Evidence map›Paper›PMID 41606634›Full record

Observational studyMolecular autism2026

Serum and cerebral folate are normal in Down Syndrome Regression Disorder.

Jonathan D Santoro, Mackenzie Silverman, Lilia Kazerooni, Samuel T Otey, Maeve C Lucas, Mariam M Yousuf, Mellad M Koshnood, Noemi A Spinazzi, Eileen A Quinn, Catherine Franklin and 3 more

Erratum issuedAbstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in Molecular autism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Jonathan D SantoroDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA. jdsantoro@chla.usc.edu.ORCID http://orcid.org/0000-0002-8350-8234
Mackenzie SilvermanDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Lilia KazerooniDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Samuel T OteyDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Maeve C LucasDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Mariam M YousufDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Mellad M KoshnoodDepartment of Pediatrics, Cottage Hospital, Santa Barbara, CA, USA.
Noemi A SpinazziChildren's Specialized Hospital, Robert Wood Johnson, Barnabas Health, Princeton, NJ, USA.ORCID http://orcid.org/0000-0001-5009-7670
Eileen A QuinnDivision of Developmental and Behavioral Pediatrics, University of Toledo, Toledo, OH, USA.ORCID http://orcid.org/0009-0008-0052-6498
Catherine FranklinMater Research Institute-UQ, The University of Queensland, Brisbane, Australia.
Taryn R LiuDivision of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Shafali S JesteDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA.ORCID http://orcid.org/0000-0003-2955-6902
Michael S RafiiDepartment of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.ORCID http://orcid.org/0000-0003-2640-2094

Funding

Non-invasive biometric screening for cerebrovascular disorders in persons with Down syndrome.K23HL155898 · NHLBI · CHILDREN'S HOSPITAL OF LOS ANGELES · PI SANTORO, JONATHAN DOUGLAS · 2021 to 2025
$1.3M
AGAPE Foundation n/aByrne Family Foundation n/aNHLBI NIH HHS K23 HL155898NHLBI NIH HHS K23HL155898
6 · The paper itself

Abstract

backgroundNeuropsychiatric regression in individuals with Down syndrome (DS), termed Down Syndrome Regression Disorder (DSRD), has been reported to occur in the 2nd and 3rd decade of life. Symptoms of DSRD include acute onset of encephalopathy, catatonia, hallucinations, obsessive compulsive tendencies and “new autistic” features. To determine whether abnormalities in folate transport and/or metabolism may play a role in the pathogenesis of this disorder, studies explored whether abnormalities in serum, red blood cell (RBC), or cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF) are associated with DSRD.

methodsProspective observational cohort study of individuals with possible or probable DSRD diagnosed between July 1, 2019, and June 30, 2025, were evaluated. Inclusion required standardized neurodiagnostic testing, including lumbar puncture. Serum folate and RBC folate and CSF 5-MTHF samples were analyzed using high-performance liquid chromatography. Associations between folate levels and clinical variables were assessed.

resultsSixty-seven individuals were enrolled. Median serum folate was 14 ng/mL (IQR 10–19) and RBC folate 729 ng/mL (IQR 604–1113); all but one recording (1%) was within the reference range. Median CSF 5-MTHF was 72 mmol/L (IQR 57–84), with all values within the normal range. In univariate, unadjusted, analyses, CSF 5-MTHF was associated with developmental regression (p = 0.04) and CSF abnormalities including elevated IgG index and oligoclonal bands (each p < 0.001), elevated total protein (p = 0.01), and pleocytosis (p = 0.03); all CSF 5-MTHF values remained within the reference range. After Benjamini–Hochberg FDR correction, associations with elevated IgG index, oligoclonal bands, and any abnormal LP finding remained significant (each q = 0.01). LIMITATIONS: This study is limited by its single center design and homogenous cohort of individuals with DSRD. In addition, this study did not have a control group of individuals with autism spectrum disorder or DS alone.

conclusionsSerum, RBC, and CSF folate concentrations are normal in individuals with DSRD, suggesting that systemic folate deficiency, and cerebral folate deficiency in particular, are not contributors to its pathogenesis. The authors advise that expanded testing for disorders of cerebral folate metabolism should not be performed in possible cases of DSRD in the absence of clinical symptoms consistent with these conditions.

Indexed as

BrainDown SyndromeFolic AcidAdolescentAdultChildChild, PreschoolErythrocytesFemaleHumansMaleProspective StudiesTetrahydrofolatesYoung Adult5-methyltetrahydrofolateFolic AcidTetrahydrofolates5-MTHFAutism spectrum disorderDown syndromeFolateRegression

Identifiers

PMID41606634
PMCPMC12922418

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.