Alterations in aperiodic and periodic EEG activity in young children with Down syndrome.

Down syndrome is the most common cause of intellectual disability, yet little is known about the neurobiological pathways leading to cognitive impairments. Electroencephalographic (EEG) measures are commonly used to study neurodevelopmental disorders, but few studies have focused on young children with DS. Here we assess resting state EEG data collected from toddlers/preschoolers with DS (n=29, age 13-48 months old) and compare their aperiodic and periodic EEG features with both age-matched (n=29) and cognitive-matched (n=58) comparison groups. DS participants exhibited significantly reduced aperiodic slope, increased periodic theta power, and decreased alpha peak amplitude. A majority of DS participants displayed a prominent peak in the theta range, whereas a theta peak was not present in age-matched participants. Overall, similar findings were also observed when comparing DS and cognitive-matched groups, suggesting that EEG differences are not explained by delayed cognitive ability.

Autism-associated brain differences can be observed in utero using MRI.

Developmental changes that occur before birth are thought to be associated with the development of autism spectrum disorders. Identifying anatomical predictors of early brain development may contribute to our understanding of the neurobiology of autism spectrum disorders and allow for earlier and more effective identification and treatment of autism spectrum disorders. In this study, we used retrospective clinical brain magnetic resonance imaging data from fetuses who were diagnosed with autism spectrum disorders later in life (prospective autism spectrum disorders) in order to identify the earliest magnetic resonance imaging-based regional volumetric biomarkers. Our results showed that magnetic resonance imaging-based autism spectrum disorder biomarkers can be found as early as in the fetal period and suggested that the increased volume of the insular cortex may be the most promising magnetic resonance imaging-based fetal biomarker for the future emergence of autism spectrum disorders, along with some additional, potentially useful changes in regional volumes and hemispheric asymmetries.

Towards targeted Cas9 (CRISPR-Cas) delivery: Preparation of IgG antibody-Cas9 conjugates using a split intein.

The CRISPR-Cas9 system has revolutionized the field of genetic engineering, but targeted cellular delivery remains a central problem. The delivery of the preformed ribonuclease-protein (RNP) complex has the advantages of fewer side effects and avoidance of potential permanent effects. We reasoned that an internalizing IgG antibody as a targeting device could address the delivery of Cas9-RNP. We opted for protein trans-splicing mediated by a split intein to facilitate posttranslational conjugation of the two large protein entities. We recently described the cysteine-less CL split intein that efficiently performs under oxidizing conditions and does not interfere with disulfide bonds or thiol bioconjugation chemistries. Using the CL split intein, we report for the first time the ligation of monoclonal IgG antibody precursors, expressed in mammalian cells, and a Cas9 precursor, obtained from bacterial expression. A purified IgG-Cas9 conjugate was loaded with sgRNA to form the active RNP complex and introduced a double-strand break in its target DNA in vitro. Furthermore, a synthetic peptide variant of the short N-terminal split intein precursor proved useful for chemical modification of Cas9. The split intein ligation procedure reported here for IgG-Cas9 provides the first step towards a novel CRISPR-Cas9 targeting approach involving the preformed RNP complex.

Validation of factor structure of the neurodevelopmental parent report for outcome monitoring in down syndrome: confirmatory factor analysis.

Introduction: The Neurodevelopmental Parent Report for Outcome Monitoring (ND-PROM), initially developed to monitor developmental and behavioral functions in children with autism spectrum disorder (ASD), assesses symptoms across a wide range of domains relevant in Down syndrome (DS). Methods: Psychometric properties of ND-PROM were assessed in 385 individuals with DS and 52 with a combined diagnosis of DS and ASD (DS+ASD), whose caregivers completed the ND-PROM questionnaire for a clinical visit in a specialized Down syndrome program at a tertiary pediatric hospital. Confirmatory factor analysis was conducted to evaluate the internal structure validity of the ND-PROM. Measurement invariance was assessed, with a comparison group of 246 individuals with ASD, and latent mean differences between the DS and ASD-only groups, as well as the combined DS+ASD groups, were assessed. Results: Findings support the existence of the 12 clinically-derived factors in the DS population: Expressive Language, Receptive Language, Adaptive skills/Toileting, Social Emotional Understanding, Social Interaction, Independent Play, Sensory Processes, Challenging Behaviors, Impulse/ADHD, and Mental Health. Differences in response patterns of development and behaviors were observed between those with DS and those with ASD, including those with DS having higher abilities in nonverbal communication, social emotional understanding, and social interaction, and fewer restricted and repetitive behaviors and interests, impulsivity or ADHD symptoms, and mental health concerns compared to those with ASD. Individuals in the DS+ASD group had more difficulties with expressive and receptive language, nonverbal and social communication, social interaction, independent play, and adaptive skills than either the DS-only group or the ASD-only groups. Discussion: The ND-PROM has a desirable factor structure and is a valid and clinically useful tool that captures a range of distinct and independent areas of developmental and behavioral functioning in DS, for individuals with and without an ASD diagnosis.

