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Objective The Bayley Scales of Infant and Toddler Development- 4th Edition (Bayley-4) and Vineland Adaptive Behavior Scales – 3rd Edition (Vineland-3) are outcome measures often considered as primary endpoints in clinical trials for Angelman syndrome (AS). We explored barriers encountered when administering these instruments to individuals with AS and associated guidance for their use in trials and research studies. Methods We interviewed nine clinicians who have administered the Bayley-4 and/or the Vineland-3 to individuals with AS and analyzed their transcripts using a quasi-deductive analysis approach. Results Barriers to administering the Bayley-4 included participant’s lack of interest, overexcitement, emotional impact on caregiver, the mental workload of administering the Bayley-4, and environmental factors (e.g., administration setting). Barriers to administering the Vineland-3 included determining the most appropriate start point, emotional impact on caregiver, distractions, conflicting answers from two caregivers, and the mental workload of administering the Vineland-3. Participants provided potential solutions to each barrier. Lastly, we identified overarching item-level concerns for both the Bayley-4 (i.e., administration challenges, items not aligned with abilities) and the Vineland-3 (i.e., misalignment of assessment criteria and condition characteristics, limitations in observation and contextual understanding, requires specialized training). Conclusion Clinical trials often rely on the Bayley-4 and Vineland-3 assessments as outcome measures, yet our identified barriers threaten their validity. The associated solutions provide a path forward for improving administration of the Bayley-4 and Vineland-3 in clinical practice, research, and future trials focused on individuals with AS and other intellectual and developmental disabilities.

Background The purpose of this study was to conduct a 20-week controlled trial of lovastatin (10 to 40 mg/day) in youth with fragile X syndrome (FXS) ages 10 to 17 years, combined with an open-label treatment of a parent-implemented language intervention (PILI), delivered via distance video teleconferencing to both treatment groups, lovastatin and placebo. Method A randomized, double-blind trial was conducted at one site in the Sacramento, California, metropolitan area. Fourteen participants were assigned to the lovastatin group; two participants terminated early from the study. Sixteen participants were assigned to the placebo group. Lovastatin or placebo was administered orally in a capsule form, starting at 10 mg and increasing weekly or as tolerated by 10 mg increments, up to a maximum dose of 40 mg daily. A PILI was delivered to both groups for 12 weeks, with 4 activities per week, through video teleconferencing by an American Speech-Language Association-certified Speech-Language Pathologist, in collaboration with a Board-Certified Behavior Analyst. Parents were taught to use a set of language facilitation strategies while interacting with their children during a shared storytelling activity. The main outcome measures included absolute change from baseline to final visit in the means for youth total number of story-related utterances, youth number of different word roots, and parent total number of story-related utterances. Results Significant increases in all primary outcome measures were observed in both treatment groups. Significant improvements were also observed in parent reports of the severity of spoken language and social impairments in both treatment groups. In all cases, the amount of change observed did not differ across the two treatment groups. Although gains in parental use of the PILI-targeted intervention strategies were observed in both treatment groups, parental use of the PILI strategies was correlated with youth gains in the placebo group and not in the lovastatin group. Conclusion Participants in both groups demonstrated significant changes in the primary outcome measures. The magnitude of change observed across the two groups was comparable, providing additional support for the efficacy of the use of PILI in youth with FXS. Trial registration US National Institutes of Health ( ClinicalTrials.gov ), NCT02642653 . Registered 12/30/2015.

Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4–8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5’ untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Newborn screening (NBS) presents an opportunity to identify a subset of babies at birth who are at risk for developmental delays and could benefit from a range of developmental services. Potential developmental services in the United States include Part C Early Intervention (EI), private therapies, and school-based services. Using parent-reported outcomes, this study examined the rates at which a sample of children diagnosed with NBS conditions used each developmental service. An online survey of 153 parents representing children with 27 different NBS conditions found that nearly 75% of children (n = 112) used at least one developmental service, with private therapies being the most frequent. Children were referred to EI relatively early and were often eligible because their medical diagnosis automatically qualified them. When examining condition-specific results for children with severe combined immunodeficiencies, congenital hypothyroidism, and Pompe disease, we found variability in rates of use, with high rates overall. Our findings suggest that many children diagnosed with an NBS condition continue to have developmental delays even after they receive appropriate medical care. Future research with more systematic follow-up is needed to understand whether the NBS program facilitates entry into these services and whether more streamlined processes could benefit children and families.

Background Individuals with Angelman syndrome (AS) often experience profound communication impairment and intellectual disability, and as a result, are often unable to self-report on their experiences of emotional distress, including experiences of anxiety. However, existing measures of anxiety primarily depend on verbal descriptions of internal states, making them unsuitable tools for assessing the nature and severity of distress through observer-report for this population. To address this gap, we developed the Measure of Observable Outcomes of Distress in Angelman Syndrome (MOOD-AS), a novel observer-reported outcome (ObsRO) instrument built through a rigorous, caregiver-centered qualitative process focused on observable expressions of distress. Methodology Following FDA and ISPOR guidance for clinical outcome assessment development, we conducted concept elicitation interviews with caregivers in the United States and the Netherlands, drafted an initial item pool, mapped items against existing anxiety measures, and performed cognitive interviews to refine the instrument. Concept elicitation interviews were analyzed using content analysis, with saturation of concept assessed quantitatively. Cognitive interviews focused on evaluating item clarity, relevance, and usability. Results Caregivers identified 120 and 119 unique observable behaviors and situations in the U.S. ( n  = 17) and Netherlands ( n  = 8) sample. Saturation of concept was achieved. Mapping to nine existing anxiety measures revealed substantial gaps in coverage of caregiver-observable behaviors. Cognitive interviews ( N  = 9) confirmed strong item clarity and relevance, resulting in minor refinements to instructions, severity ratings, and caregiver impact response options. The final MOOD-AS consists of 71 caregiver-centered items assessing observable distress and anxiety-related behaviors. Psychometric properties will be assessed in the next phase of data collection. Conclusions The MOOD-AS provides a rigorously developed ObsRO item set with strong qualitative evidence for content validity. Further psychometric evaluation will establish its measurement properties. Its development highlights the importance of systematically integrating caregiver observations when self-report is not feasible and offers a model for future outcome measure development in rare and nonverbal populations.

