Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.

Discinesia paroxística não cinesiogênica: relato de caso / Paroxysmal non-kinesigenic dyskinesia: case report

Modelo do estudo: Relato de caso. Importância do problema e comentários: A discinesia paroxística não cinesiogênica é um tipo de discinesia paroxística. É caracterizada por movimentos involuntários unilaterais ou bilaterais, do tipo coreico, distônico, balístico ou misto. É uma desordem rara e o diagnóstico precoce é crucial para seu tratamento e melhoria na qualidade de vida do indivíduo. O presente estudo relata um caso de Discinesia Paroxística Não Cinesiogênica e seus achados clínicos, além de apresentar breve revisão da literatura (AU)

Study type: Case report. Relevance and comments: Paroxysmal non-kinesigenic dyskinesia is a type of paroxysmal dyskinesia. It is characterized by involuntary unilateral or bilateral movements, of the choreic, dystonic, ballistic or mixed type. It is a rare disorder and the early diagnosis is crucial for the treatment and improvement of the individual's quality of life. The present report illustrates a case of paroxysmal non-kinesigenic dyskinesia and clinical findings, as well as a brief review of the literature (AU)

Encefalopatia por deficiência de GLUT-1: relato de caso / Encephalopathy by GLUT-1 deficiency: case report

RESUMO: Importância do problema: A Síndrome da Deficiência do Transportador de Glicose tipo 1 (GLUT1DS), descrita pela primeira vez por De Vivo em 1991, é causada por um deficitário transporte de glicose na barreira hematoencefálica e nos astrócitos devido à mutações na maioria das vezes de novo heterozigóticas no gene SLC2A1, responsável pela codificação do transportador de glicose tipo 1 (GLUT-1). Essa mutação limita a disponibilidade de glicose cerebral, levando a sua deficiência energética, sendo o mecanismo gerador de suas manifestações clínicas. Os sintomas sugestivos são convulsões, atraso no desenvolvimento, microcefalia, hipotonia, espasticidade e complexas alterações no movimento, consistindo de ataxia e distonia. Em pacientes GLUT1DS, substratos energéticos alternativos são de fundamental importância. Inúmeros trabalhos recomendam a utilização da dieta cetogênica de maneira imperiosa como mecanismo padrão ouro de tratamento. Esta, nos primeiros anos de vida em pacientes com GLUT1DS, garante um melhor resultado cognitivo e melhora nos aspectos psicomotores. Comentários: A GLUT1DS, por ser uma doença de recente descoberta, ter poucos casos descritos na literatura, características clínicas heterogêneas e falta substancial de casuística é muitas vezes subdiagnosticada. Nesse sentido, critérios de suspeição e algoritmos diagnósticos se fazem necessários. Dessa maneira, o objetivo deste artigo é chamar a atenção da comunidade médica brasileira para essa síndrome, com vistas a incrementar seu diagnóstico e melhorar o prognóstico de epilepsias de difícil controle (AU)

ABSTRACT: Glut-1 deficiency syndrome (GLUT1DS), first described by De Vivo in 1991, is caused by a deficient glucose transport in the blood-brain barrier and astrocytes by heterozygous mutations, mostly de novo, in the gene SLC2A1 encoding the glucose transporter type 1 (GLUT-1). This mutation limits the availability of cerebral glucose leading to energy deficiency, which is the underlying mechanism of the clinical manifestations. The suggestive symptoms are convulsions, developmental delay, microcephaly, hypotonia, spasticity, and complex changes in movement consisting of ataxia and dystonia. In GLUT1DS patients, altern ative energy substrates are of fundamental importance. Numerous studies recommend the use of a ketogenic diet in an imperative manner as a gold standard therapy method. This diet, in the first years of life in patients with GLUT1DS, guarantees a better cognitive result and improvement in psychomotor aspects. Because GLUT1DS is a disease of recent discovery, with a few cases described in the literature, heterogeneous clinical features and a substantial lack of casuistry is often underdiagnosed. In this sense, suspicion criteria and diagnostic algorithms become necessary. Thus, the purpose of this article is to draw the attention of the Brazilian medical community to this syndrome to increase its diagnosis and improve the prognosis of difficult-to-control epilepsy (AU)

Pediatric multiple sclerosis-a challenging demyelinating disease: case report and brief review of the literature.

Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) of unknown etiology. The peak onset is between age 20 and 40 years and usually affects more women than men. Although much knowledge has been achieved on the diagnosis and treatment of adult patients with MS, it remains a matter of debate and controversy in childhood. We present a case of MS in 9-year-old girl, review the current state of the knowledge on pediatric MS, and discuss the available tools for the diagnosis and treatment.

Abscesso cerebral piogênico por Serratia marcescens em um recém-nascido prematuro: relato de caso / Pyogenic brain abscess caused by Serratia marcescens in a Brazilian premature neonate: case report

O abscesso cerebral configura-se como uma grave doença infecciosa do sistema nervoso central ainda associada a significativa morbidade e mortalidade apesar dos avanços neurocirúrgicos, de neuroimagem, cuidados médicos intensivos e antibióticos. O tratamento do abscesso cerebral normalmente envolve a drenagem cirúrgica, antibioticoterapia apropria e direcionada ao agente principal e erradicação do foco primário. Embora incomuns na população pediátrica, os abscessos cerebrais apresentam uma importância particular na nesta faixa etária devido as potenciais conseqüências neurológicas devastadoras, especialmente nos prematuros. O objetivo do presente trabalho e relatar o caso de uma recém-nascido prematuro brasileiro com abscesso cerebral causado por Serratia marcescens e discutir as abordagens diagnosticas e terapêuticas. A suspeita precoce, o diagnostico apropriado e a imediata avaliação neurocirúrgica associados ao tratamento antibiótico adequado e de amplo espectro representam os passos essenciais para o manejo adequado e seguro de pacientes pediátricos de elevado risco.

Prenatal exposure to tobacco and alcohol are associated with chronic daily headaches at childhood: A population-based study.

The influence of prenatal events on the development of headaches at childhood has not been investigated and is the scope of our study. Of 2,173 children identified as the target sample, consents and analyzable data were provided by 1,440 (77%). Parents responded to a standardized questionnaire with a validated headache module and specific questions about prenatal exposures. Odds of chronic daily headache (CDH) were significantly higher when maternal tabagism was reported. When active and passive smoking were reported, odds ratio (OR) of CDH were 2.29 [95% confidence intervals (CI)=1.6 vs. 3.6)]; for active tabagism, OR=4.2 (95% CI=2.1-8.5). Alcohol use more than doubled the chance of CDH (24% vs. 11%, OR=2.3, 95% CI=1.2-4.7). In multivariate analyses, adjustments did not substantially change the smoking/CDH association. Prenatal exposure to tobacco and alcohol are associated with increased rates of CDH onset in preadolescent children.

Uncommon headache syndromes in the pediatric population.

Headache is one of the most common symptoms in children and adolescents, and headache syndromes are an important reason for medical consulting. According to the second edition of the International Classification of Headache Disorders, there are 196 possible headache diagnoses, of which 113 have been described in pediatric population. Herein, we focus on unusual pediatric headache syndromes. We group them as headaches with migraine features, short-duration headaches with autonomic features, short-duration headaches without autonomic features, and potentially ominous forms of headaches. Although rare as single entities, providers focusing on pediatric headaches certainly will face some of these headaches and need to be comfortable on the diagnostic approach.

Prenatal exposure to tobacco and alcohol are associated with chronic daily headaches at childhood: A population-based study / Tabagismo e ingestão alcoólica pré-natal estão associados à cefaleia crônica diária na infância: um estudo de base populacional

The influence of prenatal events on the development of headaches at childhood has not been investigated and is the scope of our study. Of 2,173 children identified as the target sample, consents and analyzable data were provided by 1,440 (77 percent). Parents responded to a standardized questionnaire with a validated headache module and specific questions about prenatal exposures. Odds of chronic daily headache (CDH) were significantly higher when maternal tabagism was reported. When active and passive smoking were reported, odds ratio (OR) of CDH were 2.29 [95 percent confidence intervals (CI)=1.6 vs. 3.6)]; for active tabagism, OR=4.2 (95 percent CI=2.1-8.5). Alcohol use more than doubled the chance of CDH (24 percent vs. 11 percent, OR=2.3, 95 percent CI=1.2-4.7). In multivariate analyses, adjustments did not substantially change the smoking/CDH association. Prenatal exposure to tobacco and alcohol are associated with increased rates of CDH onset in preadolescent children.

