Adaptive behavior in adolescents and adults with Down syndrome: Results from a 6-month longitudinal study.

Measures of adaptive behavior are important in the assessment and treatment of individuals with intellectual disabilities (ID). The purpose of the current study was to evaluate the stability of an established and a novel measure of adaptive behavior over time, and their suitability as outcome measures in clinical trials targeting individuals with Down syndrome (DS). This 6-month, longitudinal, noninterventional, multinational study included adolescents (12-17 years) and adults (18-30 years) with DS. Participants were from seven countries (11 different sites) with English, Spanish and French as their native language. The Vineland Adaptive Behavior Scales-II (VABS-II) and a newly developed Clinician Global Impression (CGI) scale were administered at baseline, 1 and 6 months. Adults had lower composite standard scores on all domains of the VABS-II compared with adolescents. The communication domain was a weakness relative to the socialization and daily living skills domains on the VABS-II and the CGI-Severity scale. These findings were stable over 6 months, as exhibited by high intraclass correlations (>0.75). These results provide valuable baseline data for use in trial design and endpoint selection for studies including individuals with DS. ClinicalTrials.gov identifier: NCT01580384.

A 3' untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR.

Fragile X syndrome is a common cause of intellectual disability and autism spectrum disorder. The gene underlying the disorder, fragile X mental retardation 1 (FMR1), is silenced in most cases by a CGG-repeat expansion mutation in the 5' untranslated region (UTR). Recently, we identified a variant located in the 3'UTR of FMR1 enriched among developmentally delayed males with normal repeat lengths. A patient-derived cell line revealed reduced levels of endogenous fragile X mental retardation protein (FMRP), and a reporter containing a patient 3'UTR caused a decrease in expression. A control reporter expressed in cultured mouse cortical neurons showed an expected increase following synaptic stimulation that was absent when expressing the patient reporter, suggesting an impaired response to neuronal activity. Mobility-shift assays using a control RNA detected an RNA-protein interaction that is lost with the patient RNA, and HuR was subsequently identified as an associated protein. Cross-linking immunoprecipitation experiments identified the locus as an in vivo target of HuR, supporting our in vitro findings. These data suggest that the disrupted interaction of HuR impairs activity-dependent translation of FMRP, which may hinder synaptic plasticity in a clinically significant fashion.

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date.

Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on earlier pharmaceutical interventions, development of appropriate outcome measures, and greater collaboration between industry, academia, advocacy, and regulatory groups will be important for addressing limitations from prior studies and developing potential effective interventions for cognition in Down syndrome.

Parental Perspectives on Pharmacological Clinical Trials: a Qualitative Study in Down Syndrome and Fragile X Syndrome.

Research studies focusing on parents' perspectives of pharmacological clinical trials have not kept pace with the number of emerging pharmacologic clinical trials in Down syndrome (DS) and Fragile X syndrome (FXS). Since individuals with DS or FXS have limited cognitive ability to make decisions about their participation in clinical trials, it is important to consider the parents' perspectives and explore the ways in which decisions are made for their children. Using a semi-structured interview, we enrolled 9 parents of a child(ren) with FXS and 15 with a child with DS to analyze their views, experiences, and knowledge of pharmacological clinical trials. Although our study is preliminary in nature, it revealed that parents are generally supportive of pharmacological clinical trials, yet there may be concerns about safety and long-term implications and consideration for their child in the decision process. There is also parental misunderstanding of the objectives of pharmacological clinical trials; thus, it is important for pharmaceutical companies, study investigators, clinicians/medical professionals, and parent advocacy groups to collaborate to provide appropriate and up-to-date educational resources that fully explain the risks and benefits of clinical trials.

Importance of a specialty clinic for individuals with fragile X syndrome.

