RESUMEN
Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.
Asunto(s)
Encéfalo , Cardiopatías Congénitas , Imagen por Resonancia Magnética , Humanos , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/genética , Femenino , Masculino , Niño , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Adolescente , Adulto Joven , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto , Preescolar , Imagen de Difusión por Resonancia Magnética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/patología , Trastornos del Neurodesarrollo/genéticaRESUMEN
OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.
Asunto(s)
Etiquetado de Productos , Enfermedades Raras , Estados Unidos , Humanos , Enfermedades Raras/tratamiento farmacológico , United States Food and Drug AdministrationRESUMEN
In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.
Asunto(s)
Comités Consultivos , Documentación , Niño , Humanos , Reproducibilidad de los Resultados , Desarrollo de Medicamentos , Evaluación de Resultado en la Atención de SaludRESUMEN
The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambian children with and without HIV-infection. Children living with HIV and HIV-exposed, uninfected (HEU) children completed traditional neuropsychological and NIHTB-CB tasks. Using pairwise correlation and a linear regression model we measured associations between traditional measure composite scores and parental ratings of children's abilities, and NIHTB-CB scores. A Receiver Operating Characteristic (ROC) curve was developed to identify participants with impairment. 389 children, 8-17 years old participated. NIHTB-CB and traditional measures converged well as a whole and when comparing analogous individual tests across the two batteries. The NIHTB-CB composite score discriminated between the groups and was positively associated with external criteria for cognitive function: parental ratings of intelligence and school performance. Some English vocabulary and/or an unfamiliar cultural context presented challenges. NIHTB-CB was associated with children's everyday cognitive abilities, though future use may require linguistic and cultural adaptation.
Asunto(s)
Trastornos del Conocimiento , Infecciones por VIH , Adolescente , Niño , Cognición , Trastornos del Conocimiento/psicología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Humanos , Pruebas Neuropsicológicas , Reproducibilidad de los Resultados , Zambia/epidemiologíaRESUMEN
Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.
Asunto(s)
Lipofuscinosis Ceroideas Neuronales/diagnóstico , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Masculino , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Lipofuscinosis Ceroideas Neuronales/genética , Estudios Prospectivos , Adulto JovenRESUMEN
Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8-17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2-7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18-15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies.
Asunto(s)
Depresión , Infecciones por VIH , Adolescente , Adulto , Niño , Cognición , Estudios Transversales , Depresión/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Estudios Prospectivos , Zambia/epidemiologíaRESUMEN
We compared anxiety symptoms in youth with and without tic disorders by comparing scores on the Multidimensional Anxiety Scale for Children (MASC) in youth with tic disorders to those in a concurrent community control group and in a group of treatment-seeking anxious youth from the Child/Adolescent Anxiety Multimodal Study (CAMS). Data from 176 youth with tic disorders, 93 control subjects, and 488 CAMS participants were included. Compared to youth with tic disorders, controls had lower total MASC scores (p < 0.0001) and CAMS participants had similar total MASC scores (p = 0.13). Separation Anxiety (p = 0.0003) and Physical Symptom (p < 0.0001) subscale scores were higher in youth with tic disorders than in CAMS participants. We conclude that the anxiety symptom profile differs in youth with and without tic disorders, which may have important implications for targeting treatment of anxiety in youth with tic disorders.
Asunto(s)
Ansiedad de Separación , Trastornos de Tic/complicaciones , Síndrome de Tourette/complicaciones , Adolescente , Ansiedad , Trastornos de Ansiedad , Niño , Terapia Cognitivo-Conductual , Familia , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.
Asunto(s)
Encéfalo/metabolismo , Mucopolisacaridosis/terapia , Enfermedades del Sistema Nervioso/terapia , Modalidades de Fisioterapia , Encéfalo/patología , Ensayos Clínicos como Asunto , Disfunción Cognitiva/fisiopatología , Humanos , Mucopolisacaridosis/genética , Mucopolisacaridosis/metabolismo , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/metabolismo , Problema de Conducta , Calidad de VidaRESUMEN
INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.
