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Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder.

ABSTRACT: Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 months of treatment. Baseline, on-therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ² = 11.82, P = 0.001), abnormal MRI (χ² = 7.78, P = 0.005), and abnormal LP (χ² = 5.45, P = 0.02), and a personal history of autoimmunity (OR: 6.11, P < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.

SUBMITTER: Santoro JD

PROVIDER: S-EPMC10409776 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder.

Santoro Jonathan D JD Spinazzi Noemi A NA Filipink Robyn A RA Hayati-Rezvan Panteha P Kammeyer Ryan R Patel Lina L Sannar Elise A EA Dwyer Luke L Banerjee Abhik K AK Khoshnood Mellad M Jafarpour Saba S Boyd Natalie K NK Partridge Rebecca R Gombolay Grace Y GY Christy Alison L AL Real de Asua Diego D Del Carmen Ortega Maria M Manning Melanie A MA Van Mater Heather H Worley Gordan G Franklin Cathy C Stanley Maria A MA Brown Ruth R Capone George T GT Quinn Eileen A EA Rafii Michael S MS

Translational psychiatry 20230808 1

Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 m ...[more]

PMID: 37553347

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Project description:BackgroundDown Syndrome Regression Disorder (DSRD) is an acute or subacute neurocognitive regression in individuals with Down syndrome (DS), characterized by a loss of previously acquired cognitive, adaptive, and social skills. DSRD profoundly affects individuals' ability to engage in activities of daily living, making them highly dependent on their caregivers who must provide significantly more support than before the DSRD diagnosis. This study aimed to examine caregiver burden, quality of life, and depression among caregivers of individuals with DSRD versus caregivers of those with DS and other neurological disorders (DSN).Design/methodsIn this cross-sectional study, caregivers of individuals with DSRD (n = 228) and DSN (n = 137) were recruited through Children's Hospital Los Angeles neurology clinic and a Facebook DSRD support group. Participants completed standardized questionnaires assessing quality of life (PedsQL Family Impact Module), caregiver burden (Zarit Caregiver Burden Assessment, ZCB), and depression (Glasgow Depression Scale, GDS), along with additional items addressing other factors of caregiver well-being. Data were analyzed using bivariate comparisons and univariate regression models to assess differences between groups.ResultsCaregivers of individuals with DSRD were more likely than caregivers of those with DSN to report increased financial burden (p = 0.003), housing changes (p = 0.02), disrupted sleep (p < 0.001), negative impacts on social networks (p < 0.001), and worsened mental health (p < 0.001). Furthermore, DSRD caregivers reported significantly higher levels of burden (mean difference [95% CI]: 8.3 [6.3, 9.7]) and depression symptoms (2 [0.7, 3.4]), reflecting greater perceived stress and burden. They also had lower quality of life scores (-27.9 [-30.2, -25.5]), indicating a more substantial impact on overall well-being and daily functioning compared to DSN caregivers. Additionally, caregivers in the DSRD group had higher odds (odds ratio [95% CI]: 4.7 [2.9, 7.7)] of meeting clinical depression criteria (GDS score ≥ 13) than caregivers in the DSN group.ConclusionsCaregivers of individuals with DSRD experience significantly greater distress and burden compared to those caring for individuals with DSN. The elevated risk of depression, combined with reduced quality of life and increased burden, underscores the multimodal nature of the challenges faced by this population.