Neuroimaging abnormalities associated with immunotherapy responsiveness in Down syndrome regression disorder.

OBJECTIVE: To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses. METHODS: A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities. RESULTS: In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities. INTERPRETATION: This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.

Cross-Sectional Analysis of Caregiver-Reported Expressive Language Profiles and Associated Covariates in Individuals with Down Syndrome.

OBJECTIVE: To describe the distribution of expressive language abilities of individuals with Down syndrome (DS) in a clinical sample and characterize demographic, environmental, and medical factors associated with varying expressive language profiles. METHODS: Cross-sectional analysis was completed on a sample of 345 individuals with DS between the ages of 4 and 22 years who were enrolled into a longitudinal clinical database between March 2018 and August 2021. Expressive language-related items on a standardized caregiver-reported questionnaire assessing domains of functioning in neurodevelopmental disorders were used to conduct latent variable modeling and determine caregiver-reported expressive language (CREL) classes across the sample. Linear regression was used to explore associations between CREL classes and predictor variables. RESULTS: Latent variable modeling revealed 3 distinct classes of CREL abilities representing higher, middle, and lower CREL. Individuals in the lower CREL class were more likely to be female, to use sign language or visual communication systems, have reduced pronunciation, attend private or residential school, and to be in a substantially separate classroom. Membership was not predicted by complex medical histories or co-occurring neurodevelopmental diagnoses. CONCLUSION: Caregiver-reported expressive language abilities in a cohort of individuals with DS were variable, with most of the individuals belonging to higher or middle CREL classes, relative to one another. Additional studies are indicated to understand factors that predict higher expressive language ability and explore how to direct services to individuals who are at risk of more profound language delays.

Co-occurring conditions in Down syndrome: Findings from a clinical database.

Individuals with Down syndrome (DS) experience a range of medical and neurodevelopmental conditions, necessitating systematic study of their occurrence and impact on neurodevelopmental outcomes. We describe the prevalence and relationships of medical, neurodevelopmental (ND), and mental health (MH) conditions in children with DS. We created a prospective clinical database of individuals with DS, integrated into the workflow of a specialty Down Syndrome Program at a specialty pediatric referral hospital. Conditions were collected through caregiver- and clinician report at clinical visits (N = 599). We calculated frequencies of medical, ND, and MH conditions and then assessed the relationship between medical, ND, and MH conditions using frequencies and comparative statistics. The most frequent co-occurring conditions were vision (72.5%), ear/hearing (71.0%), gastrointestinal (61.3%), respiratory (45.6%), and feeding (33.6%) problems, with variation in frequency by age. ND and MH conditions were reported in one quarter, most commonly autism spectrum disorder and attention-deficit/hyperactivity disorder. Those with ND and MH conditions had greater frequency of medical conditions, with highest rates of vision, ear/hearing, and gastrointestinal issues, and CHD. Systematically collected clinical data in a large cohort of children with DS reveals high prevalence of several co-occurring medical, ND, and MH conditions. Clinical care requires an understanding of the complex relationship between medical conditions and neurodevelopment.

Psychopharmacological treatments in Down syndrome and autism spectrum disorder: State of the research and practical considerations.