Asunto(s)
Distrofia Miotónica/fisiopatología , Distrofia Miotónica/psicología , Actividades Cotidianas , Adolescente , Adulto , Cuidadores , Niño , Preescolar , Comunicación , Costo de Enfermedad , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Femenino , Dedos/fisiopatología , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/fisiopatología , Mano/fisiopatología , Humanos , Masculino , Limitación de la Movilidad , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Miotonía/etiología , Miotonía/fisiopatología , Distrofia Miotónica/complicaciones , Medición de Resultados Informados por el Paciente , Adulto JovenRESUMEN
BACKGROUND: Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. METHODS: We created a "hub and spoke" model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the "hub," conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating "spoke" site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. RESULTS: A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6-9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. CONCLUSIONS: This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.
Asunto(s)
Ensayos Clínicos como Asunto/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Estudios Multicéntricos como Asunto , Estudios Cruzados , Comités de Ética en Investigación/organización & administración , Humanos , Lipofuscinosis Ceroideas Neuronales/terapia , Enfermedades Raras/terapiaRESUMEN
OBJECTIVE: To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy. STUDY DESIGN: Subjects with hypertension and normotensive control subjects had neurocognitive testing at baseline and again after 1 year, during which time the subjects with hypertension received antihypertensive therapy. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed, and parents completed rating scales of executive function. RESULTS: Fifty-five subjects with hypertension and 66 normotensive control subjects underwent both baseline and 1-year assessments. Overall, the blood pressure (BP) of subjects with hypertension improved (24-hour systolic BP load: mean baseline vs 1 year, 58% vs 38%, P < .001). Primary multivariable analyses showed that the hypertension group improved in scores of subtests of the Rey Auditory Verbal Learning Test, Grooved Pegboard, and Delis-Kaplan Executive Function System Tower Test (P < .05). However, the control group also improved in the same measures with similar effects sizes. Secondary analyses by effectiveness of antihypertensive therapy showed that subjects with persistent ambulatory hypertension at 1 year (n = 17) did not improve in subtests of Rey Auditory Verbal Learning Test and had limited improvement in Grooved Pegboard. CONCLUSIONS: Overall, children with hypertension did not improve in neurocognitive test performance after 1 year of antihypertensive therapy, beyond that also seen in normotensive controls, suggesting improvements with age or practice effects because of repeated neurocognitive testing. However, the degree to which antihypertensive therapy improves BP may affect its impact upon neurocognitive function.
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Pruebas Neuropsicológicas , Adolescente , Presión Sanguínea/efectos de los fármacos , Estudios de Casos y Controles , Niño , Función Ejecutiva/efectos de los fármacos , Femenino , Humanos , Hipertensión/psicología , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Children with primary hypertension have been reported to have diminished scores in measures of cognition. However, little is known about the relative correlation between office and ambulatory blood pressure (BP) and neurocognitive test performance, and whether short-term BP variability is associated with decreased neurocognitive function. We sought to determine whether ambulatory BP monitoring (ABPM) was more strongly associated with neurocognitive test performance compared with office BP, and whether increased short-term BP variability was associated with lower neurocognitive scores. METHODS: Seventy-five subjects ages 10-18 years, with untreated primary hypertension, and 75 matched normotensive controls completed neurocognitive testing. All subjects had office BP and ABPM prior to neurocognitive testing. RESULTS: On multivariate analyses, there was no significant association between office BP and neurocognitive tests. However, several ABPM parameters were significantly associated with neurocognitive test scores in the lower quartile, in particular 24 h SBP load and wake systolic blood pressure (SBP) index [Rey Auditory Verbal learning Test (RAVLT) List A Trial 1, 24 h SBP load, odds ratio (OR) = 1.02, wake SBP index, OR = 1.06; List A Total, 24 h SBP load, OR = 1.02, wake SBP index, OR = 1.06; Short Delay Recall, wake SBP index, OR = 1.06; CogState Maze delayed recall, 24 h SBP load, OR = 1.03, wake SBP index, OR = 1.08; Grooved Pegboard, 24 h SBP load, OR = 1.02; all p < 0.05]. In contrast, short-term BP variability measures were not associated with neurocognitive test performance. CONCLUSIONS: ABPM is superior to office BP in distinguishing hypertensive youth with lower neurocognitive test performance.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Cognición/fisiología , Disfunción Cognitiva/diagnóstico , Hipertensión/diagnóstico , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Adolescente , Presión Sanguínea/fisiología , Estudios de Casos y Controles , Niño , Disfunción Cognitiva/etiología , Disfunción Cognitiva/prevención & control , Femenino , Humanos , Hipertensión/complicaciones , MasculinoRESUMEN
The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.
