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.

Purpose: 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. Method: 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. Results: 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. Conclusion: 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. Supplemental Material: https://doi.org/10.23641/asha.25229939

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.

Purpose: This study examined relationships among family characteristics, caregiver change in use of strategies, and child growth in spoken language over the course of a parent-implemented language intervention (PILI) that was developed to address some of the challenges associated with the fragile X syndrome (FXS) phenotype. Method: Participants were 43 parent–child dyads from two different PILI studies, both of which taught parents various language facilitation strategies to support child language. Before starting the intervention, parents reported on their mental health, parenting stress, and parenting competence. This study focused on potential barriers to treatment gains by examining correlations between the measures of parent well-being and (a) parent change in use of intervention strategies taught in the PILI and (b) changes in child language outcomes from pre- to post-intervention. Results: Parents in this study had elevated mental health symptoms across several domains and increased rates of parenting stress. Furthermore, although PILI resulted in treatment gains for both parents and children, a variety of parent mental health symptoms were found to be significantly and negatively associated with change in use of strategies and growth in child language over the course of the intervention. Some inconsistent findings also emerged regarding the relationships between parenting stress and competence and change in parent strategy use and growth in child language. Conclusions: This study provides preliminary evidence that parents who are experiencing significant mental health challenges may have a more difficult time participating fully in PILIs and that there may be subsequent effects on child outcomes. Future PILIs could benefit from addressing parent well-being as a substantial part of the intervention program.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database – including challenges, lessons learned, and preliminary feasibility – and how it can be used as a model for other rare conditions.