Individuals with Down syndrome (DS) or Autism Spectrum Disorder (ASD), and especially those with both DS and co-occurring ASD (DS + ASD) commonly display behavioral and psychiatric symptoms that can impact quality of life and places increased burden on caregivers. While the mainstay of treatment in DS and ASD is focused on educational and behavioral therapies, pharmacological treatments can be used to reduce symptom burden. There is a paucity of evidence and limited clinical trials in DS and DS + ASD. Some scientific evidence is available, primarily in open label studies and case series that can guide treatment choices. Additionally, clinical decisions are often extrapolated from evidence and experience from those with ASD, or intellectual disability in those without DS. This article reviews current research in pharmacological treatment in DS, ASD, and DS + ASD, reviews co-occurring neurodevelopmental and mental health diagnoses in individuals with DS + ASD across the lifespan, and describes practical approaches to psychopharmacological management.

Clinically derived 12-factor structure and confirmatory factor analysis of the neurodevelopmental parent report for outcome monitoring.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and social interaction impairments accompanied by restrictive and repetitive behaviors or interests. Co-occurring conditions may greatly impact overall functioning and intervention needs, and contribute to individual variability and etiologic subtypes. Clinical care of individuals with ASD requires gathering a breadth of information across multiple domains. The neurodevelopmental parent report for outcome monitoring (ND-PROM) was developed to assess symptoms across core features of ASD as well as frequent concerns and comorbidities. The current study expands upon the initially reported psychometric properties of the ND-PROM and evaluates a proposed a clinically derived 12-factor structure of the ND-PROM. Methods and procedures: The ND-PROM was completed for 246 children with ASD ands tested using confirmatory factor analysis (CFA) and measurement invariance based on sex. Outcomes and results: A 12-factor correlated structure was found (expressive language, receptive language, nonverbal communication, social emotional understanding, social interaction, independent play, adaptive/toileting skills, restrictive and repetitive behaviors and interests, sensory processes, challenging behaviors, impulse/ADHD, and mental health), which did not vary by sex. Conclusions and implications: The ND-PROM captures a range of distinct aspects of developmental and behavioral functioning in ASD that can be used to track independent functioning across domains.

Hyperphagia and Down Syndrome.

CASE: A.Z. is a 14-year-old young boy with Down syndrome and intellectual disability. As a baby and toddler, A.Z. struggled with swallowing dysfunction and recurrent aspiration, which improved by the time he was school aged. At the age of 2 years, his body mass index (BMI) was 95.98% (Z score 1.75). During his early school-age years, A.Z. began eating a wider variety of foods. As he grew taller and remained active, his BMI improved briefly during this time. Between ages 10 and 12 years, concerns regarding increased appetite and excessive weight gain emerged. His BMI increased from 82.56% (Z score 0.94) to 98.27% (Z score 2.11) during this time. He became insatiable; he ate when he was happy, upset, or bored. He had a compulsive need to eat all day, which escalated while staying home during the COVID pandemic. Despite having complete meals and a variety of snacks, he overate and sought out food and snacks, no matter the time of the day. Food also became a source of contention and a trigger for verbally and physically aggressive behavior when parents attempted to restrict food intake. Behavioral therapy was recommended to address his eating patterns as a part of his behavioral management plan.Over time, many strategies were used, including a token economy reward system, setting firm limits around snacking and meals, creating a food schedule with times and forced choice options, use of coping skill training, a feelings thermometer, and communication supports. These interventions had moderate intermittent success; however, overeating and consequent power struggles continued to be the major challenge reported by the family.He was started on a long-acting stimulant medication daily, intended to address impulsive and aggressive behaviors, and with potential benefit of appetite reduction. However, although there were some improvements in behavior, there was little to no effect noted on his appetite. Of note, he was diagnosed with celiac disease and severe obstructive sleep apnea at this time. A.Z. remained compliant with his gluten-free diet despite the challenges he experienced with food seeking and portion control. Overall, despite making excellent progress in behavioral regulation and performing particularly well in structured settings outside the home (i.e., school or summer camp), A.Z. continued to binge eat and seek out food with his most recent BMI at 98.62% (Z score 2.20).CASE 2: C.J. is a 9-year-old boy with Down syndrome and intellectual disability. As a toddler, C.J. had a brief period of time in which he was noted to overeat or not sense when he was full and subsequently gag or vomit after meals. At age 5 to 6 years, C.J. began demonstrating a more voracious appetite and increased weight gain; his BMI was 99.43% (Z score 2.53). Behavioral strategies, such as food schedules with forced choice options, were recommended. C.J. responded with increased dysregulation to the limit setting. An additional trigger for C.J. was the irregular visitation schedule with his father. He also hid and hoarded food; for example, he often ate food and hid the wrappers in the trash. Locking the refrigerator and cabinets resulted in binging on whatever he could find, such as ketchup packets. If C.J. wanted food during a time outside of his schedule, he was provided a list of alternative activities to choose from. It was recommended that his parent portion foods for him and set clear expectations of eating in the kitchen alone.C.J. was trialed on a short-acting alpha-agonist agent for 1 year to help address some of his behavioral challenges. Despite initial improvement on this regimen, behavioral challenges reemerged, and his eating behaviors worsened, so the medication was stopped. After stopping the medication, C.J. responded well to the limit setting, including regulating his own portion sizes and using a portion control plate. The family believed that the short-acting alpha-agonist worsened his food-seeking behaviors, although this was not clinically apparent. Despite having continued affinity for certain foods and snacks, C.J. was no longer binge eating or hoarding and hiding food. His most recent BMI remained elevated at 99.24% (Z score 2.43).