Asunto(s)
Cognición , Mucopolisacaridosis/terapia , Sistema Nervioso Central/fisiopatología , Niño , Ensayos Clínicos como Asunto , Determinación de Punto Final , Humanos , Mucopolisacaridosis/fisiopatología , Mucopolisacaridosis I/fisiopatología , Mucopolisacaridosis I/terapia , Mucopolisacaridosis II/fisiopatología , Mucopolisacaridosis II/terapia , Mucopolisacaridosis III/fisiopatología , Mucopolisacaridosis III/terapia , Enfermedades del Sistema Nervioso/terapia , Modalidades de FisioterapiaRESUMEN
OBJECTIVE: To compare neurocognitive test performance of children with primary hypertension with that of normotensive controls. STUDY DESIGN: Seventy-five children (10-18 years of age) with newly diagnosed, untreated hypertension and 75 frequency-matched normotensive controls had baseline neurocognitive testing as part of a prospective multicenter study of cognition in primary hypertension. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed. Parents completed rating scales of executive function and the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire (PSQ-SRBD). RESULTS: Hypertension and control groups did not differ significantly in age, sex, maternal education, income, race, ethnicity, obesity, anxiety, depression, cholesterol, glucose, insulin, and C-reactive protein. Subjects with hypertension had greater PSQ-SRBD scores (P = .04) and triglycerides (P = .037). Multivariate analyses showed that hypertension was independently associated with worse performance on the Rey Auditory Verbal Learning Test (List A Trial 1, P = .034; List A Total, P = .009; Short delay recall, P = .013), CogState Groton Maze Learning Test delayed recall (P = .002), Grooved Pegboard dominant hand (P = .045), and Wechsler Abbreviated Scales of Intelligence Vocabulary (P = .016). Results indicated a significant interaction between disordered sleep (PSQ-SRBD score) and hypertension on ratings of executive function (P = .04), such that hypertension heightened the association between increased disordered sleep and worse executive function. CONCLUSIONS: Youth with primary hypertension demonstrated significantly lower performance on neurocognitive testing compared with normotensive controls, in particular, on measures of memory, attention, and executive functions.
Asunto(s)
Hipertensión/psicología , Adolescente , Niño , Cognición , Estudios Transversales , Función Ejecutiva , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Estudios ProspectivosRESUMEN
Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.
Asunto(s)
Pruebas de Estado Mental y Demencia/normas , Errores Innatos del Metabolismo/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Enfermedades Raras/tratamiento farmacológico , Cuidadores , Niño , Desarrollo Infantil , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , National Institutes of Health (U.S.) , Padres , Tecnología de Sensores Remotos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
OBJECTIVE: To differentiate developmental encephalopathies by creating a novel quantitative phenotyping tool. STUDY DESIGN: We created the Developmental Encephalopathy Inventory (DEI) to differentiate disorders with complex multisystem neurodevelopmental symptoms. We then used the DEI to study the phenotype features of 20 subjects with FOXG1 disorder and 11 subjects with MECP2 disorder. RESULTS: The DEI identified core domains of fine motor and expressive language that were severely impaired in both disorders. Individuals with FOXG1 disorder were overall more severely impaired. Subjects with FOXG1 disorder were less able to walk, had worse fine motor skills, more disability in receptive language and reciprocity, and had more disordered sleep than did subjects with MECP2 disorder (P <.05). Covariance, cluster, and principal component analysis confirmed a relationship between impaired awareness, reciprocity, and language in both disorders. In addition, abnormal ambulation was a first principal component for FOXG1 but not for MECP2 disorder, suggesting that impaired ambulation is a strong differentiating factor clinically between the 2 disorders. CONCLUSIONS: We have developed a novel quantitative developmental assessment tool for developmental encephalopathies and propose this tool as a method to identify and illustrate core common and differential domains of disability in these complex disorders. These findings demonstrate clear phenotype differences between FOXG1 and MECP2 disorders.
