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Neurology ; 92(22): e2594-e2603, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31053667


OBJECTIVE: To characterize hand stereotypies (HS) in a large cohort of participants with Rett syndrome (RTT). METHODS: Data from 1,123 girls and women enrolled in the RTT Natural History Study were gathered. Standard tests for continuous and categorical variables were used at baseline. For longitudinal data, we used repeated-measures linear and logistic regression models and nonparametric tests. RESULTS: HS were reported in 922 participants with classic RTT (100%), 73 with atypical severe RTT (97.3%), 74 with atypical mild RTT (96.1%), and 17 females with MECP2 mutations without RTT (34.7%). Individuals with RTT who had classic presentation or severe MECP2 mutations had higher frequency and earlier onset of HS. Heterogeneity of HS types was confirmed, but variety decreased over time. At baseline, almost half of the participants with RTT had hand mouthing, which like clapping/tapping, decreased over time. These 2 HS types were more frequently reported than wringing/washing. Increased HS severity (prevalence and frequency) was associated with worsened measures of hand function. Number and type of HS were not related to hand function. Overall clinical severity was worse with decreased hand function but only weakly related to any HS characteristic. While hand function decreased over time, prevalence and frequency of HS remained relatively unchanged and high. CONCLUSIONS: Nearly all individuals with RTT have severe and multiple types of HS, with mouthing and clapping/tapping decreasing over time. Interaction between HS frequency and hand function is complex. Understanding the natural history of HS in RTT could assist in clinical care and evaluation of new interventions.

Am J Med Genet A ; 179(7): 1276-1286, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31124279


Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

Brain Dev ; 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30217666


INTRODUCTION: Rett syndrome (RTT) is a complex neurodevelopmental disorder with known behavioral abnormalities, both internalizing (e.g., anxiety, social withdrawal) and externalizing (e.g., aggression, self-abuse). However, a broad evaluation of behavioral abnormalities in a large cohort is lacking. OBJECTIVE: In this report, we describe profiles of internalizing and externalizing behaviors in individuals evaluated in the multi-center U.S. Rett Natural History Study. METHODS: Cross-sectional and longitudinal data were collected from 861 females with RTT and from 48 females who have MECP2 mutations without meeting criteria for RTT. Standard statistical methods including linear regression evaluated internalizing behavioral components from the Child Health Questionnaire (CHQ-PF50) and externalizing components from the Motor Behavioral Assessment (MBA). RESULTS: We found mildly to moderately severe internalizing behaviors in nearly all individuals with RTT, while externalizing behaviors were mild and uncommon. Internalizing behavior in RTT was comparable to groups with psychiatric disorders. Participants with mixed (internalizing and externalizing) behaviors were younger and less affected overall, but showed prominent self-injury and worsening internalizing behaviors over time. CONCLUSIONS: This study revealed that internalizing behaviors are common at a clinically significant level in RTT. Understanding clinical features associated with behavioral profiles could guide treatment strategies.

Expert Opin Orphan Drugs ; 4(10): 1043-1055, 2016 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28163986


Introduction: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that primarily affects females, typically resulting in a period of developmental regression in early childhood followed by stabilization and severe chronic cognitive, behavioral, and physical disability. No known treatment exists beyond symptomatic management, and while insights into the genetic cause, pathophysiology, neurobiology, and natural history of RTT have been gained, many challenges remain. Areas covered: Based on a comprehensive survey of the primary literature on RTT, this article describes and comments upon the general and unique features of the disorder, genetic and neurobiological bases of drug development, and the history of clinical trials in RTT, with an emphasis on drug trial design, outcome measures, and implementation. Expert opinion: Neurobiologically based drug trials are the ultimate goal in RTT, and due to the complexity and global nature of the disorder, drugs targeting both general mechanisms (e.g., growth factors) and specific systems (e.g., glutamate modulators) could be effective. Trial design should optimize data on safety and efficacy, but selection of outcome measures with adequate measurement properties, as well as innovative strategies, such as those enhancing synaptic plasticity and use of biomarkers, are essential for progress in RTT and other neurodevelopmental disorders.

Case Rep Obstet Gynecol ; 2015: 324173, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26347836


A 21-year-old primigravida had a pregnancy complicated by hyperemesis gravidarum (HG) beginning at 7-week gestation. Despite medical therapy, she lost 18% of her prepregnancy weight. Early ultrasound at 14 weeks demonstrated a flattened facial profile with nasal hypoplasia (Binder phenotype) consistent with vitamin K deficiency from HG. She had a percutaneous endoscopic gastrojejunostomy tube placed for enteral feeding at 15-week gestation. At repeated anatomy ultrasound at 21-week gestation, delivery, and postnatal pediatric genetics exam, nasal hypoplasia was consistent with vitamin K deficiency embryopathy from HG. Nausea and vomiting of pregnancy is a common condition. HG, the most severe form, has many maternal and fetal effects. Evaluation of vitamin K status could potentially prevent this rare and disfiguring embryopathy.