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1.
Am J Med Genet A ; 194(6): e63546, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38303141

RESUMO

Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was "feeding difficulties and/or poor weight gain" for both NG- (90.2%) and G-tubes (71.2%), while "aspiration/breathing difficulties" was the procedural indication for 6.4% of NG-tubes and 23.1% of G-tubes. NG-tubes were generally removed by age 6 months (NG Only: 82.9%; NG/G: 98.8%), while G-tubes were often removed by age 2 years (G Only: 85.7%; NG/G: 70.5%). The severe complication rate from G-tubes was 31.7% and from NG-tubes was 1.2%. Overall, caregivers indicated the presence of an NG- or G-tube had a positive effect on quality of life. Feeding difficulties in PWS are largely managed by NG-tube alone. The severe complication rate from G-tubes was about 25 times higher than from NG-tubes; yet, G-tube placement rates have generally increased. G-tube placement puts individuals with PWS at risk for anesthesia and surgery-related complications and should be considered judiciously by a multidisciplinary team.


Assuntos
Nutrição Enteral , Intubação Gastrointestinal , Síndrome de Prader-Willi , Sistema de Registros , Humanos , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/epidemiologia , Feminino , Masculino , Pré-Escolar , Criança , Lactente , Intubação Gastrointestinal/efeitos adversos , Nutrição Enteral/efeitos adversos , Adolescente , Gastrostomia/efeitos adversos , Adulto , Adulto Jovem
2.
Value Health ; 26(2): 243-250, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36202701

RESUMO

OBJECTIVES: To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common characteristics that have a significant negative impact on individuals with PWS and their families. METHODS: The PWS Anxiousness and Distress Behaviors Questionnaire (PADQ) was developed with extensive input from clinical experts, as well as caregivers of individuals with PWS, who participated in iterative sets of qualitative interviews. The psychometric properties of the PADQ were subsequently demonstrated in a cross-sectional evaluation using data from the Global PWS Registry provided by > 400 caregivers and confirmed using data from a phase 3 clinical trial of an oxytocin analogue (intranasal carbetocin, LV-101). RESULTS: Qualitative interview participants consistently endorsed the content of the PADQ and were confident they could accurately respond to each item based on their observations of their child's behavior. Analysis of cross-sectional data supported the computation of a total PADQ score, as well as the reliability and validity of the measure. The results of analyses using longitudinal clinical trial data confirmed these properties and provided evidence for the responsiveness of the PADQ, further supporting its appropriateness for the evaluation of new treatments targeting anxiousness and distress in PWS. CONCLUSIONS: The current body of evidence supports the conclusion that the PADQ measures observable behaviors that are meaningful to patients and their families and provides a valid and reliable method to assess beneficial treatment effects for some of the most challenging behaviors associated with PWS.


Assuntos
Síndrome de Prader-Willi , Criança , Humanos , Síndrome de Prader-Willi/tratamento farmacológico , Psicometria , Reprodutibilidade dos Testes , Estudos Transversais , Ansiedade , Inquéritos e Questionários
3.
Lancet Oncol ; 22(8): 1103-1114, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34214495

RESUMO

BACKGROUND: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. METHODS: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134. FINDINGS: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached). INTERPRETATION: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial. FUNDING: US National Institutes of Health.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Células-Tronco Neurais/transplante , Terapia Viral Oncolítica/métodos , Adenoviridae , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vírus Oncolíticos
4.
BMC Psychiatry ; 21(1): 438, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488710

RESUMO

INTRODUCTION: Prader-Willi syndrome (PWS) is a rare, genetic, neurodevelopmental syndrome associated with hyperphagia and early onset obesity, growth and sex hormone insufficiencies, mild-to-moderate intellectual disability, and behavioral challenges such as compulsivity, anxiety, skin picking, social skills deficits and temper outbursts. Given high rates of psychiatric comorbidity and potential risk factors for suicide in PWS, this study sought a first estimate of the prevalence of suicidal ideation (SI) and attempts (SA) in the PWS population and any characteristics associated with suicidality in this population. METHODS: Using the Global Prader-Willi Syndrome Registry, we included all participants who had answered a question about SI. We examined the most recent data from the surveys about social, economic, and demographic factors, genetic subtype, and psychiatric symptoms and treatments. A chi-square analysis was used to compare registry participants who reported SI to those without reported SI. RESULTS: From 750 included survey respondents, 94 (12.5%) endorsed some history of SI. Of these, 25 (26.6%) also reported a history of SA, with an average age of 16.25 years at their first attempt. Those with a history of SI were predominantly male and adult age, and had higher rates of aggression and psychiatric comorbidities, therapies, and medications. CONCLUSIONS: This study indicates that the rate of SI and SA in PWS is comparable to the general population, and that suicide attempts in PWS typically begin in middle-teenage years. Despite unique challenges, individuals with PWS and their caregivers should be included in screens and psychoeducation for suicide and mental health concerns.


