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1.
Am J Med Genet A ; 179(6): 983-992, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30942555

RESUMEN

Maladaptive behaviors are challenging and a source of stress for caregivers of individuals with Angelman Syndrome (AS). There is limited information on how these maladaptive behaviors vary over time among individuals with AS due to different genetic etiologies. In this study, caregivers of 301 individuals with AS were asked questions about their child's behavior and completed the Aberrant Behavior Checklist-Community version (ABC-C). Developmental functioning was evaluated with either the Bayley Scales of Infant Development, Third Edition (Bayley-III) or the Mullen Scales of Early Learning (MSEL). Family functioning was assessed using the parent-completed Parenting Stress Index (PSI) and the Family Quality of Life questionnaire (FQoL). Approximately 70% of participants had AS due to a deletion on the maternally-inherited copy of chromosome 15q11q13. Results revealed that at baseline, individuals with AS had low scores in the domains of lethargy (mean: 2.6-4.2 depending on genotype) and stereotypy (mean: 2.3-4.2 depending on genotype). Higher cognitive functioning was associated with increased irritability (r = 0.32, p < .01). Hyperactivity (p < .05) and irritability (p < .05) increased with age across all genotypes and should be ongoing targets for both behavioral and pharmacological treatment. Concerns for short attention span were endorsed by more than 70% of caregivers at baseline. Maladaptive behaviors, particularly hyperactivity, irritability and aggression, adversely affected parental stress, and family quality of life.


Asunto(s)
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/psicología , Conducta Estereotipada , Adolescente , Adulto , Alelos , Síndrome de Angelman/genética , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Masculino , Responsabilidad Parental/psicología , Calidad de Vida , Índice de Severidad de la Enfermedad , Estrés Psicológico , Adulto Joven
2.
Am J Med Genet A ; 176(5): 1099-1107, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-28944563

RESUMEN

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.


Asunto(s)
Síndrome de Angelman/tratamiento farmacológico , Levodopa/uso terapéutico , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/fisiopatología , Síndrome de Angelman/psicología , Animales , Biomarcadores , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Modelos Animales de Enfermedad , Humanos , Levodopa/administración & dosificación , Potenciación a Largo Plazo , Ratones , Pruebas Neuropsicológicas , Resultado del Tratamiento
3.
J Autism Dev Disord ; 2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37581718

RESUMEN

In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes. Statistically significant growth was observed in all adaptive domains through at least early adolescence. Individuals with AS should continue to receive developmental services and educational supports through adolescence and into adulthood given the slow rates of growth being observed across adaptive domains.

4.
J Autism Dev Disord ; 53(2): 720-737, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517526

RESUMEN

We describe the development of 236 children with Angelman syndrome (AS) using the Bayley Scales of Infant and Toddler Development, Third Edition. Multilevel linear mixed modeling approaches were used to explore differences between molecular subtypes and over time. Individuals with AS continue to make slow gains in development through at least age 12 years of age at about 1-2 months/year based on age equivalent score and 1-16 growth score points/year depending on molecular subtype and domain. Children with a deletion have lower scores at baseline and slower rate of gaining skills while children with UBE3A variant subtype demonstrated higher scores as well as greater rates of skill attainment in all domains. The developmental profiles of UPD and ImpD were similar.


Asunto(s)
Síndrome de Angelman , Trastorno del Espectro Autista , Lactante , Niño , Humanos , Discapacidades del Desarrollo/diagnóstico , Destreza Motora , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Desarrollo Infantil
5.
J Child Psychol Psychiatry ; 53(2): 152-9, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21831244

RESUMEN

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a 'syndromic' form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (∼6 Mb) Class I deletions of chromosome 15q11-13. Questions remain regarding whether intellectual disability solely contributes to ASD features in AS and how ASD features in AS change over time. In this study, we used a dimensional approach to examine ASD symptom severity in individuals with AS Class I versus Class II deletions within the context of cognitive development over time. METHODS: A total of 17 participants with a larger, Class I deletion and 25 participants with a smaller Class II deletion (∼5 Mb) were enrolled (age range = 2-25 years; 5 years 5 months). Standardized measures of cognition, language, motor skills, adaptive skills, maladaptive behavior, autism, and sensory-seeking behaviors/aversions were given at baseline and after 12 months. RESULTS: Despite equivalent cognition and adaptive behavior, the results of repeated measures analyses of variance indicate that participants with Class I deletions have greater impairment in social affect (F = 8.65; p = .006) and more repetitive behaviors (F = 7.92; p = .008) compared to participants with Class II deletions. Although both groups improve in cognition over time, differences in ASD behaviors persist. CONCLUSIONS: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning.