Advances in human genetics have identified a significant number of genetic disorders associated with intellectual disability. As a result, appropriate clinical management of these affected individuals and their family members have become critical in addressing medical needs to improve quality of life. We examine the importance of a Fragile X Clinic for individuals with fragile X syndrome (FXS) and their family members by conducting a retrospective chart review of 123 new patients with FXS evaluated at the Fragile X Clinic at Emory University. After the initial diagnosis of a proband with FXS with cascade testing, there were 345 family members identified with a mutation (70% with premutations; 30% with full mutations). In terms of the impact of the clinic visit, males had a substantial number of new diagnoses in all behavioral disorders (P < 0.001), with anxiety (62%) being the most common. For female probands, the most frequent diagnosis was also anxiety (87%). Prior to the clinic visit, very few patients were prescribed psychotropic medications. After the clinic visit, the most frequently prescribed psychotropic medications for males were stimulants (41%; P < 0.001) and SSRIs (40%; P < 0.001). For females, only stimulants (33%; P = 0.03) and SSRIs (44%; P = 0.008) were statistically significantly prescribed. Our results revealed that there is a gap in care to address the co-morbid behavioral issues, psychopharmacologic medication management, and genetic counseling needs regarding FXS. A multidisciplinary setting and approach, such as that offered by a Fragile X Clinic, is one method of treating the complex needs of patients with FXS. © 2016 Wiley Periodicals, Inc.

Improving Health Education for Women Who Carry an FMR1 Premutation.

Women who carry an FMR1 (i.e., fragile X) premutation have specific health risks over their lifetime. However, little is known about their experience understanding these risks and navigating their health needs. The aim of this study was to use qualitative analysis to uncover both barriers and facilitators to personal healthcare using a framework of the Health Belief Model. Five focus groups were conducted with a total of 20 women who carry the FMR1 premutation using a semi-structured discussion guide. All sessions were transcribed verbatim and independently coded by two researchers. The coders used a deductive - inductive approach to determine the prominent themes related to the participants' experiences seeking healthcare for premutation-related conditions. Salient barriers to personal healthcare included difficult clinical translation of research findings, lack of knowledge among healthcare providers and among the women themselves, different priorities, and shortage of premutation-specific support and targeted educational materials. Facilitators included family members, national and community support organizations, research studies, compassionate physicians, and other premutation carriers. Addressing barriers to personal healthcare through up-to-date educational materials can help diminish misperceptions regarding health risks. Targeted educational materials will aid in information sharing and awareness for women who carry the FMR1 premutation and their physicians.

Influence of CHDs on psycho-social and neurodevelopmental outcomes in children with Down syndrome.

OBJECTIVE: To evaluate the family psycho-social outcomes of children with Down syndrome and atrioventricular septal defect, and examine the impact of these variables on the child's neurodevelopmental outcome. METHODS: This was a cross-sectional study that consisted of 57 children with Down syndrome - 20 cases and 37 controls - of ~12-14 months of age. In both groups, we assessed the development of the child, the quality of the child's home environment, and parenting stress. RESULTS: Compared with the Down syndrome without CHD group, the atrioventricular septal defect group revealed lower scores in all developmental domains, less optimal home environments, and higher parental stress. Significant differences in development were seen in the areas of cognition (p=0.04), expressive language (p=0.05), and gross motor (p<0.01). The Home Observation for Measurement of the Environment revealed significant differences in emotional and verbal responsiveness of the mother between the two groups. The Parenting Stress Index revealed that the Down syndrome with atrioventricular septal defect group had a significantly higher child demandingness subdomain scores compared with the Down syndrome without CHD group. CONCLUSIONS: The diagnosis of a CHD in addition to the diagnosis of Down syndrome may provide additional stress to the child and parents, elevating parental concern and disrupting family dynamics, resulting in further neurodevelopmental deficits. Finding that parental stress and home environment may play a role in the neurodevelopmental outcomes may prompt new family-directed interventions and anticipatory guidance for the families of children with Down syndrome who have a CHD.

Sleep profiles in children with Down syndrome.