Assuntos
Síndrome de Prader-Willi , Suicídio , Adolescente , Adulto , Ansiedade , Humanos , Masculino , Síndrome de Prader-Willi/epidemiologia , Sistema de Registros , Inquéritos e Questionários
5.
BMC Ophthalmol ; 21(1): 296, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34380467

RESUMO

BACKGROUND: There is a relative lack of information on the incidence and treatment of vision problems in Prader-Willi syndrome (PWS). Using data from the Global PWS Registry, we performed a cross-sectional study of vision problems in PWS. METHODS: Data, reported by caregivers who completed the Vision Survey in the Global PWS Registry between May of 2015 and March of 2020, were analyzed using descriptive statistics. RESULTS: There were 908 participants in this survey, with a mean age of 14.5 years (range 0-62 years). The prevalence of strabismus in this population was 40 %, with no statistically significant difference in prevalence by genetic subtype. Ninety-one percent of participants with strabismus were diagnosed before 5 years of age. Of those with strabismus, 42 % went on to have strabismus surgery, with 86 % of those having their first strabismus surgery before 5 years of age and 10.1 % having more than one strabismus surgery. Additional vision issues reported included myopia (41 %), hyperopia (25 %), astigmatism (25 %), and amblyopia (16 %). CONCLUSIONS: The prevalence of strabismus, amblyopia, and hyperopia are considerably higher in the PWS population represented in the Global PWS Registry as compared to the general population. People with PWS should be screened early and regularly for vision problems.


Assuntos
Síndrome de Prader-Willi , Estrabismo , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Humanos , Incidência , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/epidemiologia , Sistema de Registros , Estrabismo/epidemiologia , Estrabismo/etiologia , Estrabismo/cirurgia , Adulto Jovem
6.
J Transl Med ; 14(1): 134, 2016 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-27184224

RESUMO

BACKGROUND: CRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma. METHODS: This IND-enabling study performed under GLP conditions evaluated the toxicity and biodistribution of CRAd-S-pk7 administered as a single intracerebral dose to Syrian hamsters, a permissive model of adenoviral replication. Two hundred and forty animals were stereotactically administered either vehicle (n = 60) or CRAd-S-pk7 at 2.5 × 10(7), 2.5 × 10(8), or 2.5 × 10(9) viral particles (vp)/animal (each n = 60) on day 1. The animals were closely monitored for toxicology evaluation, assessment of viral distribution, and immunogenicity of CRAd-S-pk7. RESULTS: Changes in hematology, clinical chemistry, and coagulation parameters were minor and transient, and consistent with the inflammatory changes observed microscopically. These changes were considered to be of little toxicological significance. The vector remained localized primarily in the brain and to some degree in the tissues at the incision site. Low levels of vector DNA were detected in other tissues in a few animals suggesting systemic circulation of the virus. Viral DNA was detected in brains of hamsters for up to 62 days. However, microscopic changes and virus-related toxicity to the central nervous system were considered minor and decreased in incidence and severity over time. Such changes are not uncommon in studies using adenoviral vectors. CONCLUSION: This study provides safety and toxicology data justifying a clinical trial of CRAd-S-pk7 loaded in FDA-approved HB1.F3.CD neural stem cell carriers administered at the tumor resection bed in humans with recurrent malignant glioma.