Asunto(s)
Síndrome de Angelman/clasificación , Síndrome de Angelman/genética , Conducta Infantil/psicología , Trastornos Generalizados del Desarrollo Infantil/genética , Deleción Cromosómica , Discapacidad Intelectual/genética , Adolescente , Adulto , Síndrome de Angelman/fisiopatología , Niño , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Preescolar , Cromosomas Humanos Par 15/clasificación , Cromosomas Humanos Par 15/genética , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/fisiopatología , Femenino , Estudios de Seguimiento , Genoma Humano , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/fisiopatología , Masculino , Pruebas Neuropsicológicas , Trastornos de la Sensación/diagnóstico , Trastornos de la Sensación/genética , Trastornos de la Sensación/fisiopatología , Trastorno de la Conducta Social/diagnóstico , Trastorno de la Conducta Social/genética , Trastorno de la Conducta Social/fisiopatología , Adulto Joven
6.
Am J Med Genet A ; 155A(1): 81-90, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21204213

RESUMEN

Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternal copy of UBE3A. Although the "classic" features of AS are well described, few large-scale studies have delineated the clinical features in AS. We present baseline data from 92 children with a molecular diagnosis of AS between 5 and 60 months old who are enrolled in the National Institutes of Health Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study from January 2006 to March 2008. Seventy-four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations. Participants with UPD/imprinting defects were heavier (P = 0.0002), while those with deletions were lighter, than the general population (P < 0.0001). Twenty out of 92 participants were underweight, all of whom had deletions or UBE3A mutations. Eight out of 92 participants (6/13 (46%) with UPD/imprinting defects and 2/11 (18%) with UBE3A mutations) were obese. Seventy-four out of 92 participants (80%) had absolute or relative microcephaly. No participant was macrocephalic. The most common behavioral findings were mouthing behavior (95%), short attention span (92%), ataxic or broad-based gait (88%), history of sleep difficulties (80%), and fascination with water (75%). Frequent, easily provoked laughter was observed in 60%. Clinical seizures were reported in 65% of participants but all electroencephalograms (EEGs) were abnormal. We conclude that the most characteristic feature of AS is the neurobehavioral phenotype, but specific EEG findings are highly sensitive for AS. Obesity is common among those with UPD/imprinting defects.


Asunto(s)
Síndrome de Angelman/genética , Síndrome de Angelman/patología , Aberraciones Cromosómicas , Cromosomas Humanos Par 15/genética , Fenotipo , Ubiquitina-Proteína Ligasas/genética , Preescolar , Recolección de Datos , Electroencefalografía , Humanos , Lactante , Estudios Longitudinales , Mutación/genética , Estadísticas no Paramétricas
7.
Am J Med Genet A ; 155A(12): 2956-63, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22002941

RESUMEN

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.


Asunto(s)
Síndrome de Angelman/tratamiento farmacológico , Metilación de ADN/efectos de los fármacos , Suplementos Dietéticos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Psicometría , Resultado del Tratamiento
8.
JIMD Rep ; 50(1): 44-49, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31741826

RESUMEN

Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene MAN2B1. Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha-mannosidosis (ages 8-59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha-mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.

9.
J Dev Behav Pediatr ; 31(7): 592-601, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20729760

RESUMEN

OBJECTIVE: Angelman syndrome (AS) is a neurodevelopmental disorder caused by a deletion on chromosome 15, uniparental disomy, imprinting defect, or UBE3A mutation. It is characterized by intellectual disability with minimal speech and certain behavioral characteristics. We used standardized measures to characterize the developmental profile and to analyze genotype-phenotype correlations in AS. METHOD: The study population consisted of 92 children, between 5 months and 5 years of age, enrolled in a Natural History Study. Each participant was evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), the Vineland Adaptive Behavior Scales, Second Edition (VABS-II), and the Aberrant Behavior Checklist. RESULTS: Seventy-four percent had a deletion and 26% had uniparental disomy, an imprinting defect or a UBE3A mutation ("non-deletion"). The mean +/- standard deviation BSID-III cognitive scale developmental quotient (DQ) was 40.5 +/- 15.5. Participants with deletions were more developmentally delayed than the non-deletion participants in all BSID-III domains except in expressive language skills. The cognitive DQ was higher than the DQ in each of the other domains, and the receptive language DQ was higher than the expressive language DQ. In the [ corrected] VABS-II, deletion participants had weaker motor and language skills than the non-deletion participants. CONCLUSION: Children with AS have a distinct developmental and behavioral profile; their cognitive skills are stronger than their language and motor skills, and their receptive language skills are stronger than expressive language skills. Developmental outcomes are associated with genotype, with deletion patients having worse outcomes than non-deletion patients.


Asunto(s)
Síndrome de Angelman/genética , Síndrome de Angelman/psicología , Cromosomas Humanos Par 15/genética , Lenguaje Infantil , Preescolar , Cognición , Femenino , Eliminación de Gen , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Impresión Genómica , Genotipo , Humanos , Lactante , Masculino , Destreza Motora , Fenotipo , Ubiquitina-Proteína Ligasas/genética , Disomía Uniparental
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