Observational Study

. 2023 Aug 8;13(1):276.

doi: 10.1038/s41398-023-02579-z.

Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder

Jonathan D Santoro^{1

2}, Noemi A Spinazzi³, Robyn A Filipink⁴, Panteha Hayati-Rezvan⁵, Ryan Kammeyer⁶, Lina Patel⁷, Elise A Sannar⁷, Luke Dwyer⁸, Abhik K Banerjee⁹, Mellad Khoshnood⁹, Saba Jafarpour⁹, Natalie K Boyd⁹, Rebecca Partridge¹⁰, Grace Y Gombolay¹¹, Alison L Christy¹², Diego Real de Asua¹³, Maria Del Carmen Ortega¹⁴, Melanie A Manning¹⁵, Heather Van Mater¹⁶, Gordan Worley¹⁷, Cathy Franklin¹⁸, Maria A Stanley¹⁹, Ruth Brown²⁰, George T Capone²¹, Eileen A Quinn²², Michael S Rafii^{23

24}

Affiliations

¹ Division of Neurology, Children's Hospital Los Angeles, Los Angeles, CA, USA. santoroj@usc.edu.
² Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. santoroj@usc.edu.
³ Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
⁴ Division of Child Neurology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵ Division of Research on Children, Youth and Families, Keck School of Medicine of USC, Los Angeles, CA, USA.
⁶ Department of Neurology, Children's Hospital of Colorado, Aurora, CO, USA.
⁷ Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA.
⁸ Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
⁹ Division of Neurology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹⁰ Virginia Mason Health System, Issaquah, WA, USA.
¹¹ Department of Pediatrics, Division of Neurology Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹² Providence Health System, Portland, OR, USA.
¹³ Adult Down Syndrome Outpatient Clinic, Department of Internal Medicine, Fundación de Investigación Biomédica, Hospital Universitario de La Princesa, Madrid, Spain.
¹⁴ Department of Psychiatry, Clinica Universidad de Navarra, Madrid, Spain.
¹⁵ Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
¹⁶ Division of Rheumatology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
¹⁷ Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
¹⁸ Queensland Center for Intellectual and Developmental Disability, Mater Research Institute, The University of Queensland, South Brisbane, QLD, Australia.
¹⁹ Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
²⁰ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
²¹ Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²² Department of Pediatrics, University of Toledo College of Medicine and Life Science, Toledo, OH, USA.
²³ Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
²⁴ Alzheimer's Therapeutic Research Institute (ATRI), Keck School of Medicine at the University of Southern California, San Diego, CA, USA.

PMID: 37553347
PMCID: PMC10409776
DOI: 10.1038/s41398-023-02579-z

Observational Study

Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder

Jonathan D Santoro et al. Transl Psychiatry. 2023.

. 2023 Aug 8;13(1):276.

doi: 10.1038/s41398-023-02579-z.

Authors

Affiliations

¹ Division of Neurology, Children's Hospital Los Angeles, Los Angeles, CA, USA. santoroj@usc.edu.
² Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. santoroj@usc.edu.
³ Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
⁴ Division of Child Neurology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵ Division of Research on Children, Youth and Families, Keck School of Medicine of USC, Los Angeles, CA, USA.
⁶ Department of Neurology, Children's Hospital of Colorado, Aurora, CO, USA.
⁷ Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA.
⁸ Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
⁹ Division of Neurology, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹⁰ Virginia Mason Health System, Issaquah, WA, USA.
¹¹ Department of Pediatrics, Division of Neurology Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹² Providence Health System, Portland, OR, USA.
¹³ Adult Down Syndrome Outpatient Clinic, Department of Internal Medicine, Fundación de Investigación Biomédica, Hospital Universitario de La Princesa, Madrid, Spain.
¹⁴ Department of Psychiatry, Clinica Universidad de Navarra, Madrid, Spain.
¹⁵ Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
¹⁶ Division of Rheumatology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
¹⁷ Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
¹⁸ Queensland Center for Intellectual and Developmental Disability, Mater Research Institute, The University of Queensland, South Brisbane, QLD, Australia.
¹⁹ Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
²⁰ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
²¹ Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²² Department of Pediatrics, University of Toledo College of Medicine and Life Science, Toledo, OH, USA.
²³ Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
²⁴ Alzheimer's Therapeutic Research Institute (ATRI), Keck School of Medicine at the University of Southern California, San Diego, CA, USA.

PMID: 37553347
PMCID: PMC10409776
DOI: 10.1038/s41398-023-02579-z

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.

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Conflict of interest statement

Dr. JDS reports receiving federal funding from the NHLBI and NICHD for the study of autoimmune disease in persons with Down syndrome and the role of immunotherapy in persons with Down syndrome regression disorder. Drs. LP and RK also receive federal funding from the NICHD for the study of autoimmune disease in persons with Down syndrome and the role of immunotherapy in persons with Down syndrome regression disorder.

Figures

**Fig. 1. Therapeutic response to immunotherapy.**
Clinical features, including behavioral and neuropsychiatric assessments over the study period.

**Fig. 2. Longitudinal Therapeutic Responses in Individuals with and without Relapse.**
Clinical features, including behavioral and neuropsychiatric assessments over the study period for patients with and without neurologic relapse.

**Fig. 3. Prevalence of Neurodiagnostic Abnormalities in Individuals with and without Relapse.**
Neurodiagnostic abnormality presence in patients with (n = 44) and without (n = 38) neurologic relapse.

See this image and copyright information in PMC

Update of

Immunotherapy Responsiveness and Risk of Relapse in Down Syndrome Regression Disorder.
Santoro J, Spinazzi N, Filipink R, Hayati-Rezvan P, Kammeyer R, Patel L, Sannar E, Dwyer L, Banerjee A, Khoshnood M, Jafarpour S, Boyd N, Partridge R, Gombolay G, Christy A, Real de Asua D, Del Carmen Ortega M, Manning M, Van Mater H, Worley G, Franklin C, Stanley M, Brown R, Capone G, Quinn E, Rafii M. Santoro J, et al. Res Sq [Preprint]. 2023 Feb 13:rs.3.rs-2521595. doi: 10.21203/rs.3.rs-2521595/v1. Res Sq. 2023. Update in: Transl Psychiatry. 2023 Aug 8;13(1):276. doi: 10.1038/s41398-023-02579-z. PMID: 36824719 Free PMC article. Updated. Preprint.

References

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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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