Assuntos
Adenoviridae/genética , Vetores Genéticos/administração & dosagem , Replicação Viral , Animais , Formação de Anticorpos/imunologia , Peso Corporal , Encéfalo/patologia , Encéfalo/virologia , Cricetinae , DNA Viral/análise , Modelos Animais de Doenças , Comportamento Alimentar , Feminino , Vetores Genéticos/metabolismo , Genoma , Imunocompetência , Imunoglobulina G/imunologia , Inflamação/patologia , Injeções Intraventriculares , Masculino , Mesocricetus , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Tecidual
7.
J Pediatr ; 175: 137-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27283463

RESUMO

OBJECTIVE: To assess medical resource utilization associated with Prader-Willi syndrome (PWS) in the US, hypothesized to be greater relative to a matched control group without PWS. STUDY DESIGN: We used a retrospective case-matched control design and longitudinal US administrative claims data (MarketScan) during a 5-year enrollment period (2009-2014). Patients with PWS were identified by Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 759.81. Controls were matched on age, sex, and payer type. Outcomes included total, outpatient, inpatient and prescription costs. RESULTS: After matching and application of inclusion/exclusion criteria, we identified 2030 patients with PWS (1161 commercial, 38 Medicare supplemental, and 831 Medicaid). Commercially insured patients with PWS (median age 10 years) had 8.8-times greater total annual direct medical costs than their counterparts without PWS (median age 10 years: median costs $14 907 vs $819; P < .0001; mean costs: $28 712 vs $3246). Outpatient care comprised the largest portion of medical resource utilization for enrollees with and without PWS (median $5605 vs $675; P < .0001; mean $11 032 vs $1804), followed by mean annual inpatient and medication costs, which were $10 879 vs $1015 (P < .001) and $6801 vs $428 (P < .001), respectively. Total annual direct medical costs were ∼42% greater for Medicaid-insured patients with PWS than their commercially insured counterparts, an increase partly explained by claims for Medicaid Waiver day and residential habilitation. CONCLUSION: Direct medical resource utilization was considerably greater among patients with PWS than members without the condition. This study provides a first step toward quantifying the financial burden of PWS posed to individuals, families, and society.


Assuntos
Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde/estatística & dados numéricos , Síndrome de Prader-Willi/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Lactente , Recém-Nascido , Seguro Saúde/economia , Estudos Longitudinais , Masculino , Medicaid/economia , Medicare/economia , Pessoa de Meia-Idade , Síndrome de Prader-Willi/terapia , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
8.
Pharmacogenomics ; 25(4): 207-216, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38506331

RESUMO

Aim: The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Methods: Caregivers consented to PGx testing for their child and completed a survey before receiving results. Results: Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Conclusion: Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.


Assuntos
Farmacogenética , Síndrome de Prader-Willi , Criança , Humanos , Farmacogenética/métodos , Cuidadores , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética , Inquéritos e Questionários , Testes Farmacogenômicos
9.
Neurotherapeutics ; 21(3): e00339, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430811

RESUMO

Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field.


Assuntos
Estimulação Encefálica Profunda , Síndrome de Prader-Willi , Estimulação Transcraniana por Corrente Contínua , Estimulação Magnética Transcraniana , Estimulação do Nervo Vago , Humanos , Síndrome de Prader-Willi/terapia , Estimulação do Nervo Vago/métodos , Estimulação do Nervo Vago/instrumentação , Estimulação Magnética Transcraniana/métodos , Estimulação Encefálica Profunda/métodos , Estimulação Encefálica Profunda/instrumentação , Estimulação Transcraniana por Corrente Contínua/métodos
10.
J Neurodev Disord ; 16(1): 22, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38671361

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602. METHODS: To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP). RESULTS: Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants. CONCLUSION: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families. TRIAL REGISTRATION: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).


Assuntos
Preparações de Ação Retardada , Diazóxido , Hiperfagia , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/tratamento farmacológico , Feminino , Masculino , Hiperfagia/tratamento farmacológico , Hiperfagia/etiologia , Criança , Adulto , Adolescente , Diazóxido/administração & dosagem , Diazóxido/farmacologia , Adulto Jovem , Pré-Escolar , Estudos de Coortes
11.
Mol Genet Genomic Med ; 11(12): e2262, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37533374

RESUMO

BACKGROUND: Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternally expressed MAGEL2 gene in the Prader-Willi syndrome-region on chromosome 15q. In addition to hypotonia and intellectual disability, individuals with SYS are frequently affected by neonatal contractures and autism spectrum disorder. In this study, we focus on the burden of disease on patients and their families for the first time. METHODS: Based on the online SYS Patient Voices Survey the perspective of 81 primary caregivers on SYS was assessed. RESULTS: The perceived severity of muscular and developmental manifestations dominated the evaluation of the phenotype in early childhood, while behavioral issues were considered more impactful later in life. Importantly, an apprehension toward symptoms with a later onset was observed in caregivers of younger children. Available therapeutic options, while mostly effective, did not sufficiently alleviate the total burden of disease. Overall, parents stated that caring for an individual with SYS was very challenging, affecting their daily lives and long-term planning. CONCLUSION: Our study demonstrates the necessity for treatments that, adapted to age and in accordance with the caregivers' prioritization, improve the patients' medical condition and thus facilitate their and their families' social participation.