Project description:ObjectiveTo develop standardization for nomenclature, diagnostic work up and diagnostic criteria for cases of neurocognitive regression in Down syndrome.BackgroundThere are no consensus criteria for the evaluation or diagnosis of neurocognitive regression in persons with Down syndrome. As such, previously published data on this condition is relegated to smaller case series with heterogenous data sets. Lack of standardized assessment tools has slowed research in this clinical area.MethodsThe authors performed a two-round traditional Delphi method survey of an international group of clinicians with experience in treating Down syndrome to develop a standardized approach to clinical care and research in this area. Thirty-eight potential panelists who had either previously published on neurocognitive regression in Down syndrome or were involved in national or international working groups on this condition were invited to participate. In total, 27 panelists (71%) represented nine medical specialties and six different countries reached agreement on preliminary standards in this disease area. Moderators developed a proposed nomenclature, diagnostic work up and diagnostic criteria based on previously published reports of regression in persons with Down syndrome.ResultsDuring the first round of survey, agreement on nomenclature for the condition was reached with 78% of panelists agreeing to use the term Down Syndrome Regression Disorder (DSRD). Agreement on diagnostic work up and diagnostic criteria was not reach on the first round due to low agreement amongst panelists with regards to the need for neurodiagnostic testing. Following incorporation of panelist feedback, diagnostic criteria were agreed upon (96% agreement on neuroimaging, 100% agreement on bloodwork, 88% agreement on lumbar puncture, 100% agreement on urine studies, and 96% agreement on "other" studies) as were diagnostic criteria (96% agreement).ConclusionsThe authors present international consensus agreement on the nomenclature, diagnostic work up, and diagnostic criteria for DSRD, providing an initial practical framework that can advance both research and clinical practices for this condition.

Project description:BackgroundDown Syndrome Regression Disorder (DSRD) is a rare and poorly understood disorder of the central nervous system, characterized by acute or subacute neuropsychiatric symptoms in previously healthy individuals with Down syndrome (DS). Many patients exhibit immunotherapy-responsiveness, indicative of immune dysregulation as a potential underlying etiology. While hypotheses are emerging regarding the role of interferon signaling in DSRD and other autoimmune conditions associated with DS, it is unclear why a small subset of individuals with DS develop DSRD. The aim of this study was to investigate genes of immune regulation in persons with DSRD.MethodsThis study included individuals with DSRD aged 10-30 years with trio exome sequencing performed during the diagnostic work up. Descriptive statistics and univariate analysis (Chi-square and Fisher's exact test) were used to describe and compare the characteristics of individuals with and without variants.ResultsForty-one individuals with DSRD had trio exome sequencing results. Eight (20%) had heterozygous de novo variants of immune regulatory genes, with four variants being pathogenic or likely pathogenic (UNC13D, XIAP, RNASEH2A, and DNASE1L3). All genes harboring pathogenic variants were associated with interferon type-1 inflammatory response. Individuals harboring variants were more likely to have a preceding trigger (p = 0.03, 95% CI 1.21-97.06), rapid clinical decline in less than 1 month (p = 0.01, 95% CI 1.67-52.06), and MRI abnormalities (p < 0.001, 95% CI 4.89-527.71).DiscussionA distinct subset of individuals with DSRD exhibited pathogenic variants in immune regulation genes associated with interferon-mediated inflammatory response, coinciding with previously established links between these genes and interferonopathies such as Aicardi-Goutieres syndrome. Our observations suggest that these variants might potentially contribute to the development of DSRD in individuals with DS.

Project description:ImportanceAlthough autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood.ObjectiveTo examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD.Design, setting, and participantsWe performed a nested case-control study (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September 15, 2008, through September 14, 2012) within a population-based longitudinal cohort. Participants were drawn from the Nurses' Health Study II, a cohort of 116,430 female nurses recruited in 1989. Case participants were index children with reported ASD; control participants were frequency matched by year of birth of case participants among those not reporting ASD. Of 3161 eligible participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1 parent and were included in these analyses.ExposureThe SRS scores, as reported by nurse mothers and their spouses, were examined in association with risk of ASD using crude and adjusted logistic regression analyses. The SRS scores of the children were examined in association with SRS scores of the parents using crude and adjusted linear regression analyses stratified by case status.Main outcomes and measuresAutism spectrum disorder, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised.ResultsA total of 1649 individuals were included in these analyses, including 256 ASD case participants, 1393 control participants, 1233 mothers, and 1614 fathers. Risk of ASD was increased by 85.0% among children whose parents had concordantly elevated SRS scores (odds ratio [OR], 1.85; 95% CI, 1.08-3.16) and by 52.0% when the score of either parent was elevated (OR, 1.52; 95% CI, 1.11-2.06). Elevated scores of the father significantly increased the risk of ASD in the child (OR, 1.94; 95% CI, 1.38-2.71), but no association was seen with elevated scores of the mother. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in 23 points (P < .001).Conclusions and relevanceThese findings support the role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.

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Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder.

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Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder.

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