Down syndrome (DS) is the most common genetic cause of intellectual disability and results from an extra chromosome 21 (Trisomy 21). Sleep issues and/or obstructive sleep apnea (OSA) are assumed to be part of the DS phenotype with a high prevalence but are often under recognized. This cross-sectional study of children with DS examines the caregiver-reported sleep behaviors of 108 children with DS, ranging in age from 1.50 to 13.40 years (mean = 5.18 years) utilizing a standardized assessment tool, the Children's Sleep Habit Questionnaire (CSHQ). The CSHQ revealed 76% of children with DS had sleep problems, which began at a young age, and continue to persist and may recur with increasing age. Furthermore, children with DS who undergone adenoidectomy and tonsillectomy for OSA continued to have sleep problems suggesting that ongoing monitoring of sleep issues is needed in this population. Implications of sleep problems and recommended anticipatory guidance and intervention are discussed.

Neurodevelopmental outcomes in children with Down syndrome and infantile spasms.

Down syndrome (DS) is the most common genetic cause of intellectual disability in the United States. The prevalence of seizure in individuals with DS is 1-13%, and infantile spasm (IS) occurs in 6-32% of those with seizures. Since IS is relatively common in children with DS, it is important to understand the impact IS has on the neurodevelopmental outcomes in order to provide appropriate anticipatory guidance to help maximize the potential of these children. Our study is the first to compare the neurodevelopmental outcomes of children with DS and IS (DS + IS) to children with DS and no history of seizures (DS - IS). Using the Bayley Scales of Infant and Toddler Development III, we assessed the neurodevelopment of 29 subjects (eight DS + IS and 21 DS - IS). Neurodevelopmental outcome was poor in the DS + IS cohort, but the delay in treatment does not appear to contribute to any differences in their developmental scores. However, when compared to children with DS - IS, the DS + IS cohort scored approximately 20 points less in all domains including cognitive, motor, and language (P < 0.05). Our results indicate that IS may impact the neurodevelopmental outcomes of children with DS + IS; thus, it is important to provide ongoing developmental and educational assessments and potentially additional therapies for children with DS + IS.

Climbing the branches of a family tree: diagnosis of fragile X syndrome.

OBJECTIVE: To determine the average number of family members diagnosed with a Fragile X Mental Retardation-1 (FMR1) mutation after a proband receives the initial diagnosis of fragile X syndrome (FXS). STUDY DESIGN: We reviewed pedigrees of families who had been evaluated at the Fragile X Syndrome Center at Emory University in Atlanta, Georgia. Through these pedigrees, we determined the number of additional family members diagnosed as FMR1 premutation carriers or with full mutation FXS after the initial diagnosis in each proband. RESULTS: The fragile X pedigree review identified 176 probands, including 108 males (61%) and 68 females (39%). A total of 785 family members were diagnosed with expanded fragile X alleles, including 278 males (35%) and 507 females (65%). These family members included 227 individuals with full mutation FXS (219 males and 8 females) and 558 premutation carriers (59 males and 499 females). After the initial diagnosis of a proband with FXS, on average at least 5 additional family members were diagnosed with an FMR1 mutation. CONCLUSION: Our findings confirm that obtaining a detailed family history after diagnosis of a proband with FXS is likely to identify multiple family members with FMR1 mutations. It is important that the pediatrician or other health care provider making a diagnosis of FXS recognize the value of a detailed family history for timely diagnosis and treatment of additional individuals who may be FMR1 premutation carriers or have full mutation FXS.

Implications of delayed diagnosis of infantile spasm in a child with Down syndrome.

Trisomy 21, leading to Down syndrome (DS) is the most common genetic cause of intellectual disability. Approximately 1-13% of children with DS have co-morbid seizures, with infantile spasm being the most frequent type of seizure identified. Although the clinical and electroencephalography findings of infantile spasm are similar between children with DS and typically developing children, there is often a delay in the diagnosis of these seizures in children with DS. We present the case of a male infant with DS, where the diagnosis of infantile spasm was delayed by 5 mo. His case was associated with developmental regression and intractable seizure activity following diagnosis. The case highlights the implications of delayed diagnosis on treatment strategies and developmental outcomes. Keywords: Down syndrome, infantile spasm, delayed diagnosis.

Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus.

BACKGROUND: Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by an expansion of CGG repeats located in the 5' untranslated region (UTR) of the FMR1 gene, which leads to hypermethylation and silencing of this locus. Although a dramatic increase in DNA methylation of the FMR1 full mutation allele is well documented, the extent to which these changes affect DNA methylation throughout the rest of the genome has gone unexplored. METHODS: Here we examined genome-wide methylation in both peripheral blood (N = 62) and induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls. RESULTS: We not only found the expected significant DNA methylation differences in the FMR1 promoter and 5' UTR, we also saw that these changes inverse in the FMR1 gene body. Importantly, we found no other differentially methylated loci throughout the remainder of the genome, indicating the aberrant methylation of FMR1 in FXS is locus-specific. CONCLUSIONS: This study provides a comprehensive methylation profile of FXS and helps refine our understanding of the mechanisms behind FMR1 silencing.

Timing of diagnosis of 47,XXY and 48,XXYY: a survey of parent experiences.

47,XXY/Klinefelter syndrome is the most common sex chromosomal aneuploidy, yet 64% of males with this condition go undiagnosed. 48,XXYY is less common and there is less known about the diagnosis. The objective of this study is to describe the diagnosis experiences of parents of males with 47,XXY and 48,XXYY. Parents of 89 males with 47,XXY and 76 males with 48,XXYY completed a survey that gathered data about their experiences leading to a diagnosis, including the current age of the child, age at diagnosis, reasons for initial concern, and the specialists providing the diagnosis. In the 47,XXY cohort diagnosed postnatally, 59% presented with developmental delay, with a mean age at first parental concern of 5.2 years and mean age of diagnosis at 10.0 years. The remaining 41% presented with endocrinologic issues with a mean age at first concern of 19.1 years and mean age of diagnosis at 21.1 years. In the 48,XXYY group, 93% presented with developmental delay, with mean age at first parental concern of 2.4 years and mean age of diagnosis at 7.6 years. Hence, the average time from initial parental concern to diagnosis of 47,XXY or 48,XXYY ranges from 2 to 5 years, with those presenting with developmental issues having a longer lag to diagnosis compared to those presenting with endocrinologic issues. Increased awareness of the developmental, psychological, and medical features of 47,XXY and 48,XXYY is important to facilitate timely diagnosis and initiation of appropriate screenings and treatments that are important for optimal outcomes.

Diagnosis of fragile X syndrome: a qualitative study of African American families.

Fragile X syndrome (FXS) is an inherited genetic condition with critical consequences to the proband and family members at all levels in the generations. Although evidence demonstrates that the rates of diagnosis for FXS are the same in all racial groups, age of diagnosis in African American children has been reported to occur later than in Caucasian children. Additionally, African American families are seriously under-represented in existing FXS research studies. As such, it is important to understand the possible disparities in the underlying factors to receiving a diagnosis in African American families with FXS. Herein, a qualitative approach was adopted to describe the overall FXS diagnosis experiences (pre-diagnosis, diagnosis, and post-diagnosis stages) of a convenience sample of 10 African American mothers. We identified three major findings among our participants: (1) FXS testing is not ordered immediately once a parent expresses concerns of developmental delays to the pediatricians, (2) the diagnosis is sometimes delivered in an insensitive manner with information often being outdated and unbalanced towards negative aspects, (3) communication issues among family members exists once the diagnosis is discovered. Although these qualitative data may not be representative of the whole group, these findings have significant implications for genetic counseling and our understanding in providing support and advocacy for African American families with FXS.

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome.

BACKGROUND: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. METHODS: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. RESULTS: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. CONCLUSIONS: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. TRIAL REGISTRATION: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Neurodevelopmental outcomes in children with Down syndrome and congenital heart defects.