Assuntos
Transtorno do Espectro Autista , Proteínas Intrinsicamente Desordenadas , Criança , Recém-Nascido , Humanos , Pré-Escolar , Transtorno do Espectro Autista/genética , Cuidadores , Proteínas/genética , Efeitos Psicossociais da Doença , Percepção , Peptídeos e Proteínas de Sinalização Intracelular
12.
Sci Rep ; 13(1): 20573, 2023 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996659

RESUMO

The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is an observer-reported outcome measure that has been widely used in interventional studies to assess changes in hyperphagic behaviors in individuals with Prader-Willi syndrome (PWS). However, HQ-CT scores in the wider PWS population and the general population have not been reported. Here we report HQ-CT scores from more than 400 individuals with PWS and 600 typical individuals, aged 5-26. Overall, HQ-CT scores were significantly higher in those with PWS compared to typically developing individuals at all ages evaluated. In addition, while HQ-CT scores in the typically developing population decreased with age, scores increased with age in PWS. To further understand the variability of HQ-CT scores in the PWS population, semi-structured interviews were conducted with caregivers of a small subset of adults with PWS who had unexpectedly low HQ-CT scores. These caregivers reported that strict adherence to a food routine, food security measures and supervised food preparation reduced the frequency and intensity of hyperphagic behaviors measured by HQ-CT. Thus, hyperphagic behaviors are captured by the HQ-CT for most individuals with PWS, but for some individuals residing in settings with highly structured food routines, HQ-CT scores may not fully reflect the extent of PWS-associated hyperphagia.


Assuntos
Síndrome de Prader-Willi , Adulto , Humanos , Alimentos , Hiperfagia/epidemiologia , Inquéritos e Questionários , Tomografia Computadorizada por Raios X , Ensaios Clínicos como Assunto
13.
J Neurodev Disord ; 15(1): 37, 2023 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-37936142

RESUMO

OBJECTIVE: The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]). METHODS: Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences. RESULTS: The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications. CONCLUSION: Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.


Assuntos
Síndrome de Angelman , Transtornos Cromossômicos , Síndrome de Prader-Willi , Humanos , Criança , Lactente , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Trissomia
14.
Dis Model Mech ; 16(2)2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36637363

RESUMO

Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. We report the generation, molecular validation and phenotypic characterization of a novel rat model with a truncating Magel2 mutation modeling variants associated with Schaaf-Yang syndrome-causing mutations. Within the hypothalamus, a brain region in which human MAGEL2 is paternally expressed, we demonstrated, at the level of transcript and peptide detection, that rat Magel2 exhibits a paternal, parent-of-origin effect. In evaluations of behavioral features across several domains, juvenile Magel2 mutant rats displayed alterations in anxiety-like behavior and sociability measures. Moreover, the analysis of peripheral organ systems detected alterations in body composition, cardiac structure and function, and breathing irregularities in Magel2 mutant rats. Several of these findings are concordant with reported mouse phenotypes, indicating the conservation of MAGEL2 function across rodent species. Our comprehensive analysis revealing impairments across multiple domains demonstrates the tractability of this model system for the study of truncating MAGEL2 mutations.


Assuntos
Síndrome de Prader-Willi , Humanos , Ratos , Camundongos , Animais , Síndrome de Prader-Willi/genética , Proteínas/metabolismo , Fenótipo , Encéfalo/metabolismo , Modelos Biológicos , Antígenos de Neoplasias/genética
15.
J Clin Med ; 11(7)2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35407648

RESUMO

Individuals with Prader-Willi syndrome (PWS) may be at higher risk of developing blood clots as compared to the typical population, but this risk is poorly understood. It is also unclear if laboratory testing of D-dimer concentration might be useful to screen for thrombosis in PWS. Here, we surveyed the thrombosis history of 883 individuals with PWS and evaluated the D-dimer concentration in a subset of 214 asymptomatic individuals, ages 5-55. A history of at least one blood clot was reported by 3.6% of respondents. Thrombosis increased with age, but no significant difference was found on the basis of sex or family history. Genetic subtype was a significant factor when considering only those with a known subtype, and individuals with a history of edema had significantly more blood clots. In the D-dimer sub-study, ≈15% of participants had high D-dimer concentrations, and 3.7% had D-dimer values more than twice the normal upper limit. One participant with a high D-dimer result was found to have a blood clot. No significant differences in D-dimer results were found on the basis of age, sex, genetic subtype, family history of blood clots, edema history, or BMI. The D-dimer test does not appear to be a sensitive and specific screening tool for blood clots in asymptomatic individuals with PWS.

