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.
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.
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.
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.
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.
•Among patients who initially desired amputation, only 36.4% continued to desire amputation after receiving an IDEO brace.•Patients with footdrop and weakness, due to loss of plantarflexion force for ...toe-off on their own, were more likely to continue IDEO use.•Patients with a prior ankle or hindfoot fusion were less likely to continue IDEO use.•There was a trend favoring enrollment in a return-to-run therapy program for longer lower extremity preservation.
The Intrepid Dynamic Exoskeletal Orthosis (IDEO) brace is a custom energy-storing orthosis design meant to improve gait, stability, and function after lower extremity injury or limb salvage. Early studies demonstrated the potential for the IDEO to improve functional performance, in conjunction with its paired return to run (RTR) rehabilitation program, compared to other brace types, and an impressively decreased rate of late amputation. The current study aimed to investigate these functional and revision outcomes from our institution to determine which patients may benefit most from IDEO bracing and what factors of the IDEO design and rehabilitation program are most important for improved outcomes after lower extremity trauma and/or loss of function.
We performed a retrospective review of all patients treated with a IDEO style brace at a single military lower extremity trauma referral center between May 2003 and November 2017. We reviewed the medical records for initial diagnosis, post-orthotic rehabilitation program, IDEO use characteristics, pain, change in desire for amputation, and whether patient underwent eventual amputation.
We identified 213 patients with 222 lower extremities treated with IDEO brace. Of these, 76 limbs were treated for combat-related injuries. At one year follow-up, use status could not be determined for 37 extremities (16.7%). Of the 185 limbs with use data available, 116 (61.1%) continued regular brace use, and 37 (15.7%) reported intermittent use. Patients diagnosed with footdrop or weakness were more likely to continue use (OR 2.33, p=0.04), while patients with a previous fusion were less likely to continue use (OR 0.45, p=0.049). Undergoing any dedicated therapy increased chances of continued use (OR 3.37, p<0.001). At final follow-up, 16 patients (7.5%) underwent delayed lower extremity amputations following IDEO treatment. Overall, 27.2% of patients who initially desired amputation eventually underwent amputation despite IDEO brace use. Patients who underwent amputation reported higher pain levels (2 versus 5, p<0.001).
In select patients, the IDEO may decrease the desire for delayed amputation and permit higher levels of activity; however, its efficacy appears tied to the rehabilitative regimen, pain levels, and initial diagnosis. These findings should guide post-surgical extremity bracing prescriptions and expectations.
Individuals with fragile X syndrome (FXS) have significant delays in cognition and language, as well as anxiety, symptoms of autism spectrum disorder, and challenging behaviors such as hyperactivity ...and aggression. Biological mothers of children with FXS, who are themselves
premutation or full mutation carriers, are at elevated risk for mental health challenges in addition to experiencing stress associated with parenting a child with significant disabilities. However, little is known about fathers in these families, including the ways in which parental well-being influences the mother-father relationship and the impact of child characteristics on paternal and couple functioning.
The current study examined features of, and relationships between, parental well-being, couple well-being, and child functioning in 23 families of young boys with FXS. Mothers and fathers independently completed multiple questionnaires about their individual well-being, couple functioning, and child behavior. One parent per family also completed an interview about the child's adaptive skills.
Results suggest that both mothers and fathers in these families experience clinically significant levels of mental health challenges and elevated rates of parenting stress relative to the general population. Findings also indicate that the couples' relationship may be a source of strength that potentially buffers against some of the daily stressors faced by these families. Additionally, parents who reported less parenting stress had higher couples satisfaction and dyadic coping. Finally, parents of children with less severe challenging behaviors exhibited fewer mental health challenges, less parenting stress, and higher levels of both couples satisfaction and dyadic coping. Parents of children with higher levels of adaptive behavior also reported less parenting stress and higher couples satisfaction.
Overall, this study provides evidence that families of children with FXS need access to services that not only target improvements in the child's functioning, but also ameliorate parental stress. Family-based services that include both mothers and fathers would lead to better outcomes for all family members.
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. Keywords: Child development, Developmental disabilities, Intellectual disability, Activities of Daily Living
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.
The premutation of the fragile X messenger ribonucleoprotein 1 (
) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased ...levels of
mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations,
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
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.
Past research shows that parentally responsive behavior toward the child positively influences language development in both neurotypical children and children with intellectual and developmental ...disabilities, including those with fragile X syndrome (FXS); however, most studies have focused exclusively on the mother-child relationship. The current study examined relationships between parent behavior (i.e., responsivity and behavior management) and child language performance in both mother-child and father-child interactions, as well as relationships between child characteristics and both parent behavior and child language.
Participants were 23 families of young boys with FXS between 3 and 7 years of age. Mothers and fathers independently completed questionnaires assessing child characteristics and separately engaged in 12-min play-based interactions with their child via telehealth. One parent also completed a comprehensive interview assessing child adaptive behavior. Video recordings of the parent-child interactions were transcribed and coded for parent and child behavior, and measures of parent and child language were obtained from the transcripts.
Mothers and fathers used similar rates of responsive behaviors during parent-child interactions, and parental responsivity was positively associated with some aspects of child language performance (i.e., talkativeness and lexical diversity). Parental behavior, however, was not associated with syntactic complexity. Older children and children with higher levels of adaptive behavior had parents who used higher rates of responsive behaviors. Fathers used higher rates of behavior management strategies compared to mothers, and this type of parent behavior was not associated with child language.
Overall, this study provides evidence that interventions focused on increasing parental responsiveness would be beneficial for families of children with FXS and that these interventions should be delivered early given the association between responsivity and child age.
https://doi.org/10.23641/asha.25229939.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we ...conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States.
We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS.
We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns.
Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.
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.
PDF