A influência de eventos pré-natais na fisiopatogenia das cefaleias na infância ainda não foi investigada e é o objetivo desse estudo. Da amostra-alvo de 2.173 crianças, um consentimento pós-informado e dados suficientes para as análises foram obtidos de 1.440 (77 por cento). Os pais responderam a um questionário padrão com um módulo de cefaleia validado na população brasileira e questões específicas sobre antecedentes pré-natais. O risco de cefaleia crônica diária (CCD) foi significativamente maior nas crianças cujas mães fumaram durante a gestação. Quando presentes tabagismo ativo e passivo, o risco (OR) de CCD foi de 2,29 [intervalo de confiança (IC) de 95 por cento=1,6-3,6)]; para tabagismo ativo, OR=4,2 (IC 95 por cento=2,1-8,5). O uso de álcool durante a gestação dobrou o risco de CCD (24 por cento vs. 11 por cento, OR=2,3, IC 95 por cento=1,2-4,7). Nas análises multivariadas, os ajustes não modificaram, substancialmente a associação entre tabagismo materno durante a gestação e CCD. A exposição pré-natal ao tabaco e ao álcool encontra-se associada à CCD de início na infância.

Childhood periodic syndromes: a population-based study.

The objective of the present study was to estimate the prevalence and relative risk of symptoms suggestive of childhood periodic syndrome in migraine, migraine subtypes, and tension-type headache, relative to control subjects. The target population was all children (age 5-12 years) enrolled in public elementary schools in one Brazilian city (n = 2173). Consent was obtained for 1994 children; analyzable data were available for 1906 children, for a final sample of 1113 children with migraine, tension-type headache, or no headache. Parents were interviewed using validated questionnaires. Headache diagnosis was assigned according to the International Classification of Headache Disorders, 2nd edition. Relative risk of symptoms was drawn by headache categories relative to controls. For episodic migraine, the relative risk of all symptoms except nocturnal enuresis was significantly increased: motion sickness, recurrent limb pain, recurrent abdominal pain, and parasomnias, such as sleep talking, somnambulism, and bruxism. For tension-type headache, only nocturnal enuresis and motion sickness were not more common than in controls. In multivariate analyses, any interictal symptom was independently associated with any headache (P < 0.001), migraine headaches (P < 0.001), and tension-type headaches (P < 0.01). These findings indicate that interictal symptoms suggestive of childhood periodic syndromes are common in the population, and are associated with migraine and specific migraine subtypes, but also with tension-type headache.

Migraine, tension-type headache, and attention-deficit/hyperactivity disorder in childhood: a population-based study.

OBJECTIVES: Primary headache syndromes (eg, migraine and tension-type headache [TTH]) and attention-deficit/hyperactivity disorder (ADHD) are prevalent in childhood and may cause impairment in social and academic functioning. We tested if ADHD or its symptoms are associated with specific headache syndromes or with headache frequency. STUDY DESIGN: Cross-sectional epidemiological study with direct interviews to parents and teachers using validated and standardized questionnaires. SETTING: Populational study. PARTICIPANTS: Children aged 5 to 11 years (n = 1856). OUTCOME MEASURES: Prevalence of ADHD as a function of headache status in crude and adjusted analyses. RESULTS: The prevalence of migraine was 3.76%. Infrequent episodic TTH occurred in 2.3% of the sample, and frequent episodic TTH occurred in 1.6%. The prevalence of ADHD was 6.1%. The prevalence of ADHD was not significantly different by headache category. For hyperactivity-impulsivity symptoms, the prevalence was 8.1% in children without headache, 23.7% in children with migraine (relative risk [RR], 2.6; 95% confidence interval [CI], 1.6-4.2), and 18.4% in children with probable migraine (RR, 2.1; 95% CI, 1.4-3.2). For inattention, no significant differences were seen. In multivariate analyses, ADHD or inattention symptoms were not predicted by headache subtypes or headache frequency. Hyperactivity-impulsivity symptoms were significantly associated with any headache (P < 0.01), TTH (P < 0.01), or migraine (P < 0.001). CONCLUSION: Migraine and TTH are not comorbid to ADHD overall, but are comorbid to hyperactive-impulsive behavior. Providers and educators should be aware of the association.

