RESUMO
Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals and caregivers, no disease-modifying treatments are available. To support holistic clinical management and the development of AS-specific outcome measures for clinical studies, we conducted primary and secondary research identifying the impact of symptoms on individuals with AS and their unmet need. This qualitative research adopted a rigorous step-wise approach, aggregating information from published literature, then evaluating it via disease concept elicitation interviews with clinical experts and caregivers. We found that the AS-defining concepts most relevant for treatment included: impaired expressive communication, seizures, maladaptive behavior, cognitive impairment, motor function difficulties, sleep disturbance, and limited self-care abilities. We highlight the relevance of age in experiencing these key AS concepts, and the difference between the perceptions of clinicians and caregivers towards the syndrome. Finally, we outline the impact of AS on individuals, caregivers, and families.
Assuntos
Síndrome de Angelman , Cuidadores , Humanos , Modelos Teóricos , Assistência Centrada no Paciente , Pesquisa QualitativaRESUMO
AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.
Assuntos
Aminopeptidases/antagonistas & inibidores , Depressores do Apetite/uso terapêutico , Cinamatos/uso terapêutico , Cicloexanos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Glicoproteínas/antagonistas & inibidores , Hiperfagia/prevenção & controle , Obesidade/prevenção & controle , Síndrome de Prader-Willi/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Sesquiterpenos/uso terapêutico , Adolescente , Adulto , Aminopeptidases/metabolismo , Depressores do Apetite/administração & dosagem , Depressores do Apetite/efeitos adversos , Índice de Massa Corporal , Cinamatos/administração & dosagem , Cinamatos/efeitos adversos , Cicloexanos/administração & dosagem , Cicloexanos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/efeitos adversos , Feminino , Glicoproteínas/metabolismo , Humanos , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Análise de Intenção de Tratamento , Masculino , Metionil Aminopeptidases , Obesidade/etiologia , Síndrome de Prader-Willi/fisiopatologia , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/efeitos adversos , Índice de Gravidade de Doença , Trombose Venosa/induzido quimicamente , Trombose Venosa/fisiopatologia , Redução de Peso/efeitos dos fármacos , Adulto JovemRESUMO
Angelman syndrome (AS) is due to deficient ubiquitin protein ligase 3a, the gene for which (UBE3A) maps to chromosome 15q11-q13 and is imprinted such that only the maternally inherited gene is expressed. The paternally inherited UBE3A gene is silenced, a process mediated by an antisense transcript. We conducted a trial using methylation-promoting dietary supplements (betaine, metafolin, creatine, and vitamin B(12) ) in an attempt to reduce antisense transcript production, increase UBE3A expression, and ameliorate the symptoms of AS. Neuropsychological evaluations, biochemical testing, and assessment of DNA methylation were performed at the beginning and at the end of 1 year of supplementation. The primary outcome measures were changes in the level of developmental function (cognitive, motor, and language) as measured using standardized instruments. The secondary outcomes measures were changes in biochemical parameters and global DNA methylation. These data were compared to those of a control group from a previous randomized double-blind trial using folic acid and betaine. There were no statistically significant changes in the developmental performance of children treated with supplements. There were no unexpected changes in biochemical parameters and no change in site-specific DNA methylation when comparing samples from before and after treatment. There were 10 adverse events that resulted in study withdrawal of 7 participants (worsening of seizures, onset, or worsening of sleep problems, constipation, and anorexia). Supplementation with betaine, metafolin, creatine, and vitamin B(12) appears safe but ineffective in decreasing the severity of AS.
Assuntos
Síndrome de Angelman/tratamento farmacológico , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Psicometria , Resultado do TratamentoRESUMO
Angelman syndrome (AS) is caused by reduced or absent expression of the maternally inherited ubiquitin protein ligase 3A gene (UBE3A), which maps to chromosome 15q11-q13. UBE3A is subject to genomic imprinting in neurons in most regions of the brain. Expression of UBE3A from the maternal chromosome is essential to prevent AS, because the paternally inherited gene is not expressed, probably mediated by antisense UBE3A RNA. We hypothesized that increasing methylation might reduce expression of the antisense UBE3A RNA, thereby increasing UBE3A expression from the paternal gene and ameliorating the clinical phenotype. We conducted a trial using two dietary supplements, betaine and folic acid to promote global levels of methylation and attempt to activate the paternally inherited UBE3A gene. We performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. We report herein the data on 48 children with AS who were enrolled in a double-blind placebo-controlled protocol using betaine and folic acid for 1 year. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends.