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Multicenter Study
. 2024 Dec 28;14(1):30865.
doi: 10.1038/s41598-024-81819-8.

Diagnostic abnormalities, disease severity and immunotherapy responsiveness in individuals with Down syndrome regression disorder

Jonathan D Santoro  1   2 , Saba Jafarpour  3 , Laura Keehan  4 , Mellad M Khoshnood  3   5 , Lilia Kazerooni  3 , Natalie K Boyd  3 , Benjamin N Vogel  3 , Lina Nguyen  3 , Melanie Manning  4   6 , Deepti Nagesh  3   5 , Noemi A Spinazzi  7 , Aaron D Besterman  8 , Eileen A Quinn  9 , Michael S Rafii  5   10
Affiliations
Multicenter Study

Diagnostic abnormalities, disease severity and immunotherapy responsiveness in individuals with Down syndrome regression disorder

Jonathan D Santoro et al. Sci Rep. .

Abstract

Introduction: Down Syndrome Regression Disorder (DSRD) is a neuropsychiatric condition causing insomnia, catatonia, encephalopathy, and obsessive-compulsive behavior in otherwise healthy individuals with Down syndrome (DS). Smaller cohorts have identified heterogenous diagnostic abnormalities which have predicted immunotherapy responsiveness although pattern analysis in a large cohort has never been performed.

Methods: A multi-center, retrospective study of individuals with DSRD was performed. Individuals met international consensus criteria for DRSD and were aged 10-30 years. Clinical, demographic, and diagnostic data was extracted for all individuals. Serum studies were compared to a group of individuals with DS only.

Results: A total of 164 individuals with DSRD were identified. Individuals with DSRD were more likely to have a positive antinuclear antibody, low complement 3, abnormal cytokines, and elevated ferritin levels. In a minority of individuals, EEG (30%), MRI (33%) and cerebrospinal fluid (CSF) (21%) were abnormal. Individuals with CSF abnormalities demonstrated greater disease severity at diagnosis on the BFCRS and NPI-Q (p = 0.02 and p < 0.001). Abnormalities in cytokines (p = 0.03), neuroimaging (p < 0.001), and CSF (p = 0.02) were predictive of immunotherapy responsiveness. When MRI and LP were both abnormal or when EEG, MRI and LP were all abnormal, the odds of immunotherapy responsiveness approached 100% (p = 0.01, 95%CI: 1.75-105.1, OR: 13.56 and p = 0.02, 95%CI: 1.37-86.87, OR: 10.91, respectively).

Conclusions: In a population of individuals diagnosed with DSRD, abnormalities in serum cytokine levels, neuroimaging findings, and CSF analysis emerged as indicators of disease severity and responsiveness to immunotherapy.

Keywords: CSF; Cytokine; Diagnostic; Down syndrome; Regression; Serum.

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Conflict of interest statement

Declarations. Competing interests: Dr. Santoro receives research support from the National Institutes of Health and consulting fees from UCB, TG pharmaceuticals and Cycle Pharmaceuticals. Dr. Rafii has received grants or contracts from Eisai (AHEAD Study) and Eli Lilly (A4 Study), which were paid to his institution. He has received consulting fees from AC Immune, Corium and Ionis. He has participated on a Data Safety Monitoring Board or Advisory Board for Alzheon, Aptah Bio, Biohaven, Embic, Keystone Bio and Positrigo. All other authors reported no biomedical financial interests or potential conflicts of interest. Legend: Cerebrospinal fluid (CSF), electroencephalogram (EEG), magnetic resonance imaging (MRI).

Figures

Fig. 1
Fig. 1
SWI signal abnormality in the basal ganglia of individuals with DSRD. Legend: white arrows correspond to SWI signal abnormalities in the bilateral basal ganglia.
Fig. 2
Fig. 2
Likelihood of lab or neurodiagnostic study capture at various time points after symptom onset.
See this image and copyright information in PMC

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