Primary headaches in childhood--a population-based study.

The aim of this study was to estimate the prevalence of primary headaches in pre-adolescent children, as well as headache frequency and days of treatment in this population. Sample consisted of 1994 children (aged 5-12 years). Parents were interviewed by a paediatric headache specialist using a questionnaire that allowed the classification of headaches using the criteria of the Second Edition of the International Classification of Headache Disorders. The most severe headache type was classified (mutually-exclusive diagnoses). Prevalence and prevalence ratios were calculated overall, as well as by age, gender and race. The overall prevalence of migraine was 3.76%, non-significantly higher in boys (3.9%) than in girls (3.6%). Prevalence of probable migraine was significantly higher than the prevalence of migraine for all ages (overall prevalence of 17.1%). Chronic migraine (CM) happened in 0.8% (girls, 1.15%; boys, 0.5%). Infrequent episodic tension-type headache (ETTH) happened in 2.3% of the sample while prevalence of frequent ETTH was 1.6%. Probable TTH happened in 13.5%. Most children with migraine had consulted a medical doctor because of their headaches, and the proportion was higher among children with CM (93.7%). Prevalence of primary headaches is high in young children. Probable diagnoses are more common than full diagnoses. Consultation rates are elevated.

Migrânea na infância e adolescência: avanços que contribuem para a prática clínica / Migraine in childhood and adolescence: advances contributing to clinical practice

A pesquisa das cefaleias na infância vive hoje uma grande evolução de conceitos. O reconhecimento das numerosas peculiaridades observadas na migrânea na infância e adolescência, consequência da interação de processos neuroquímicos e maturacionais subjacentes, pode ajudar-nos a compreender melhor os processos de dor em um sistema nervoso em franco desenvolvimento. Com esse racional, valemo-nos desta revisão para apresentar evidências científicas recentes que refletem esses avanços na compreensão da migrânea e de outras cefaleias na infância e adolescência, sem perder de vista a aplicabilidade desses novos conceitos na prática clínica diária. A partir de dados inéditos do Projeto Atenção Brasil, um amplo estudo epidemiológico sobre cefaleia, saúde mental e hábitos em crianças e adolescentes brasileiros, os autores discutem os principais resultados recentemente publicados por eles na literatura sobre epidemiologia das cefaleias primárias, exposições no período pré-natal e risco de cefaleia crônica diária na infância, agregação familiar das cefaleias primárias e síndromes periódicas da infância. Um resumo sobre tratamento sintomático e profilático da migrânea na infância é apresentado ao final, bem como as implicações desses avanços para a prática clínica diária.

Frequency of headaches in children is influenced by headache status in the mother.

BACKGROUND: Migraine aggregates within families. Nonetheless the familial aggregation of chronic daily headaches (CDH) and of episodic headaches of different frequencies has been very poorly studied. Accordingly herein we test the hypothesis that frequency of primary headaches aggregates in the family. METHODS: Sample consisted of 1994 children (5-12 years) identified in the population. Validated questionnaires were used to interview the parents. Crude and adjusted prevalences of low-frequency (1-4 headache days/month), intermediate-frequency (5-9 days/month), high-frequency (10-14 headache days/month), and CDH (15 or more headache days/month) in children were calculated as a function of headaches in the mother. RESULTS: Frequency of headaches in the mother predicted frequency of headaches in the children; when the mother had low frequency headaches, the children had an increased chance to have low or intermediate headache frequency (relative risk = 1.4, 1.2-1.6) but not CDH. When the mother had CDH, risk of CDH in the children was increased by almost 13-fold, but the risk of infrequent headaches was not increased. In multivariate models, headaches in the children were independently predicted by headaches in the mother (P < .001); headache frequency in the children was also predicted by frequency in the mother (P < .001). CONCLUSIONS: Frequency of headaches in children is influenced by frequency of headaches in the mother and seems to aggregate in families. Future studies should focus on the determinants of headache aggregation, including genetic and non-genetic factors.