16.
PLoS One ; 16(3): e0248739, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33765021

RESUMO

OBJECTIVES: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by maladaptive behaviors, amongst which hyperphagia is a life-long concern for individuals with PWS and their caregivers. The current study examined the contribution of hyperphagia and other factors to caregiver burden across lifespan, in 204 caregivers of individuals with PWS living in the US, using the Zarit Burden Interview (ZBI) and the hyperphagia questionnaire (HQ-CT). RESULTS: We found a strong relationship between ZBI and HQ-CT especially in individuals with PWS older than 4 y and showed that HQ-CT scores of individuals with PWS is positively correlated with ZBI scores of their caregivers. The weight status of individuals with PWS was not associated with HQ-CT and ZBI scores, except for obese individuals who had significantly higher HQ-CT scores when compared to normal weight PWS individuals. We looked at PWS symptoms and care-related issues that impacted individuals and caregivers the most. We found that care-related tasks had the biggest negative impact on caregivers of children aged 0-4 y, whereas anxiety, temper tantrums, and oppositional behaviors of older individuals with PWS had the biggest impact on their caregivers concomitant with their high caregiver burden. Finally, we assessed the variability of HQ-CT and ZBI over 6 months in a subgroup of 83 participants. Overall, neither measure differed between 6 months and baseline. Most individual's absolute HQ-CT score changes were between 0-2 units, whereas absolute ZBI score changes were between 0-6 points. Changes in the caregiver's or individual's life had little or no effect on HQ-CT and ZBI scores. CONCLUSIONS: This study demonstrates a relationship between hyperphagia and caregiver burden and sheds light on predominant symptoms in children and adolescents that likely underly PWS caregiver burden. The stability and relationship between HQ-CT and ZBI support ZBI as an additional outcome measure in PWS clinical trials.


Assuntos
Transtornos de Ansiedade/psicologia , Sobrecarga do Cuidador/psicologia , Cuidadores/psicologia , Hiperfagia/psicologia , Síndrome de Prader-Willi/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto Jovem
17.
Orphanet J Rare Dis ; 15(1): 233, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883323

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder in which hyperphagia (excessive appetite) is a hallmark feature. Understanding how weight changes over time in this population is important for capturing the contemporary natural history of the disorder as well as assessing the impact of new treatments for hyperphagia. Therefore, we aimed to determine the feasibility of a remote assessment of weight change over time in PWS. METHODS: We developed a text message-based, prospective cohort study of adolescents and adults with PWS to assess changes in weight and body mass index (BMI) over a six-month period. Weight was collected weekly, while changes in height, living situation, access to food, activity level, and medication were collected at three-month intervals. RESULTS: One hundred and sixty-five participants enrolled in the study, with a mean age of 19.7 years (range 12-48). There was considerable variability in weight across participants (range: 76.8-207.7 kg). Thirty-three percent of the participants were normal weight, while 15% were overweight and 52% were obese. Overall, the weight of the study participants increased over the study period (mean weight change + 2.35%), while BMI was relatively stable, albeit high (mean BMI of 31.4 at baseline, mean BMI percent change + 1.42%). Changes in living situation, activity, food access, and medication had limited impact on weight and BMI changes. Multivariable analysis found that time, sex, age, and percentage of life on growth hormone (GH) therapy were statistically significant fixed effects. Participants submitted more than 95% of possible weight data points across the 26 weeks of the study. CONCLUSIONS: This remote, observational study of weight change in PWS showed small increases in weight and BMI over a six-month period. Participants were highly compliant with this text message-based study, suggesting that mobile technology-based data collection was manageable for the participants. We anticipate that the results of this study will inform clinical trials for hyperphagia/obesity related therapies in PWS and provide a basis for understanding the efficacy of new therapies for hyperphagia in the real-world setting.