Trisomy 21, the chromosomal condition responsible for Down syndrome (DS, OMIM #190685), is the most common identifiable genetic cause of intellectual disability. Approximately half of all children with DS are born with a significant congenital heart defect (CHD), the most common of which is an atrioventricular septal defect (AVSD). As children with comorbid DS and CHD increasingly survive cardiac surgery, characterization of their early developmental trajectories is critical for designing early interventions to maximize individual potential. Herein, the developmental domains (cognitive, language, and motor) of children with DS and AVSD (DS + AVSD, n = 12) were compared to children with DS and a structurally normal heart (DS - CHD, n = 17) using the Bayley Scales of Infant and Toddler Development III. The DS + AVSD cohort mean age was relatively the same as controls with DS - CHD, 14.5 ± 7.3 months compared with 14.1 ± 8.4 months, respectively. Although the motor domain was the only domain that showed a statistically significant difference between groups (P < 0.05), both cognitive standard scores (P = 0.63) and language composite standard scores (P = 0.10) were lower in the DS + AVSD cases compared with the DS - CHD controls although it is not statistically significant. Since this is the first study to examine the early developmental outcomes of children with DS + AVSD, the findings may be useful for clinicians in providing anticipatory guidance.

Developmental outcomes of Down syndrome and Dandy-Walker malformation.

Dandy-Walker syndrome (DWS), or Dandy-Walker complex, is a congenital brain malformation of the posterior fossa, typically resulting in developmental delay and cognitive disability. The co-occurrence of Down syndrome (DS) and DWS is relatively uncommon; thus, its impact on developmental outcomes has not been fully elucidated. Herein, we report a case of a 37-month-old child with DS and DWS, who is functioning at the following age-equivalent: gross motor at a 9-mo level, fine motor 6 mo, expressive language 14 mo, receptive language 9 mo. As such, it is important to determine how the DWS influences developmental outcomes, and appreciate the importance of early interventional therapy.

The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome.

OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression-Severity and Clinical Global Impression-Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13-45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALSGOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated.

A Conceptual Model of Angelman Syndrome and Review of Relevant Clinical Outcomes Assessments (COAs).

BACKGROUND: Angelman syndrome (AS) is a rare, neurological genetic disorder for which no clinical outcomes assessments (COAs) or conceptual models (CM) have been developed. OBJECTIVE: This study aimed to identify symptoms and impacts relevant and important in this patient population and develop a conceptual model of AS, and to evaluate the content validity of selected COA instruments with potential for inclusion in clinical studies of AS to capture treatment benefit. METHODS: For both concept elicitation (CE) and cognitive interviews (CI), caregivers of children, adolescents, and adults with AS and clinicians with AS experience were targeted. For CI, clinicians discussed the Modified Performance-Oriented Mobility Assessment (MPOMA-G) and ProtoKinetics Zeno Walkway™ and caregivers reviewed the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT), the Anxiety, Depression and Mood Scale (ADAMS), the Aberrant Behavior Checklist-Community (ABC-C), and the Morning Diary. RESULTS: Four clinicians and 34 caregivers participated in CE interviews; three clinicians and 36 caregivers participated in CI. A conceptual model, initially informed by literature, was refined based on interview data. Five domains of symptoms, signs, and characteristics of AS were identified: cognitive and executive functioning, social-emotional, emotional-expressive behavior, sensory-compulsive behavior, and physical. Patient impacts were identified in three domains: activities of daily living, school, and social/community. Caregiver impacts were identified in five domains: mental health, physical health, work, home, and social. While all instruments demonstrated the ability to provide relevant data for the AS population, each instrument either contained some items irrelevant to individuals with AS or was missing important concepts based on the interviews. No single instrument covered all relevant domains specific to AS. CONCLUSION: Future work should consider the adaptation of existing COAs and the development of a novel AS-specific instrument for use in clinical research to ensure outcomes important to this patient population are captured.