Co-occurring conditions in children with Down syndrome and autism: a retrospective study.

BACKGROUND: Down syndrome (DS) is one of the most common genetic causes of intellectual disability, and it is associated with an increased incidence of numerous co-occurring conditions. Autism spectrum disorder (ASD) is common in persons with DS, with rates reported as high as 39%. However, little is known regarding co-occurring conditions in children with both DS and ASD. METHODS: A single-center retrospective review of prospective longitudinally collected clinical data was performed. Any patient with a confirmed diagnosis of DS evaluated at a large, specialized Down Syndrome Program in a tertiary pediatric medical center between March 2018 and March 2022 was included. A standardized survey which included demographic and clinical questions was administered during each clinical evaluation. RESULTS: In total, 562 individuals with DS were included. The median age was 10 years (IQR: 6.18-13.92). Of this group, 72 (13%) had a co-occurring diagnosis of ASD (DS+ASD). Individuals with DS+ASD were more likely to be male (OR 2.23, CI 1.29-3.84) and had higher odds of a current or prior diagnosis of constipation (OR 2.19, CI 1.31-3.65), gastroesophageal reflux (OR 1.91, CI 1.14-3.21), behavioral feeding difficulties (OR 2.71, CI 1.02-7.19), infantile spasms (OR 6.03, CI 1.79-20.34) and scoliosis (OR 2.73, CI 1.16-6.40). There were lower odds of congenital heart disease in the DS+ASD group (OR 0.56, CI 0.34-0.93). There was no observed difference in prematurity or Neonatal Intensive Care Unit complications between groups. Individuals with DS+ASD had similar odds of having a history of congenital heart defect requiring surgery to those with DS only. Furthermore, there was no difference in rates of autoimmune thyroiditis or celiac disease. There was also no difference in rates of diagnosed co-occurring neurodevelopmental or mental health conditions in this cohort, including anxiety disorders and attention-deficit/hyperactivity disorder. CONCLUSIONS: This study identifies a variety of medical conditions which are more frequent in children with DS+ASD than DS alone, providing important information for the clinical management of these patients. Future research should investigate the role of some of these medical conditions in the development of ASD phenotypes, and whether there may be distinct genetic and metabolic contributions towards these conditions.

Quality of Life and Family Impact in Down Syndrome, Autism Spectrum Disorder, and Co-occurring Down Syndrome and Autism Spectrum Disorder.

OBJECTIVE: Families of children with neurodevelopmental disorders have developmental, behavioral, and social-emotional needs that affect quality of life (QoL). This study assesses the validity and utility of a caregiver QoL measure; characterizes QoL in families with children with Down syndrome (DS), autism spectrum disorder (ASD), and a dual diagnosis of DS and ASD (DS + ASD); and compares and explores differences in QoL based on diagnosis. METHODS: Caregivers of children and adolescents with ASD (n = 610) and DS (n = 177) completed the Pediatric Quality of Life Inventory Family Impact Module 2.0, yielding overall, parent functioning, family functioning, and subscale scores, and a Parent Global Impression (PGI) rating. An ASD cohort (n = 177) was sex matched to the DS cohort (n = 177) to mitigate potential sex bias. Additional analyses compared these groups with children and adolescents with DS + ASD (n = 37). RESULTS: Analyses showed that the Pediatric Quality of Life Inventory was valid and reliable in DS, ASD, and DS + ASD populations. No differences were reported in PGI ratings among groups. Caregivers in the DS group demonstrated higher QoL and family functioning compared with the ASD and DS + ASD groups. The DS group reported significantly better Emotional Functioning and Communication and less Worry than the ASD group. Compared with the ASD group, caregivers of the DS + ASD group indicated more concerns with Physical Functioning. Notably, the DS + ASD group had significantly lower levels of QoL than the DS group in nearly all caregiver functioning domains. CONCLUSION: This study highlights differences in QoL within and between neurodevelopmental disorder groups, which may help identify families requiring additional support, advocacy, and community engagement.

Down syndrome regression disorder: updates and therapeutic advances.

PURPOSE OF REVIEW: Down syndrome regression disorder (DSRD) is a symptom cluster consisting of neuropsychiatric regression without cause. Although knowledge of this condition has accelerated over the last decade, prior studies have been limited by heterogenous nomenclature, diagnostic approaches and therapeutic interventions. This review highlights recent advances in the diagnosis and clinical approach to DSRD and reviews the most up-to-date literature on therapeutic interventions for this condition. RECENT FINDINGS: Several multicentre studies have reported exciting findings on the presence of neurodiagnostic study abnormalities and responses to a variety of therapeutics, including psychotropics (including benzodiazepines), electroconvulsive therapy and immunotherapy. Differential response rates have been observed in the presence and absence of a variety of clinical and diagnostic factors. SUMMARY: Individuals with DSRD are responsive to a variety of psychiatric pharmacotherapy and immunotherapy underscoring this phenotype may have multiple causes. Multidisciplinary care is helpful in the evaluation and management of individuals with this condition.

Cardiometabolic profiles in children and adults with overweight and obesity and down syndrome.

Individuals with Down syndrome (DS) are at increased risk for being overweight/obese, but the associated cardiometabolic risk (CR) is not clear. Cross-sectional anthropometric and clinical laboratory data from a multi-site, international cohort of individuals with DS were analyzed to determine cardiometabolic risk by reporting observed distributions of cardiometabolic biomarkers in overweight/obese individuals with DS throughout the lifespan. Descriptive statistics and regression analyses by age categories determined the distributive percentiles for cardiometabolic biomarkers and tested for adiposity as a predictor of CR. Across seven DS clinics, data were collected on 240 patients between the ages of 3 and 63 years, with one quarter overweight and three quarters obese among children and nearly all adults being obese. In children and adults, most cardiometabolic biomarker profiles showed distributive values within normal ranges. Blood lipids were positively associated with body mass index (BMI) in children (high density lipid-cholesterol, p = 0.01; low density lipid-cholesterol, p = 0.02). Levels of hs-CRP were elevated in both children and adults, with BMI positively associated with hs-CRP in adults with DS (p = 0.04). Liver enzyme values were positively associated with BMI in children and adults. The data suggest that in contrast to the general population, in individuals with Down syndrome, being overweight and obese does not appear to confer a significantly increased risk for cardiometabolic disease by biomarker profile. Individuals with DS who are overweight/obese appear to have unique cardiometabolic profiles unrelated to adiposity, notable for increased hs-CRP and normal HA1c levels.

Electrostatic anti-CD33-antibody-protamine nanocarriers as platform for a targeted treatment of acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target "undruggable" oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML. METHODS: Our AML-targeting system consists of an internalizing anti-CD33-antibody-protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application. RESULTS: The nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton's kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation. CONCLUSIONS: We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.

Development and implementation of a longitudinal clinical database for down syndrome in a large pediatric specialty clinic: Methodology and feasibility.

Down syndrome (DS) is a complex condition associated with multiple medical, developmental, and behavioral concerns. A prospective, longitudinal clinical database was integrated into a specialty Down Syndrome Program, with the goals of better understanding the incidence, course, and impact of co-occurring medical, neurodevelopmental, and mental health conditions in DS. We describe the process of developing the database, including a systematic approach to data collection and database infrastructure, and report on feasibility, challenges, and solutions of initial implementation. Between March 2018 and November 2021, data from 842 patients (ages 4.8 months to 26 years) was collected. Challenges included caregiver form completion as well as time and personnel required for successful implementation. With full integration into clinical visit flow, the database proved to be feasible. The database enables identification of patterns of development and health throughout the lifespan and it facilitates future data sharing and collaborative research to advance care.

Is Developmental Regression in Down Syndrome Linked to Life Stressors?

OBJECTIVE: Unexplained regression in Down syndrome (URDS) involves a loss of acquired skills resulting in functional deterioration. Despite extensive workup and treatment, few individuals regain baseline function. This study aimed to understand the role of psychosocial stressors in URDS. METHODS: We describe psychosocial stressors in 14 cases of URDS. Specifically, we examined psychosocial stressors in the context of presentation and clinical symptoms. We also examined co-occurring neurodevelopmental disorders and medical and mental health conditions. RESULTS: All individuals experienced psychosocial stressors within one year of diagnosis of URDS. The most common psychosocial stressors were moving to a new home or school. CONCLUSION: Psychosocial stressors are commonly reported preceding URDS. Knowledge about psychosocial stressors' impact may lead to preventive interventions, improved monitoring, and earlier diagnosis. Future research should focus on understanding psychosocial stressors to help identify individuals at risk for URDS and contribute to treatment.

Unexplained regression in Down syndrome: Management of 51 patients in an international patient database.

Research to guide clinicians in the management of the devastating regression which can affect adolescents and young adults with Down syndrome is limited. A multi-site, international, longitudinal cohort of individuals with a clinical diagnosis of Unexplained Regression in Down syndrome (URDS) was collated through seven Down syndrome clinics. Tiered medical evaluation, a 28-item core symptom list, and interim management are described naturalistically. Improvement-defined by the percentage of baseline function on a Parent-reported Functional Score, overall improvement in symptoms on a Clinician-administered Functional Assessment, or report of management type being associated with improvement-was analyzed. Improvement rates using ECT, IVIG, and others were compared. Across seven clinics, 51 patients with URDS had regression at age 17.6 years, on average, and showed an average 14.1 out of 28 symptoms. Longitudinal improvement in function was achieved in many patients and the medical management, types of treatment, and their impact on function are described. Management with intravenous immunoglobulin (IVIG) was significantly associated with higher rate of improvement in symptoms at the next visit (p = 0.001). Our longitudinal data demonstrates that URDS is treatable, with various forms of clinical management and has a variable course. The data suggests that IVIG may be an effective treatment in some individuals. Our description of the management approaches used in this cohort lays the groundwork for future research, such as development of standardized objective outcome measure and creation of a clinical practice guideline for URDS.

Differences in clinical presentation, severity, and treatment of COVID-19 among individuals with Down syndrome from India and high-income countries: Data from the Trisomy 21 Research Society survey.

Background: People with Down syndrome (DS) are one of the highest risk groups for mortality associated with COVID-19, but outcomes may differ across countries due to different co-morbidity profiles, exposures, and societal practices, which could have implications for disease management. This study is designed to identify differences in clinical presentation, severity, and treatment of COVID-19 between India and several high-income countries (HICs). Methods: We used data from an international survey to examine the differences in disease manifestation and management for COVID-19 patients with DS from India vs HIC. De-identified survey data collected from April 2020 to August 2021 were analysed. Results: COVID-19 patients with DS from India were on average nine years younger than those from HICs. Comorbidities associated with a higher risk for severe COVID-19 were more frequent among the patients from India than from HICs. Hospitalizations were more frequent among patients from India as were COVID-19-related medical complications. Treatment strategies differed between India and HICs, with more frequent use of antibiotics in India. The average severity score of 3.31 was recorded for Indian DS in contrast to 2.3 for European and 2.04 for US cases. Conclusions: Presentation and outcomes of COVID-19 among individuals with DS were more severe for patients from India than for those from HIC. Global efforts should especially target vaccination campaigns and other risk-reducing interventions for individuals with DS from low-income countries.