Assuntos
Síndrome de Prader-Willi , Envio de Mensagens de Texto , Adolescente , Adulto , Índice de Massa Corporal , Criança , Humanos , Hiperfagia , Pessoa de Meia-Idade , Síndrome de Prader-Willi/tratamento farmacológico , Estudos Prospectivos , Adulto Jovem
18.
Genes (Basel) ; 10(9)2019 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540108

RESUMO

Advances in technologies offer new opportunities to collect and integrate data from a broad range of sources to advance the understanding of rare diseases and support the development of new treatments. Prader-Willi syndrome (PWS) is a rare, complex neurodevelopmental disorder, which has a variable and incompletely understood natural history. PWS is characterized by early failure to thrive, followed by the onset of excessive appetite (hyperphagia). Additional characteristics include multiple endocrine abnormalities, hypotonia, hypogonadism, sleep disturbances, a challenging neurobehavioral phenotype, and cognitive disability. The Foundation for Prader-Willi Research's Global PWS Registry is one of more than twenty-five registries developed to date through the National Organization of Rare Disorders (NORD) IAMRARE Registry Program. The Registry consists of surveys covering general medical history, system-specific clinical complications, diet, medication and supplement use, as well as behavior, mental health, and social information. Information is primarily parent/caregiver entered. The platform is flexible and allows addition of new surveys, including updatable and longitudinal surveys. Launched in 2015, the PWS Registry has enrolled 1696 participants from 37 countries, with 23,550 surveys completed. This resource can improve the understanding of PWS natural history and support medical product development for PWS.


Assuntos
Síndrome de Prader-Willi/patologia , Sistema de Registros , Saúde Global , Humanos , Síndrome de Prader-Willi/epidemiologia , Síndrome de Prader-Willi/genética
19.
PLoS One ; 13(3): e0194655, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29579119

RESUMO

OBJECTIVES: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long- term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact. RESULTS: Caregivers participating in this study were predominantly mothers, 30-59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregiver`s children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption. CONCLUSIONS: Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We identified the ZBI as a good predictor of that impact. Our findings draw attention to the critical unmet need for support for caregivers of individuals with PWS.


Assuntos
Cuidadores/psicologia , Síndrome de Prader-Willi/patologia , Adaptação Psicológica , Adulto , Afeto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/patologia , Depressão , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Adulto Jovem
20.
J Med Econ ; 21(12): 1230-1237, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30256699

RESUMO

OBJECTIVES: Prader-Willi syndrome (PWS) is a rare genetic disorder associated with varying degrees of hyperphagia, obesity, intellectual disability, and anxiety across the affected individuals' lifetimes. This study quantified caregiver priorities for potential treatment endpoints to identify unmet needs in PWS. METHODS: The authors partnered with the International Consortium to Advance Clinical Trials for PWS (PWS-CTC) and a diverse stakeholder advisory board to develop a best-worst scaling instrument. Seven relevant endpoints were assessed using a balanced incomplete block design. Caregivers were asked to determine the most and least important of a sub-set of four endpoints in each task. Caregivers were recruited nationally though patient registries, email lists, and social media. Best-worst score was calculated to determine caregiver priorities; ranging from 0 (least important) to 10 (most important). A novel kernel-smoothing approach was used to analyze caregiver endpoint priority variations with relation to age of the PWS individual. RESULTS: In total, 457 caregivers participated in the study. Respondents were mostly parents (97%), females (83%), and Caucasian (87%) who cared for a PWS individual ranging from 4-54 years. Caregivers value treatments addressing hyperphagia (score = 7.08, SE = 0.17) and anxiety (score = 6.35, SE = 0.16) as most important. Key variations in priorities were observed across age, including treatments targeting anxiety, temper outbursts, and intellectual functions. CONCLUSIONS: This study demonstrates that caregivers prioritize hyperphagia and, using a novel method, demonstrates that this is independent of the age of the person with PWS. This is even the case for parents of young children who have yet to experience hyperphagia, indicating that these results are not subject to a hypothetical bias.


Assuntos
Cuidadores/psicologia , Determinação de Ponto Final/métodos , Preferência do Paciente/psicologia , Síndrome de Prader-Willi/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ansiedade/terapia , Criança , Pré-Escolar , Feminino , Humanos , Hiperfagia/terapia , Masculino , Pessoa de Meia-Idade , Pais/psicologia , Doenças Raras , Adulto Jovem
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