An epidemiologic study of headaches in Brazilian schoolchildren with a focus on pain frequency.

The purpose of this study was to assess the prevalence and frequency of the headaches in Brazilian schoolchildren. A cross-sectional study was conducted between March and November 2004 in São José do Rio Preto, São Paulo State, Brazil. A sample of 5,232 children from elementary schools was selected using proportional stratified sampling method. To collect data, a questionnaire was handed out in the schools to the schoolchildren to be answered by parents or guardians. From the total answers received, 84.2% reported headache complaints during the last year. There were significant complaint differences between males and females. Females were reported as having more frequent headaches than males with daily ones occurring twice as many times. A greater headache frequency was also reported for increasing age. The study has shown that headache prevalence was high, with a predominantly higher frequency (monthly, weekly and daily) with girls and older age groups.

An epidemiologic study of headaches in brazilian schoolchildren with a focus on pain frequency / Um estudo epidemiológico de cefaléias em escolares brasileiros, com foco sobre a frequência da dor

The purpose of this study was to assess the prevalence and frequency of the headaches in Brazilian schoolchildren. A cross-sectional study was conducted between March and November 2004 in São José do Rio Preto, São Paulo State, Brazil. A sample of 5,232 children from elementary schools was selected using proportional stratified sampling method. To collect data, a questionnaire was handed out in the schools to the schoolchildren to be answered by parents or guardians. From the total answers received, 84.2 percent reported headache complaints during the last year. There were significant complaint differences between males and females. Females were reported as having more frequent headaches than males with daily ones occurring twice as many times. A greater headache frequency was also reported for increasing age. The study has shown that headache prevalence was high, with a predominantly higher frequency (monthly, weekly and daily) with girls and older age groups.

O objetivo deste estudo foi avaliar a prevalência e frequência de cefaléia em escolares brasileiros. Um estudo transversal foi conduzido entre Março e Novembro de 2004 em São José do Rio Preto, Estado de São Paulo, Brasil. Uma amostra de 5.232 crianças das escolas foi selecionada utilizando método de amostragem estratificada proporcional. Para a coleta dos dados, um questionário foi entregue nas escolas aos estudantes para ser respondida pelos pais e/ou responsáveis. Do total de respostas recebidas, 84,2 por cento relataram cefaléia durante o último ano. Houve diferenças significativas na frequência da queixa de cefaléia entre meninos e meninas. As meninas relataram cefaléias mais frequentes do que os meninos, com prevalência de cefaléias diárias duas vezes maior em meninas. Uma maior frequência de cefaléia foi também relatada com o aumento da idade. O estudo demonstrou que a prevalência de cefaléia foi alta, com uma maior frequência (mensais, semanais e diárias) em meninas e no grupo etário mais velho.

Studying the evolution and the magnetic resonance findings of reversible posterior leukoencephalopathy in children.

PURPOSE: To describe the evolution and the magnetic resonance imaging (MRI) findings of the reversible posterior leukoencephalopathy (RLPS) in children. METHOD: Nine children with neurologic symptoms and sudden increase of the arterial pressure were studied by brain MRI. RESULTS: All children evaluated had lesions seen on FLAIR-weighted images of the parietal-occipital regions. Other regions were also involved. Four patients presented restriction on diffusion-weighted images and only two with reduction of the apparent diffusion coefficient (ADC), which evolved with neurologic sequels and persistence of the lesions on the control examination. The other patients had complete regression of the lesions after therapy. CONCLUSION: MRI is important to suggest the diagnosis of RPLS in patients with arterial hypertension and unspecific neurologic symptoms. Moreover, the outcome is not favorable all the time and the association of D-WI with ADC can be an instrument capable of predicting irreversible lesions.