Background Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. Methods Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. Results Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25–92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0–13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. Conclusion Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.

Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder and the most common type of muscular dystrophy in children. As newborn screening (NBS) for DMD undergoes evaluation for the Recommended Uniform Screening Panel and is already mandated in multiple states, refining NBS algorithms is of utmost importance. NBS for DMD involves measuring creatine kinase-MM (CK-MM) concentration—a biomarker of muscle damage—in dried blood spots. The current test is FDA-approved for samples obtained less than 72 h after birth. Separate reference ranges are needed for samples collected later than 72 h after birth. In this study, we investigated the relationship between age and CK-MM in presumed healthy newborns to inform NBS algorithm designs. In patients with DMD, CK-MM is persistently elevated in childhood and adolescence, while it may be transiently elevated for other reasons in healthy newborns. CK-MM decrease over time was demonstrated by a population sample of 20,306 presumed healthy newborns tested between 0 and 60 days of life and repeat testing of 53 newborns on two separate days. In the population sample, CK-MM concentration was highest in the second 12 h period of life (median = 318 ng/mL) when only 57.6% of newborns tested below 360 ng/mL, the lowest previously published cutoff. By 72 h of age, median CK-MM concentration was 97 ng/mL, and 96.0% of infants had concentrations below 360 ng/mL. Between 72 h and 60 days, median CK-MM concentration ranged from 32 to 37 ng/mL. Establishing age-related cutoffs is crucial for optimizing the sensitivity and specificity of NBS for DMD.

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.

Children with fragile X syndrome (FXS) have significant delays in many domains of functioning. Biological mothers of children with FXS are at an increased genetic risk for experiencing cognitive, physical, and mental health challenges. Parental mental health challenges and stress are often associated with reduced marital cohesion and satisfaction, which is likely to spill over and negatively affect the parent-child relationship for both mothers and fathers. Past research shows that parentally responsive behavior positively influences language development in both neurotypical children and children with intellectual and developmental disabilities, including those with FXS. However, the majority of past studies on parent-child interactions, and families of children with FXS more generally, have focused exclusively on the mother-child relationship. Therefore, very little is known about fathers in these families, including their well-being and their role in the child’s development. The current dissertation fills this gap by examining multiple features of the family environment, including the mother-father relationship, the mother-child relationship, and the father-child relationship in 23 families of children with FXS. Study 1 examined parental and couple well-being and associations between child functioning and these domains. Mothers and fathers independently completed questionnaires regarding their mental health, parenting stress, couples satisfaction, and dyadic coping in their relationship. Parents also independently completed questionnaires regarding their child’s challenging behaviors and symptoms of autism spectrum disorder (ASD). One parent also completed an interview about the child’s adaptive functioning. Results from this study indicated that mothers and fathers in these families experienced elevated levels of clinically significant mental health challenges and parenting stress compared to levels reported in the general population. However, despite these challenges, the majority of both mothers and fathers reported average to above average levels of couple well-being (i.e., couples satisfaction and dyadic coping). Multilevel models indicated that higher levels of parenting stress predicted lower levels of both couples satisfaction and dyadic coping. Additionally, multilevel models indicated that higher levels of child challenging behavior predicted higher levels of mental health challenges and parenting stress as well as lower levels of couples satisfaction and dyadic coping. Moreover, the parents of children with higher levels of adaptive functioning reported lower levels of parenting stress and higher levels of couples satisfaction. There were no significant differences in these relationships between mothers and fathers. Study 2 examined relationships among maternal responsivity, paternal responsivity, and parental and couple functioning. Mothers and fathers separately engaged in 12-minute dyadic play-based interactions with their child. These interactions were recorded via secure teleconferencing in the families’ homes. Recordings were transcribed and coded for the presence of parentally responsive behaviors and behavior management strategies. Results indicated significant correspondences between mothers’ and fathers’ frequencies and rates of responsive behaviors during the parent-child dyadic interactions. However, overall, mothers used comments more frequently than fathers, and fathers used a higher proportion of behavior management utterances compared to mothers. Multilevel models indicated that higher levels of parenting stress predicted lower rates of parental responsivity and higher rates of behavior management, but these effects were only marginally significant. Couples satisfaction did not predict either category of parent behavior. Study 3 examined relationships among maternal responsivity, paternal responsivity, and child language; it also examined relationships between child characteristics (i.e., challenging behavior, ASD symptoms, and adaptive behavior) and child language as well as parent behavior. Measures of parent and child language were obtained from the transcripts of the mother-child and father-child interactions. The measures were talkativeness, lexical diversity, and syntactic complexity. Multilevel models indicated that both maternal and paternal responsivity were positively associated with child talkativeness and lexical diversity. Parental responsivity, however, was not associated with child syntactic complexity. Findings also indicated that older children and children with higher levels of adaptive behavior had parents who used higher rates of responsive behaviors; these children also had higher levels of talkativeness, lexical diversity, and syntactic complexity. Additionally, fathers used higher rates of behavior management strategies compared to mothers, and this type of parental behavior was not associated with child language performance. The findings of this dissertation advance our understanding of family relationships in families of children with FXS as well as features of dyadic relationships within families that promote optimal outcomes.