analysed. RESULTS: follow-up ranged between 24 and 151 months (mean 57 months). The overall prevalence of epilepsy was 62%. Incidence of epilepsy was predominant in patients with hemiplegic and tetraplegic palsies: 70.6% and 66.1%, respectively. First seizure occurred during the first year of life in 74.2% of patients with epilepsy. Generalized and partial were the predominant types of epilepsy (61.3% and 27.4%, respectively). Thirty-three (53.2%) of 62 patients were seizure free for at least 1 year. Neonatal seizures and family history of epilepsy were associated with a higher incidence of epilepsy. CONCLUSIONS: epilepsy in cerebral palsy can be predicted if seizures occur in the first year of life, in neonatal period and if there is family history of epilepsy.

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Epilepsy in children with cerebral palsy

Status Dystonicus (SD) is characterized by generalized muscle contractions in dystonic patients. We report 5 cases of SD, two of which in patients with dystonic cerebral palsy, one in a patient with primary segmental dystonia, one in a patient with Hallervorden-Spatz syndrome and one in a patient with Wilson's disease (WD). Three patients were admitted to an intensive care unit and treated with propofol and midazolam, and two were submitted to neurosurgical procedures (bilateral pallidotomy and bilateral pallidal deep brain stimulation). Triggering factors were identified in three patients as follows: infection, stress-induced and zinc therapy for WD. On follow-up, two patients presented with significant improvement of dystonia, whereas the other three cases the clinical picture ultimately returned to baseline pre-SD condition.

/pdf/status-dystonicus-study-of-five-cases-hvzz9wsfcd.pdf

Status dystonicus: study of five cases

Sudden unexpected, unexplained death in epilepsy (SUDEP) has been reported to be responsible for 2 to 17% of all deaths in patients with epilepsy. This study was conducted to determine the circumstances of SUDEP and the autopsy findings in these patients. Fifty-three individuals whose cause of death was related to epilepsy were identified and in 30 cases relatives or friends were interviewed about the circumstances of death and other information which allowed to classify the patients as SUDEP or not. The death certificates were also reviewed. We found 20 cases of SUDEP. Most of them were found dead lying on the bed with no evidence of seizure event, and most of them had pulmonary and/or cerebral edema as the cause of death. The incidence and the risk of SUDEP can only be fully ascertained if all sudden deaths had postmortem examination. Consensus in certifying SUDEP cases would allow better accuracy in national mortality rate.

/pdf/sudden-unexpected-unexplained-death-in-epilepsy-autopsied-2ffpsxxvhd.pdf

Sudden unexpected, unexplained death in epilepsy autopsied patients

PURPOSE: The purpose of this study was to evaluate the presence of signs and symptoms of temporomandibular disorders (TMD) in children with headaches in a neuropediatric ambulatory. METHOD: Fifty patients between 4 and 18 years of age were examined: 31 had headaches (24 migraine, 4 tension type and 3 unspecific headache) and 19 formed the control group. The data collection was comprised of a structured questionnaire answered by the children's parents, and a subjective evaluation about the children’s emotional state. A specific questionnaire for TMD was applied, followed by a clinical dental examination of the children. As signs of TMD, mouth opening limitation, mandibular trajectory deviation in opening mouth, and joint noise were considered. As symptoms, pain on palpation of masseter and temporal muscles and on the poromandibular joint. RESULTS: A significant increase in signs and symptoms of TMD was found in patients with headaches when compared to the control group. There was also a significant difference in signs and symptoms of TMD according to age (increased with age) and emotional state (tense> calm). CONCLUSION: There is a higher frequency of TMD in pediatric patients with headaches; thus, it is important to look for TMD signs and symptoms in this population.

Evaluation of the signs and symptoms of temporomandibular disorders in children with headaches

The aim of the study was to detect neurological abnormalities in human immunodeficiency virus (HIV) infected children. This was achieved by a prospective evaluation, from November/1995 to April/2000, of 43 HIV infected children (group I) and 40 HIV seroreverters children (group II) through neurological exam and neurodevelopmental tests: Denver Developmental Screening Test (DDST) and Clinical Adaptive Test / Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS). A control group (III), of 67 children, were evaluated by CAT/CLAMS. Hyperactivity, irritability and hypotonia were the findings on neurological examination, without statistical differences between group I and II. On CAT/CLAMS, the group I developmental quotient (DQ) was significantly lower than the other groups. The same occurred in DDST, with group I presenting significantly more failures than group II. Nineteen HIV children of group I had brain computed tomographic scan, with abnormalities in three of them (basal ganglia calcification, white matter hypodensity and asymmetry of lateral ventricles). We conclude that in HIV infected children a neurodevelopment delay occur early in the disease, and it can be detected by screening tests.

https://www.arquivosdeneuropsiquiatria.org/wp-content/uploads/articles_xml/1678-4227-anp-S0004-282X2001000500007/1678-4227-anp-S0004-282X2001000500007.pdf

Sérgio A. Antoniuk

Papers

Epilepsy in children with cerebral palsy

Status dystonicus: study of five cases

Sudden unexpected, unexplained death in epilepsy autopsied patients

Evaluation of the signs and symptoms of temporomandibular disorders in children with headaches

Developmental milestones of vertically HIV infected and seroreverters children: follow up of 83 children