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2.
PLoS One ; 10(5): e0127045, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25996915

RESUMO

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.


Assuntos
Hemiplegia/genética , ATPase Trocadora de Sódio-Potássio/genética , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Hemiplegia/fisiopatologia , Humanos , Lactente , Masculino , Sistema de Registros
3.
Muscle Nerve ; 44(2): 246-51, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21698647

RESUMO

INTRODUCTION: The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. METHODS: Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. RESULTS: The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. DISCUSSION: MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up.


Assuntos
Destreza Motora/fisiologia , Atrofias Musculares Espinais da Infância/fisiopatologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Reprodutibilidade dos Testes
4.
Pediatrics ; 123(3): e534-41, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19254988

RESUMO

OBJECTIVES: Alternating hemiplegia of childhood is a predominantly sporadic neurodevelopmental syndrome of uncertain etiology. In more than 3 decades since its description, little progress has been made in understanding its etiology or in identifying effective treatments. In 1998, in collaboration with the Alternating Hemiplegia of Childhood Foundation, an international registry was established to help document clinical outcomes and promote research efforts. PATIENTS AND METHODS: We present phenotypic data on 103 patients who met existing diagnostic criteria for alternating hemiplegia of childhood. Although some of these subjects may have been included in previously published reviews, our focus was directed toward the earliest manifestations of symptoms and evolution of features over time. Data sources included written questionnaires, face-to-face and telephone interviews, clinical examination, and medical charts. Characteristics of disease onset, medical comorbidities, episode triggers, diagnostic workup, and treatment are presented. RESULTS: Paroxysmal eye movements were the most frequent early symptom, manifesting in the first 3 months of life in 83% of patients. Hemiplegic episodes appeared by 6 months of age in 56% of infants. Background slowing shown by electroencephalography during typical paroxysmal events, including hemiplegic, tonic, or dystonic episodes was frequent (21 of 42 cases). Distinct convulsive episodes with altered consciousness believed to be epileptic in nature were reported in 41% of patients. Ataxia (96%) and cognitive impairment (100%) were frequent nonepisodic symptoms. Empiric pharmacologic treatment approaches offered little benefit in most subjects and resulted in adverse effects in 20% of patients. Prolonged episodes were completely or temporarily aborted during sleep in all subjects. CONCLUSIONS: This descriptive analysis of a large cohort of children indicates that paroxysmal ocular movements are an early, highly suggestive symptom, followed by paroxysmal episodes of focal dystonia or flaccid, alternating hemiplegia in early infancy in the majority of subjects. Current challenges in diagnosis and management contribute to poor outcomes. Early diagnosis and multicenter collaboration are needed to facilitate trials to identify more effective therapies.


Assuntos
Hemiplegia/diagnóstico , Adolescente , Fatores Etários , Ataxia/diagnóstico , Ataxia/etiologia , Encéfalo/patologia , Criança , Pré-Escolar , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Estudos de Coortes , Eletroencefalografia , Feminino , Seguimentos , Hemiplegia/etiologia , Humanos , Lactente , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Exame Neurológico , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/etiologia , Tomografia por Emissão de Pósitrons , Psicotrópicos/efeitos adversos , Psicotrópicos/uso terapêutico , Convulsões/diagnóstico , Convulsões/etiologia , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Adulto Jovem
5.
J Pediatr Rehabil Med ; 2(4): 297-307, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20467579

RESUMO

After pediatric traumatic brain injury (TBI), early prognosis of expected function is important for optimizing care. The power of several common brain injury severity measures for predicting functional outcome in children with TBI was investigated; the severity variables studied were Glasgow Coma Scale (GCS) score, time to follow commands (TFC), duration of post-traumatic amnesia (PTA), and total duration of impaired consciousness (TFC+PTA). Outcome was assessed using the Functional Independence Measure for Children (WeeFIM) at discharge from inpatient rehabilitation (n = 120) and, in a subset of children, at 3 months following discharge. Correlations and multiple linear regression analyses were conducted using GCS, TFC, PTA, and TFC+PTA to predict age-corrected WeeFIM scores. Models in which TFC and PTA duration were entered as separate variables and as a combined variable (TFC+PTA) were all significantly predictive of WeeFIM scores at discharge; however, TFC accounted for the greatest portion of variance in WeeFIM scores. Among children with moderate to severe TBI who received inpatient rehabilitation, TFC was the best predictor of general functional outcome at discharge and follow-up. Our findings highlight the need for careful and consistent assessment of TFC to assist in predicting functional outcomes as early and accurately as possible.

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