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Background <p>Neuropsychiatric 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.</p> Methods <p>Prospective 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.</p> Results <p>Sixty-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 (<i>p</i> = 0.04) and CSF abnormalities including elevated IgG index and oligoclonal bands (each <i>p</i> &lt; 0.001), elevated total protein (<i>p</i> = 0.01), and pleocytosis (<i>p</i> = 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).</p> Limitations <p>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.</p> Conclusions <p>Serum, 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.</p>

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Serum and cerebral folate are normal in Down Syndrome Regression Disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月28日

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  • 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,
  • Taryn R. Liu,
  • Shafali S. Jeste,
  • Michael S. Rafii

摘要

Background

Neuropsychiatric 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.

Methods

Prospective 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.

Results

Sixty-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.

Conclusions

Serum, 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.