Asunto(s)
Encefalopatías/diagnóstico , Factores de Transcripción Forkhead/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteínas del Tejido Nervioso/genética , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Mutación , FenotipoRESUMEN
AIM: The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile-onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic areas with the greatest disease burden in an international population of patients with early-onset myotonic dystrophy type-1 (DM1). METHOD: We distributed surveys to parents of patients with CDM/ChDM/JDM. Patients with CDM/ChDM/JDM were members of the US National Registry of DM1 Patients and Family Members, the Canadian Neuromuscular Disease Registry, or the Swedish Health System. Surveys inquired about 325 symptoms and 20 themes associated with CDM/ChDM/JDM. Parents identified the importance of each symptom and theme to their affected child. The prevalence of each symptom and theme were compared across subgroups of patients. The statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests. RESULTS: One hundred and fifty parents returned surveys. The most frequently reported symptomatic themes in children were issues involving communication (81.7%) and problems with hands or fingers (79.6%). Problems with communication and fatigue were the issues that were reported to have the greatest impact on childrens' lives, while 24.1% of children reported cardiac disorders and 15.8% had problems with anesthesia. INTERPRETATION: A range of symptoms contribute to the burden of disease faced by children with DM1. Many of these symptoms are under-recognized.
Asunto(s)
Cooperación Internacional , Distrofia Miotónica/fisiopatología , Distrofia Miotónica/psicología , Padres/psicología , Adolescente , Edad de Inicio , Niño , Trastornos de la Comunicación/etiología , Fatiga/etiología , Femenino , Enfermedades Gastrointestinales/etiología , Encuestas Epidemiológicas , Humanos , Masculino , Distrofia Miotónica/epidemiología , Calidad de Vida/psicologíaRESUMEN
OBJECTIVE: Despite evidence of elevated risk factors for suicidal thoughts and behavior in youth with Tourette syndrome and chronic tic disorders (CTD), few studies have actually examined that relationship. This study documented the frequency and clinical correlates of suicidal thoughts and behaviors in a sample of children and adolescents with CTD (N = 196, range 6-18 years old). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control. METHOD: Youth and parents completed a battery of measures that assessed co-occurring psychiatric diagnoses, child emotional and behavioral symptoms, and impairment due to tics or co-occurring conditions. RESULTS: A structured diagnostic interview identified that 19 youths with CTD (9.7%) experienced suicidal thoughts and/or behaviors, which was elevated compared to 3 youths (3%) who experienced these thoughts in a community control sample (N = 100, range 6-18 years old, P = .03). For youth with CTD, suicidal thoughts and behaviors were frequently endorsed in the context of anger and frustration. The Child Behavior Checklist (CBCL) anxious/depressed, withdrawn, social problems, thought problems, and aggressive behavior subscales, as well as the total internalizing problems scale, were associated with the presence of suicidal thoughts and/or behaviors. Suicidal thoughts and/or behaviors were significantly associated with tic symptom severity; tic-related impairment; and obsessive-compulsive, depressive, anxiety, and attention-deficit/hyperactivity disorders' symptom severity. CBCL anxiety/depression scores mediated the relationship between tic severity and suicidal thoughts and behaviors. CONCLUSIONS: Findings suggest that about 1 in 10 youth with CTD experience suicidal thoughts and/or behaviors, which are associated with a more complex clinical presentation and often occur in the presence of anger and frustration.
Asunto(s)
Ideación Suicida , Trastornos de Tic/psicología , Adolescente , Ansiedad/psicología , Trastornos de Ansiedad/psicología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Depresión/psicología , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Síndrome de Tourette/psicologíaRESUMEN
AIM: To evaluate seizure phenomenology, treatment, and course in individuals with juvenile neuronal ceroid lipofuscinosis (JNCL). METHOD: Data from an ongoing natural history study of JNCL were analyzed using cross-sectional and longitudinal methods. Seizures were evaluated with the Unified Batten Disease Rating Scale, a disease-specific quantitative assessment tool. RESULTS: Eighty-six children (44 males, 42 females) with JNCL were assessed at an average of three annual visits (range 1-11). Eighty-six percent (n=74) experienced at least one seizure, most commonly generalized tonic-clonic, with mean age at onset of 9 years 7 months (SD 2y 10mo). Seizures were infrequent, typically occurring less often than once every 3 months, and were managed with one to two medications for most participants. Valproate (49%, n=36) and levetiracetam (41%, n=30) were the most commonly used seizure medications. Myoclonic seizures occurred infrequently (16%, n=14). Seizure severity did not vary by sex or genotype. Seizures showed mild worsening with increasing age. INTERPRETATION: The neuronal ceroid lipofuscinoses (NCLs) represent a group of disorders unified by neurodegeneration and symptoms of blindness, seizures, motor impairment, and dementia. While NCLs are considered in the differential diagnosis of progressive myoclonus epilepsy, we show that myoclonic seizures are infrequent in JNCL. This highlights the NCLs as consisting of genetically distinct disorders with differing natural history.